Opoksa – Patofizjologia i mechanizm

Opoksa
Patofizjologia i mechanizm

Wirus opoksy (MPXV), należący do rodzaju Orthopoxvirus, charakteryzuje się liniowym, dwuniciowym DNA o długości około 197 kb i średnicy 200-250 nm. Patogeneza zależy od szczepu (klad I i II z podkladami Ia, Ib, IIa, IIb), statusu immunologicznego pacjenta oraz powikłań. Klad I, szczególnie podklad Ib wykazujący wyższą transmisyjność, powoduje cięższe postacie choroby. Inkubacja trwa do 14 dni, po czym pojawiają się objawy prodromalne: gorączka, ból, powiększenie węzłów chłonnych (szczególnie pachwinowych), a następnie wysypka ewoluująca od grudek do krost i strupów, trwająca 2-4 tygodnie. W fazie pęcherzykowej obserwuje się charakterystyczne zmiany histopatologiczne z akantozą, spongiozą i naciekiem zapalnym. Wirus replikuje się w komórkach nabłonkowych, dendrytycznych i makrofagach, wykorzystując mechanizmy unikania odpowiedzi immunologicznej, m.in. hamując ekspresję interferonów i MHC klasy I. W zakażeniu występują dwie formy wirionów: IMV (jednobłonowe) i EEV (dwubłonowe), różniące się mechanizmem wnikania i uwalniania z komórki. Kluczowe enzymy wirusa to kinaza B1R i fosfopilaza F13, z mutacjami w F13 związanymi z opornością na tekowirimat.

Patogeneza opoksy (wcześniej znanej jako małpia ospa)

Opoksa jest chorobą wywołaną przez wirus opoksy (MPXV), należący do rodzaju Orthopoxvirus z rodziny Poxviridae. Wirus charakteryzuje się ceglastym lub owalnym kształtem o średnicy około 200-250 nm. Jego genom składa się z liniowego, dwuniciowego DNA o długości około 197 kb, kodującego około 180 białek. Dodatkowo wirus opoksy posiada hantelowaty nukleokapsyd otoczony owalnymi cząsteczkami zawierającymi lipidy¹².

Patogeneza opoksy zależy od różnych czynników, w tym od konkretnego szczepu wirusa, statusu immunologicznego osoby zakażonej oraz potencjalnych powikłań. Wczesne objawy zakażenia obejmują ból, gorączkę, zmęczenie i powiększenie węzłów chłonnych, przy czym często obserwuje się znaczne powiększenie węzłów pachwinowych, co może pomóc w odróżnieniu zakażenia wirusem opoksy od zakażeń innymi ortopokswirusami³.

Klady wirusa opoksy i ich charakterystyka

Wirus opoksy jest genetycznie podzielony na dwie główne grupy (klady): klad z Basenu Kongo (Afryka Środkowa) – klad I oraz klad zachodnioafrykański – klad II⁴. W kwietniu 2024 roku, po wykryciu nowego wariantu, klad I został podzielony na podklady oznaczone jako Ia i Ib. Podobnie klad II jest podzielony na podklady: IIa i IIb⁵.

Klad I jest uważany za bardziej chorobotwórczy w porównaniu do kladu II, powodując cięższą postać choroby i wyższą śmiertelność⁶⁵. Klad Ib, który pojawił się w 2024 roku podczas wybuchu epidemii w wielu krajach, charakteryzuje się wyższą transmisyjnością⁷. Na podstawie analizy genomowej i filogenetycznej z 2022 roku, dominujący szczep wirusa opoksy został zidentyfikowany jako należący do linii B.1 kladu zachodnioafrykańskiego⁸.

Mechanizm transmisji wirusa

Zrozumienie sposobu transmisji jest istotne w ustanowieniu skutecznych środków zwalczania opoksy. Po ekspozycji na wydzieliny z dróg oddechowych lub płyny ustrojowe pacjentów z opoksą, wirus opoksy wnika do pobliskich tkanek przez błony śluzowe (takie jak oczne, oddechowe, ustne, cewki moczowej i odbytnicy) lub uszkodzoną skórę⁹.

Zakażenie może nastąpić przez¹⁰¹¹:

Inokulację skórną – wirus opoksy może wniknąć do organizmu człowieka przez mikrouszkodzenia skóry
Drogą oddechową – wnikając przez układ oddechowy (jama ustna, nosogardziel)
Kontakt bezpośredni – poprzez kontakt skóra-do-skóry, kontakt seksualny
Transmisję wertykalną – z matki na płód

Fazy zakażenia wirusem opoksy

Faza inkubacji

Po wniknięciu do organizmu, wirus opoksy replikuje się w miejscu inokulacji, a następnie rozprzestrzenia się w organizmie za pośrednictwem tkankowych komórek odpornościowych i okolicznych węzłów chłonnych. Jest to okres inkubacji zakażenia wirusem opoksy, który zwykle trwa do dwóch tygodni. W tym okresie osoby zakażone są zazwyczaj bezobjawowe i nie mają zmian skórnych¹²¹³.

Podczas okresu inkubacji wirus może zainfekować komórki nabłonkowe, komórki dendrytyczne i makrofagi w drogach oddechowych lub keratynocyty, fibroblasty, komórki Langerhansa, komórki dendrytyczne i makrofagi w skórze. Wirus wiąże się z glikozaminoglikanami na powierzchni komórki gospodarza i wnika do komórki poprzez endocytozę¹⁴.

Na podstawie badań na modelu naczelnym z drogą oddechową zakażenia MPXV, wykazano, że podczas okresu inkubacji wirus najpierw pojawia się w oskrzelikach oddechowych i pęcherzykach płucnych (4 dzień po zakażeniu). Następnie rozprzestrzenia się do regionalnych węzłów chłonnych i narządów układu siateczkowo-śródbłonkowego (dzień 6), w tym migdałków, śledziony, wątroby i okrężnicy, gdzie się replikuje¹⁵.

Faza prodromalna

Po okresie inkubacji, osoby zakażone wirusem opoksy zaczynają wykazywać nietypowe objawy, w tym gorączkę i dreszcze, ból głowy, ból mięśni i powiększenie węzłów chłonnych. Te początkowe objawy prodromalne opoksy zwykle trwają trzy dni¹⁶.

Podczas fazy prodromalnej wirus kontynuuje rozprzestrzenianie się przez krwiobieg i węzły chłonne, prowadząc do wtórnej wiremii i docierając do odległych narządów, w tym skóry. W tej fazie wirus opoksy stosuje strategie unikania odpowiedzi immunologicznej, wiążąc się z interferonami typu I, opóźniając aktywację immunologiczną i hamując stan zapalny, co sprzyja rozprzestrzenianiu się objawów i choroby¹⁷.

Wirus ostatecznie wykrywany jest we krwi około 8 dnia, a jego stężenie wzrasta do 10 dnia wraz z rozprzestrzenianiem się zmian skórnych¹⁸.

Faza wysypkowa

Po gorączce i powiększeniu węzłów chłonnych, rozpoczyna się wysypka, która pojawia się najpierw na głowie i twarzy, a następnie stopniowo rozprzestrzenia się po całym ciele. Wysypka ewoluuje od grudek do pęcherzyków i krost, ostatecznie tworząc strupy, które goją się, pozostawiając blizny. Ta postępująca faza wysypkowa trwa około 2-4 tygodni¹⁹.

W obecnym wybuchu opoksy wśród mężczyzn uprawiających seks z mężczyznami (MSM), zaobserwowano niecodzienny obraz kliniczny – wysypka pojawia się głównie wokół obszaru genitalnego lub odbytu, a następnie rozprzestrzenia się po całym ciele²⁰.

Histopatologicznie zmiany skórne opoksy w fazie pęcherzykowej składają się z akantozy naskórka i spongiozy z egzocytozą limfocytów i neutrofili. W centrum zmiany formuje się pęcherzyk obejmujący cały naskórek, utworzony przez zwyrodnienie balonowate keratynocytów i gromadzenie się płynu międzykomórkowego. Mieszany naciek zapalny jest obecny na granicy skórno-naskórkowej u podstawy pęcherzyka, składający się z limfocytów, eozynofilów i neutrofili²¹.

Zmiana rozwija się w krosta zawierającą resztki apoptotycznych keratynocytów, kilka żywych keratynocytów i komórki zapalne. Żywe keratynocyty mogą być wielojądrowe lub wykazywać uszkodzenia cytopatyczne, takie jak eozynofilowe ciałka wtrętowe, wyraźne jąderka i „matowa” chromatyna. Mieszany naciek zapalny występuje również w okolicy okołonaczyniowej, okołoprzydatkowej i skórnej. Na koniec krostka zasycha i tworzy strup²².

Mechanizmy molekularne infekcji wirusem opoksy

Cykl replikacyjny wirusa

Proces zakażenia i replikacji wirusa opoksy można podsumować w trzech odrębnych etapach²³:

Inwazja wirusa – wniknięcie wirusa do komórki gospodarza
Replikacja i synteza wirusa
Składanie, dojrzewanie i uwalnianie wirusa

Na wczesnych etapach zakażenia wirusem opoksy obecne są dwa różne zakaźne cząstki wirusowe²⁴²⁵:

Zewnątrzkomórkowe wiriony otoczkowe (EEV – extracellular enveloped virions)
Wewnątrzkomórkowe dojrzałe wiriony (IMV – intracellular mature virions)

Te cząstki wirusowe różnią się glikoproteinami powierzchniowymi i składem błony otoczkowej, przy czym IMV wykazują strukturę jednobłonową, a EEV posiadają strukturę dwubłonową. IMV są uwalniane tylko po lizie komórki i wnikają do komórek gospodarza przez bezpośrednią fuzję i endocytozę, podczas gdy EEV wnikają przez fuzję błon²⁶.

Po wniknięciu IMV lub EEV do komórki gospodarza, odsłonięty rdzeń wirusowy jest transportowany do obwodu jądra komórkowego przez struktury mikrotubul ze średnią prędkością 52μm/min. Rdzeń wirusowy składa się z centralnego genomu wirusowego i otoczonego nukleokapsydu. Mechanizm odpłaszczania nukleokapsydu obejmuje ubikwitynację białek kapsydu jądrowego i degradację przez proteasomy. Po zakończeniu odpłaszczania, genom wirusa opoksy rozpoczyna wydajną replikację, szybko się namnażając jak fabryka²⁷.

W obrębie fabryki replikacyjnej, odkryte poprzez mikroskopię elektronową, nowopowstały DNA wirusowy może przejść transkrypcję pośrednią i translację, generując białka pośrednie, które obejmują czynniki transkrypcyjne niezbędne do późnej transkrypcji oraz białka późne, które przyczyniają się do struktury wirusa i uczestniczą we wczesnej transkrypcji i translacji²⁸.

Rola enzymów wirusowych w patogenezie

Polimeraza RNA zależna od DNA (DdRp) odgrywa kluczową rolę w katalizowaniu procesu replikacji wirusów DNA w cytoplazmie. Ze względu na jej biologiczne znaczenie, DdRp jest uważana za potencjalny cel terapeutyczny dla wirusa opoksy²⁹.

Wirus dysponuje również własnymi enzymami, takimi jak kinaza B1R, która odgrywa ważną rolę w replikacji DNA wirusa i ucieczce przed odpowiedzią immunologiczną gospodarza³⁰.

Fosfopilaza F13 to kluczowy enzym w tworzeniu zewnętrznej otoczki cząstki wirusowej. Zaobserwowano, że warianty opoksy odporne na leczenie tekowirymatem (TPOXX) mają mutacje w tym enzymie. Wykazano, że tekowirimat działa jak rodzaj kleju, który wiąże dwie fosfolipazy F13 razem, uniemożliwiając spełnianie jej roli w rozprzestrzenianiu cząstek wirusowych³¹.

Rola struktur komórkowych w patogenezie

Retikulum endoplazmatyczne (ER) odgrywa kluczową rolę w otaczaniu i stabilizacji genomu wirusowego. Obserwacje mikroskopii elektronowej wykazały, że fabryka replikacyjna jest otoczona znaczną ilością błony ER. ER odgrywa kluczową rolę w syntezie wirusowych białek błonowych. Następnie te białka błonowe, wraz z innymi białkami strukturalnymi wirusa, wchodzą do fabryki wirusowej, otaczają rdzeń genów, tworząc struktury w kształcie półksiężyca³².

Wewnątrz fabryki replikacyjnej struktury w kształcie półksiężyca rozwijają się w kształty elipsoidalne lub sferyczne, reprezentując cząstki niedojrzałego wirionu (IV). Cząstki IV przechodzą proteolityczne cięcie kilku białek kapsydu i kondensację rdzenia, co prowadzi do powstania dojrzałych cząstek wirusowych znanych jako IMV³³.

Gdy IMV proliferują, powodują lizę komórek gospodarza, uwalniając następnie cząstki wirusowe IMV. Dodatkowo, część IMV opuszcza fabrykę wirusową przez centrum organizujące mikrotubule i zostaje otoczona przez sieć trans-Golgiego (TGN) lub błony jądrowe, tworząc wewnątrzkomórkowy wirus otoczkowy (IEV)³⁴.

W porównaniu do jednowarstwowej struktury błonowej IMV, IEV posiada trójwarstwową strukturę błonową. We wczesnym stadium zakażenia, większość IMV jest otaczana, tworząc IEV. Jednak w późniejszych stadiach zakażenia, IMV stają się dominującą formą, prawdopodobnie z powodu wyczerpania TGN i błon jądrowych³⁵.

Interakcje wirusa z układem immunologicznym gospodarza

Odpowiedź immunologiczna na zakażenie

Zakażenie wirusem opoksy stymuluje adaptacyjną odpowiedź immunologiczną obejmującą aktywowane efektorowe komórki T CD4+ i CD8+, przeciwciała neutralizujące (IgM i IgG) oraz produkcję cytokin zapalnych Th1 (interferon gamma [IFN-γ], IL-1ra, IL-6, IL-8 i TNF). Te odpowiedzi immunologiczne ograniczają replikację wirusa i indukują długotrwałą odporność u wyzdrowiejących pacjentów³⁶.

Wrodzone komórki immunologiczne działają jako pierwsza linia obrony przeciwko zakażeniom wirusowym i są głównymi celami ataku wirusowego. Podczas wczesnych etapów zakażenia wirusem opoksy, monocyty są rekrutowane do miejsca zakażenia i stają się wczesnymi celami zakażenia wirusowego. Poziom antygenów wirusa opoksy wykrywanych w monocytach może służyć jako wskaźnik ciężkości zakażenia i prognozy. Dodatkowo, komórki NK (natural killer) odgrywają kluczową rolę w generowaniu silnej odpowiedzi immunologicznej po zakażeniu wirusem opoksy³⁷.

Istotna jest również odpowiedź efektorowych cząsteczek immunologicznych podczas zakażenia wirusem opoksy, która odgrywa kluczową rolę w progresji i ciężkości choroby. Na początku zakażenia wirus opoksy może tłumić ekspresję chemokin, prowadząc do zmniejszenia ekspresji cząsteczek efektorowych, takich jak IFN-γ i TNF-α. To hamowanie aktywacji komórek T utrudnia inicjację odpowiedzi immunologicznej humoralnej, pozwalając wirusowi łatwiej uniknąć układu odpornościowego³⁸.

Jednak ciężkie zakażenie opoksą często prowadzi do burzy cytokinowej w późniejszych etapach. Powoduje to wzrost cytokin związanych z Th2 i spadek cytokin związanych z Th1, charakteryzujący się zwiększoną ekspresją IL-2, IL-4 i IL-8 oraz zmniejszeniem TNF-α, IL-2 i IL-12³⁹.

Mechanizmy unikania odpowiedzi immunologicznej

Wirus opoksy wykształcił różne strategie unikania odpowiedzi immunologicznej, które umożliwiają mu ustalenie przetrwałego zakażenia w organizmie gospodarza⁴⁰:

Wytwarzanie rozpuszczalnych receptorów przynętowych dla cytokin, które konkurencyjnie wiążą się z cytokinami gospodarza, zapobiegając ich interakcji z receptorami komórkowymi
Wydzielanie białek, które zakłócają dalsze ścieżki sygnałowe aktywowane przez zaangażowanie receptorów cytokin
Zakłócanie głównego kompleksu zgodności tkankowej (MHC) klasy I w prezentacji antygenów, albo przez regulację w dół ekspresji MHC klasy I na zakażonych komórkach, albo przez hamowanie przetwarzania i prezentacji antygenów wirusowych
Hamowanie ekspresji cząsteczek kostymulujących na komórkach prezentujących antygen
Przechodzenie zmienności antygenowej, generując różnorodne warianty wirusowe o zmienionych profilach antygenowych
Modulacja ekspresji antygenów wirusowych na powierzchni zakażonych komórek
Rozwijanie mechanizmów unikania apoptozy komórek gospodarza

MPXV może ukrywać swoje cząsteczki DNA przed komórkowymi sensorami DNA, co utrudnia aktywację szlaków transdukcji sygnału⁴¹. Dodatkowo wirus koduje białko podobne do Bcl-2, które reguluje wewnętrzny szlak apoptotyczny. Ponadto białko SPI-2 kodowane przez gen B12R hamuje zarówno kaspazę-1, jak i kaspazę-8, zakłócając odpowiednio szlak pyroptozy lub apoptozy⁴².

Wirus wytwarza również białka, które blokują aktywację genów stymulowanych przez interferon (ISG), jednocześnie celując w cząsteczki sygnałowe, takie jak STAT1 i STAT2, które są kluczowe dla odpowiedzi przeciwwirusowej zapośredniczonej przez IFN⁴³.

Białko M2 wirusa opoksy wchodzi w interakcję z ludzkimi cząsteczkami B7.1 i B7.2 i zapobiega wiązaniu CD28 i CTLA4 z ich ligandem B7.1/2, co wpływa na aktywację i proliferację komórek T⁴⁴.

Czynniki wpływające na patogenezę opoksy

Czynniki genetyczne wirusa

Struktura genomowa wirusa opoksy ściśle przypomina inne ortopokswirusy, charakteryzując się wysoce konserwatywnym regionem centralnym, zmiennymi regionami na lewym i prawym końcu oraz powtarzalnymi odwróconymi terminalami. Region centralny wirusa opoksy wykazuje ponad 90% homologii sekwencyjnej z innymi ortopokswirusami, szczególnie w ramach otwartej ramki odczytu (ORF) zlokalizowanej między C10L a A25R⁴⁵.

Charakterystyki specyficzne dla gatunków i szczepów ortopokswirusów często znajdują się w zmiennych regionach na końcach genomu. Lepsza znajomość tych ORF może dostarczyć wglądu w jego tropizm gospodarza, patogenezę i różnice w regulacji immunologicznej⁴⁶.

Linia B.1 wykazuje liczne mutacje w genach związanych z wirulencją, rozpoznawaniem gospodarza i unikaniem odpowiedzi immunologicznej. W porównaniu do wcześniej uzyskanych pełnych sekwencji genomowych wirusa opoksy wyizolowanych w Nigerii w latach 2017-2018, szczepy wirusa opoksy, które pojawiły się w 2022 roku, wykazały wyższą liczbę polimorfizmów pojedynczych nukleotydów (SNP). Szczep wirusa opoksy wyizolowany w 2022 roku wykazuje około 50 SNP, wskazując na około 6-12-krotny wzrost przewidywanej częstości substytucji wirusa opoksy w porównaniu do szczepów wyizolowanych w latach 2018-2019⁴⁷.

Znaczenie funkcjonalne tych mutacji nie jest jeszcze w pełni zrozumiałe, ale ta wysoka częstość mutacji może pomóc wyjaśnić nagłe pojawienie się i zwiększoną zdolność transmisji wirusa opoksy w regionach nieendemicznych⁴⁸.

Czynniki związane z gospodarzem

Ciężkie przypadki zakażenia wirusem opoksy mogą prowadzić do powikłań, takich jak choroba krwotoczna, choroba martwicza, choroba obturacyjna, zapalenie istotnych narządów i posocznica. Współczynnik śmiertelności opoksy w regionach nieepidemiicznych w 2022 roku wynosił około 0,04%⁴⁹.

Osoby z immunosupresją, w tym dzieci, starsi dorośli i osoby z niedoborami odporności (takie jak pacjenci z HIV i osoby stosujące leki immunosupresyjne), są bardziej podatne na doświadczanie tych ciężkich objawów⁵⁰. Ponadto osoby z immunosupresją są bardziej skłonne do przyczyniania się do ewolucji wirusa opoksy, czyniąc go coraz bardziej dostosowanym do ludzkich gospodarzy i powodując szerokie rozprzestrzenianie się⁵¹.

U osób zakażonych HIV z liczbą komórek CD4 poniżej 100 komórek na mm³, ciężkie powikłania były częstsze niż u tych z liczbą komórek CD4 między 300 a 350 komórek na mm³, w tym zmiany martwicze skóry, zajęcie płuc i wtórne zakażenia z posocznicą⁵²⁵³.

Czynniki środowiskowe

Główne czynniki środowiskowe wpływające na transmisję choroby obejmują polowanie, schwytanie zwierząt, spożywanie dziczyzny, handel zwierzętami i podróże do krajów endemicznych⁵⁴. Jednak w epidemii z 2022 roku większość zakażonych ludzi w krajach nieendemicznych miała historię bezpośredniego kontaktu z osobami klinicznymi lub bezobjawowymi poprzez aktywność seksualną⁵⁵.

Wraz z globalnym zaprzestaniem podawania szczepionek przeciwko ospie, odsetek osób z ochroną krzyżową przeciwko wirusowi opoksy gwałtownie spadł, czyniąc opoksę potencjalnym zagrożeniem bioterrorystycznym⁵⁶.

Terapeutyczne implikacje patogenezy

Leki przeciwwirusowe

Obecnie naukowcy są zaangażowani w rozwój leków przeciwko opoksie poprzez zakłócanie syntezy DNA lub RNA genomu wirusowego. Analogi nukleozydów są związkami chemicznymi, które mają podobną strukturę do naturalnie występujących nukleozydów. Te leki konkurencyjnie wiążą się z wirusową polimerazą DNA lub RNA, zakłócając proces replikacji przez powodowanie terminacji syntezy łańcucha DNA lub RNA⁵⁷.

Ze względu na ich zdolność do hamowania replikacji wirusowej, leki te często wykazują szerokowidmową aktywność przeciwwirusową. Cidofowir, niecykliczny monofosforan analogu nukleozydu, może być stosowany w leczeniu ortopokswirusów i wykazuje silną aktywność przeciwwirusową in vitro (wirus opoksy, stężenie efektywne połówkowe (EC₅₀)=2,52μg/mL, indeks selektywności (SI)=15, w ludzkich fibroblastach płuc zarodkowych) oraz in vivo (wirus opoksy, 5mg/kg, makaki jawajskie, iniekcja dootrzewnowa; wirus opoksy, 5mg/kg, człowiek, dożylnie)⁵⁸.

Po wybuchu opoksy w 2022 roku, Cidofowir został szybko zastosowany w badaniach klinicznych w leczeniu opoksy. Jednak Cidofowir jest dwuwartościowym anionem o niskiej biodostępności. U pacjentów z upośledzoną funkcją nerek lub poddawanych terapii nerkozastępczej, jego metabolity mogą gromadzić się w proksymalnych komórkach kanalików nerkowych, prowadząc do uszkodzenia nerek⁵⁹.

Aby przezwyciężyć ograniczenia Cidofowiru, opracowano jego pochodną, Brincidofowir. Brincidofowir został zmodyfikowany za pomocą technologii koniugacji lipidów, co skutkuje poprawioną absorpcją komórkową i możliwościami konwersji. Został zatwierdzony przez FDA w 2021 roku do leczenia ospy. W przeciwieństwie do Cidofowiru, Brincidofowir nie wymaga metabolizmu przez nerkowy system transportu anionów, wykazując tym samym wyższą biodostępność i brak znaczącej nefrotoksyczności in vitro (VACV, EC₅₀=0,19μM, w komórkach Vero) i in vivo (wirus opoksy, 10mg/kg, myszy, zgłębnik żołądkowy; wirus opoksy, 200mg, człowiek, doustnie)⁶⁰.

Jednak Brincidofowir nadal wykazuje pewne działania niepożądane, takie jak reakcje żołądkowo-jelitowe i uszkodzenie funkcji wątroby⁶¹.

Poza Brincidofowirem, opracowano inne związki oparte na modyfikacjach strukturalnych Cidofowiru. Na przykład, NPP-669 jest syntetyzowany przez połączenie długołańcuchowego sulfonianu z Cidofowirem. Ta modyfikacja poprawia jego rozpuszczalność w wodzie i powinowactwo do lipidów poprzez modyfikację łańcucha alkilowego. W rezultacie ta modyfikacja strukturalna zwiększa stabilność metaboliczną i biodostępność, jednocześnie zmniejszając nefrotoksyczność⁶².

Rybawiryna, znany analog nukleozydu, blokuje syntezę nukleotydów wirusowych, a tym samym hamuje replikację wirusową i transmisję. Ma szerokowidmową skuteczność przeciwwirusową przeciwko różnym wirusom DNA i RNA, w tym wirusowi opoksy. Badania wykazały, że rybawiryna może hamować replikację ortopokswirusów in vitro (wirus opoksy, EC₅₀=5,9μg/mL, w komórkach Vero) i in vivo (wirus ospy krowiej, 50mg/kg, myszy, iniekcja podskórna)⁶³.

Immunoterapia

Immunopatologia wywołana przez wirus opoksy prowadzi do niekorzystnych wyników klinicznych, a immunoterapia dla opoksy ma potencjał do zmniejszenia ciężkich przypadków. Terapeutyki oparte na przeciwciałach, komórki immunologiczne, cząsteczki efektorowe immunologiczne i modulacja komórkowej transdukcji sygnału to potencjalne immunoterapie⁶⁴.

Połączenie leków przeciwwirusowych z immunoterapią może być bardziej skuteczne i zapewnić większe korzyści kliniczne niż monoterapia przeciwwirusowa. Terapeutyki oparte na przeciwciałach wykazały znaczący postęp w leczeniu niektórych chorób zakaźnych i są obecnie aktywnie badane⁶⁵.

Immunoglobulina, osocze ozdrowieńców i przeciwciała neutralizujące oferują obiecujące opcje jako wspomagające leczenie w przypadkach z niewystarczającą skutecznością leków przeciwwirusowych u pacjentów z ciężką postacią choroby. Co istotne, osoby, które wcześniej zostały zaszczepione szczepionką przeciwko ospie, wytwarzają więcej przeciwciał neutralizujących, które mogą zapewniać ochronę krzyżową przeciwko zakażeniu wirusem opoksy⁶⁶.

Niektóre kraje zatwierdziły dożylne podawanie immunoglobuliny przeciw wirusowi ospy (VIGIV) do zarządzania powikłaniami związanymi ze szczepieniem przeciwko ospie. Dla osób z ciężkim niedoborem funkcji komórek T z powodu przeciwwskazań do szczepienia przeciwko ospie, VIGIV można rozważyć jako środek profilaktyczny in vitro i in vivo oraz w jednym przypadku klinicznym⁶⁷.

Nowe kierunki badawcze w patogenezie opoksy

Techniki omiczne w badaniu opoksy

Rozwój technologii wieloomicznych i technik sekwencjonowania o wysokiej przepustowości (HTS) umożliwił precyzyjną identyfikację i charakterystykę różnych celów molekularnych wirusa opoksy, co jest kluczowe dla rozwoju nowych leków przeciw wirusowi opoksy skierowanych na nowe mechanizmy⁶⁸.

Ponadto, technologie wieloomiczne ujawniły wzorce ekspresji genów podczas zakażenia opoksą i zidentyfikowały konkretne receptory i ścieżki regulowane podczas progresji opoksy. Poprzez precyzyjną modulację tych receptorów i ścieżek, możliwe jest opracowanie leków do terapii opoksy⁶⁹.

Dzięki połączeniu Ważonej Analizy Sieci Ko-ekspresji Genów (WGCNA) z analizą interakcji gospodarz-patogen (HPI), uzyskuje się nowatorskie podejście do badania opoksy. WGCNA identyfikuje kluczowe moduły genów i centra regulacyjne wpływające na zakażenie opoksą, podczas gdy analiza HPI ujawnia, w jaki sposób białka wirusowe wchodzą w interakcje z komponentami gospodarza, aby zmieniać procesy komórkowe⁷⁰.

Odkrywanie nowych leków

Aby zwalczać potencjalne długoterminowe wybuchy i pojawianie się szczepów wirusa opoksy opornych na leki, konieczne jest przyspieszenie postępu badań. W rozwoju leków przeciwko opoksie należy dać pierwszeństwo następującym aspektom⁷¹:

Poprawa specyficzności i efektywności dostarczania leków
Rozwój leków przeciwko opoksie, które są mniej podatne na oporność
Eksploracja rozwoju sekwencyjnych i kombinowanych terapii lekowych
Zwrócenie uwagi na modyfikacje leków w celu złagodzenia lub wyeliminowania toksyczności

Wysoka przepustowość badań przesiewowych sprzedawanych leków lub leków klinicznie ustalonych ma potencjał do przyspieszenia identyfikacji środków przeciwwirusowych, oszczędzając cenny czas. Na przykład, potencjalny lek przeciwwirusowy rybawiryna wykazała skuteczność terapeutyczną przeciwko zakażeniu opoksą. Podobnie, szeroko stosowany inhibitor EGFR gefitinib wykazał obiecującą aktywność przeciwwirusową przeciwko wirusowi opoksy⁷².

Nowe cele terapeutyczne

Analiza centralności sieci interakcji gospodarz-patogen ujawniła białka węzłowe, w tym EGFR, TRAF6 i CASP8, które wydają się odgrywać istotne role w regulacji odpowiedzi immunologicznej. W szczególności stwierdzono, że EGFR jest zaangażowany w wnikanie wirusa i supresję odpowiedzi immunologicznej, podczas gdy TRAF6 i CASP8 były związane z odpowiedziami zapalnymi i szlakami apoptozy⁷³.

Przewidziano 11 kinaz, w tym JAK1, TYK2 i MAPK1, jako potencjalne cele regulacyjne zaangażowane w patogenezę opoksy. Dodatkowo zidentyfikowano 15 czynników transkrypcyjnych, takich jak IRF7, STAT1 i NFKB1, które odgrywają kluczową rolę w napędzaniu ekspresji genów przeciwwirusowych⁷⁴⁷⁵.

Aktywna indukcja pyroptozy może być osiągnięta przez użycie nigericyny, aktywatora inflamasomu i induktora pyroptozy, jako strategii przeciwko zakażeniu opoksą. Badania wykazały, że nigericyna skutecznie zmniejszyła miana wirusa i wykazała silniejszy efekt przeciwwirusowy i niższe wartości EC50 w porównaniu do grupy kontrolnej leczonej cidofowirem⁷⁶.

W dążeniu do skutecznych metod leczenia opoksy kluczowe jest identyfikowanie białek wirusa i gospodarza, które ułatwiają interakcje wirus-gospodarz. Białka te odgrywają istotne role w cyklu życiowym wirusa, co czyni je obiecującymi celami dla odkrywania leków⁷⁷.

Skupiając się na tych potencjalnych celach, badacze mogą opracować nowatorskie strategie terapeutyczne mające na celu zakłócenie mechanizmów, poprzez które wirus się replikuje i rozprzestrzenia⁷⁸.

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Materiały źródłowe

#1 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
Mpox virus, a member of the genus orthopoxvirus in the family Poxviridae, is characterized by its brick-shaped or oval morphology with a diameter of ~200-250nm. Its genome consists of a linear, double-stranded DNA with a length of ~197kb and encoding about 180 proteins. Additionally, Mpox virus possesses dumbbell-shaped nucleocapsid enveloped by ovoid lipid-containing particles. The genomic structure of Mpox virus closely resembles that of other orthopoxviruses, characterized by a highly conserved central core region, variable regions at the left and right ends, and a tandemly repeated inverted terminal repeat. The central core region of Mpox virus shares more than 90% sequence homology with other orthopoxviruses, particularly within the open reading frame (ORF) located between C10L and A25R. Species and strain-specific characteristics of orthopoxviruses are often found in the variable regions at the ends of the genome. A better understanding about these ORFs may provide insights into its host tropism, pathogenesis, and differences in immune regulation. Based on a genomic and phylogenetic analysis conducted in 2022, the prevalent strain of Mpox virus was identified as belonging to the B.1 lineage of the West African clade. The B.1 lineage exhibits multiple mutations in genes associated with virulence, host recognition, and immune evasion. In comparison to previously obtained complete genome sequences of Mpox virus isolated in Nigeria from 2017 to 2018, the Mpox virus strains that emerged in 2022 exhibited a higher number of single nucleotide polymorphisms (SNPs). The Mpox virus strain isolated in 2022 exhibit ~50 SNPs, indicating an approximately 6-12-fold increase in the predicted substitution rate of Mpox virus compared to the strains isolated from 2018-2019. The functional significance of these mutations is yet to be fully understood, but this high mutation rate may help explain the sudden appearance and heightened transmissibility of Mpox virus in non-endemic regions.
#2 Monkeypox: scientifically, how worried should we be? | CAS
https://www.cas.org/resources/cas-insights/monkeypox
Virology and pathogenesis of mpox. The mpox virus is characterized by its brick-shaped or oval morphology with a diameter of ~200-250nm. Its genome consists of a linear, double-stranded DNA with a length of ~197kb, encoding about 180 proteins. Additionally, mpox virus possesses a dumbbell-shaped nucleocapsid enveloped by ovoid lipid-containing particles. The mpox isolates are classified into three genetically distinct clades: (i) the clade I (formerly designated as clade 1), which is also known as Central African or Congo Basin clade, containing isolates from the Congo Basin with mortality rates of around 10.6%, (ii) the clade IIa (formerly designated as clade 2) also known as West African clade and contains isolates from the countries in western Africa with mortality rates of around 3.6%, and (iii) clade IIb (formerly designated as clade 3), which is descendant from clade IIa and includes the isolates of the 2022 mpox outbreak.
#3 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
Mpox is a self-limiting disease, and the severity of infection can be influenced by various factors, such as the specific viral strain, individual immune status, and potential complications that may arise. Common early symptoms of Mpox virus infection include pain, fever, fatigue, and lymphadenectasis, with significant inguinal lymphadenectasis often observed. The presence of lymphadenectasis can help to distinguish Mpox virus infection from other orthopoxviruses infection. Furthermore, understanding the transmission mode is essential in establishing effective measures to combat Mpox. Following exposure to the respiratory secretions or body fluids of Mpox patients, the Mpox virus enters nearby tissues through mucous membranes (such as ocular, respiratory, oral, urethral, and rectal) or broken skin. It then spreads throughout the body via tissue-resident immune cells and draining lymph nodes. This constitutes the latent period for Mpox virus infection, which typically lasts up to two weeks. Throughout this period, individuals infected with Mpox are generally asymptomatic and devoid of lesions. Following the latent period, individuals infected with Mpox virus begin to exhibit atypical symptoms, including fever and chills, headache, muscle pain, and lymphadenectasis. These initial prodromal symptoms of Mpox typically last for three days. After the fever and lymphadenectasis, rashes begin to appear on the head and face, and gradually spread throughout the body. The rash evolves from papules to vesicles and pustules, and ultimately forming crusts that heal, leaving behind scars. This progressive rash phase lasts about 2-4 weeks. In the current outbreak of Mpox among men who have sex with men (MSM), some unusual clinical signs have been observed with rashes appearing primarily around the genital or anal area and subsequently spreading throughout the body. Severe cases of Mpox virus infection can lead to complications such as hemorrhagic disease, necrotic disease, obstructive disease, inflammation of vital organs, and septicemia. The case fatality rate of Mpox in non-epidemic regions during 2022 was ~0.04%. Immunocompromised individuals, including children, older adults, and those with immunodeficiencies (such as HIV patients and individuals using immunosuppressive medications), are more susceptible to experiencing these severe manifestations. In addition, immunocompromised individuals are more likely to contribute to the evolution of Mpox, making it increasingly adaptable to human hosts and resulting in widespread transmission.
#4 Pathogenicity and virulence of monkeypox at the human-animal-ecology interface
https://pmc.ncbi.nlm.nih.gov/articles/PMC10012937/
Additionally, longer-term preparedness should be emphasized using the One Health approach, such as systems strengthening, surveillance and detection of the virus across regions, early case detection, and integrating measures to mitigate the socio-economic effects of outbreaks. […] The understanding of the nature of the sylvatic cycle of the virus is also not yet established. […] The virus is genetically divided into two distinct clades, the Central African or Congo Basin clade and the West African clade. […] The Congo basin clade is relatively less pathogenic compared to the West African clade, which spread to non-endemic countries. […] The pathobiology of human mpox is nearly similar to that of smallpox, although the basic case reproduction number (R0) of smallpox is 6, whereas it is 1.29 in the case of mpox.
#5 Mpox – Wikipedia
https://en.wikipedia.org/wiki/Mpox
Mpox is caused by the monkeypox virus, a zoonotic virus in the genus Orthopoxvirus. […] The two major subtypes of virus are clade I and clade II. In April 2024, after detection of a new variant, clade I was split into subclades designated Ia and Ib. Clade II is similarly divided into subclades: clade IIa and clade IIb. […] Clade I is estimated to cause more severe disease and higher mortality than clade II.
#6 Factsheet for health professionals on mpox
https://www.ecdc.europa.eu/en/all-topics-z/monkeypox/factsheet-health-professionals
Human mpox (formerly known as monkeypox) is a zoonotic disease caused by the monkeypox virus (MPXV). […] Genetic differences between the viral genomes of the two clades might explain differences in viral clearance and pathogenesis. […] Clade I has been associated with more severe disease and higher mortality. […] The disease severity may vary depending on the virus strain, transmission route, host susceptibility, and the quantity of virus inoculated, with invasive modes of exposure causing more severe disease while having a shorter incubation period. […] In the 2022 outbreak, a clinical presentation of symptoms which is somewhat different than those previously reported in endemic areas, has also arisen. […] The lesions progressed from the stage of macules to papules, vesicles, pseudo-pustules containing solid debris, crusts, and finally scabs, before falling off within 7-14 days.
#7 Mpox (monkeypox): For health professionals – Canada.ca
https://www.canada.ca/en/public-health/services/diseases/mpox/health-professionals.html
Mpox is a viral zoonotic infectious disease caused by the MPXV (MPXV) an Orthopoxvirus. […] The original Congo-Basin clade Ia virus has the highest case fatality rate. The other clades including clade Ib and II are associated with a relatively less severe symptoms and outcomes, although evidence is still emerging with respect to clade Ib. […] Clade Ib has been implicated in the 2024 multi-country outbreak. […] Infection is thought to occur when the virus enters the body through skin, the respiratory tract, or mucous membranes. […] Although spread through the air is possible, current data continue to support a minimal role of spread through the air for clade I and II mpox. However, this possibility should continue to be examined given ongoing viral evolution. […] Mpox illness is usually self-resolving within a period of 2 to 4 weeks. The spectrum of severity varies from a single skin lesion to disseminated, multi-organ infection.
#8 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
Mpox virus, a member of the genus orthopoxvirus in the family Poxviridae, is characterized by its brick-shaped or oval morphology with a diameter of ~200-250nm. Its genome consists of a linear, double-stranded DNA with a length of ~197kb and encoding about 180 proteins. Additionally, Mpox virus possesses dumbbell-shaped nucleocapsid enveloped by ovoid lipid-containing particles. The genomic structure of Mpox virus closely resembles that of other orthopoxviruses, characterized by a highly conserved central core region, variable regions at the left and right ends, and a tandemly repeated inverted terminal repeat. The central core region of Mpox virus shares more than 90% sequence homology with other orthopoxviruses, particularly within the open reading frame (ORF) located between C10L and A25R. Species and strain-specific characteristics of orthopoxviruses are often found in the variable regions at the ends of the genome. A better understanding about these ORFs may provide insights into its host tropism, pathogenesis, and differences in immune regulation. Based on a genomic and phylogenetic analysis conducted in 2022, the prevalent strain of Mpox virus was identified as belonging to the B.1 lineage of the West African clade. The B.1 lineage exhibits multiple mutations in genes associated with virulence, host recognition, and immune evasion. In comparison to previously obtained complete genome sequences of Mpox virus isolated in Nigeria from 2017 to 2018, the Mpox virus strains that emerged in 2022 exhibited a higher number of single nucleotide polymorphisms (SNPs). The Mpox virus strain isolated in 2022 exhibit ~50 SNPs, indicating an approximately 6-12-fold increase in the predicted substitution rate of Mpox virus compared to the strains isolated from 2018-2019. The functional significance of these mutations is yet to be fully understood, but this high mutation rate may help explain the sudden appearance and heightened transmissibility of Mpox virus in non-endemic regions.
#9 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
Mpox is a self-limiting disease, and the severity of infection can be influenced by various factors, such as the specific viral strain, individual immune status, and potential complications that may arise. Common early symptoms of Mpox virus infection include pain, fever, fatigue, and lymphadenectasis, with significant inguinal lymphadenectasis often observed. The presence of lymphadenectasis can help to distinguish Mpox virus infection from other orthopoxviruses infection. Furthermore, understanding the transmission mode is essential in establishing effective measures to combat Mpox. Following exposure to the respiratory secretions or body fluids of Mpox patients, the Mpox virus enters nearby tissues through mucous membranes (such as ocular, respiratory, oral, urethral, and rectal) or broken skin. It then spreads throughout the body via tissue-resident immune cells and draining lymph nodes. This constitutes the latent period for Mpox virus infection, which typically lasts up to two weeks. Throughout this period, individuals infected with Mpox are generally asymptomatic and devoid of lesions. Following the latent period, individuals infected with Mpox virus begin to exhibit atypical symptoms, including fever and chills, headache, muscle pain, and lymphadenectasis. These initial prodromal symptoms of Mpox typically last for three days. After the fever and lymphadenectasis, rashes begin to appear on the head and face, and gradually spread throughout the body. The rash evolves from papules to vesicles and pustules, and ultimately forming crusts that heal, leaving behind scars. This progressive rash phase lasts about 2-4 weeks. In the current outbreak of Mpox among men who have sex with men (MSM), some unusual clinical signs have been observed with rashes appearing primarily around the genital or anal area and subsequently spreading throughout the body. Severe cases of Mpox virus infection can lead to complications such as hemorrhagic disease, necrotic disease, obstructive disease, inflammation of vital organs, and septicemia. The case fatality rate of Mpox in non-epidemic regions during 2022 was ~0.04%. Immunocompromised individuals, including children, older adults, and those with immunodeficiencies (such as HIV patients and individuals using immunosuppressive medications), are more susceptible to experiencing these severe manifestations. In addition, immunocompromised individuals are more likely to contribute to the evolution of Mpox, making it increasingly adaptable to human hosts and resulting in widespread transmission.
#10 Epidemiology, clinical manifestations, and diagnosis of mpox (formerly monkeypox) – UpToDate
https://www.uptodate.com/contents/epidemiology-clinical-manifestations-and-diagnosis-of-mpox-monkeypox
Pathogenesis […] Infections caused by orthopoxviruses can be classified as either systemic or localized (at the site of virus entry). The type of infection depends on the species of orthopoxvirus and the route of entry. Generalized disease usually manifests as a diffuse rash. In contrast, after cutaneous inoculation, a localized rash may appear at the site of virus entry, followed or not by disseminated lesions due to a viremia. […] Infection via cutaneous inoculation â Monkeypox virus (MPXV) can enter the human host through microabrasions in the skin. The pathogenesis of human mpox following skin inoculation is felt to be similar to that of smallpox and other orthopoxviruses. Several orthopoxviruses can cause infection in animals after being introduced through the skin as well; this includes MPXV and variola virus in nonhuman primates and ectromelia virus (ECTV) in mice.
#11 Pathogenicity and virulence of monkeypox at the human-animal-ecology interface
https://pmc.ncbi.nlm.nih.gov/articles/PMC10012937/
As a zoonotic virus, primary transmission occurs through contact with infected animals. […] The viral inoculation to the body takes place through the respiratory tract (oropharynx or nasopharynx) and person-to-person transmission (intradermal). […] After entry into the body, the virus replicates at the inoculation site and in the local lymph nodes. […] Primary viremia leads the viral spread towards other organs, like the liver and spleen, and replicates. […] When the secondary viremia takes place and the virus is transferred towards the cutaneous parts of the body, then mucosal and other lesions develop. […] The mechanism of mpox pathobiology, clinical courses, and viral shedding is presented in Figure 4. […] The clinical features include the cutaneous, gastrointestinal tract, and respiratory tract involvement along with other systemic illnesses.
#12 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
Mpox is a self-limiting disease, and the severity of infection can be influenced by various factors, such as the specific viral strain, individual immune status, and potential complications that may arise. Common early symptoms of Mpox virus infection include pain, fever, fatigue, and lymphadenectasis, with significant inguinal lymphadenectasis often observed. The presence of lymphadenectasis can help to distinguish Mpox virus infection from other orthopoxviruses infection. Furthermore, understanding the transmission mode is essential in establishing effective measures to combat Mpox. Following exposure to the respiratory secretions or body fluids of Mpox patients, the Mpox virus enters nearby tissues through mucous membranes (such as ocular, respiratory, oral, urethral, and rectal) or broken skin. It then spreads throughout the body via tissue-resident immune cells and draining lymph nodes. This constitutes the latent period for Mpox virus infection, which typically lasts up to two weeks. Throughout this period, individuals infected with Mpox are generally asymptomatic and devoid of lesions. Following the latent period, individuals infected with Mpox virus begin to exhibit atypical symptoms, including fever and chills, headache, muscle pain, and lymphadenectasis. These initial prodromal symptoms of Mpox typically last for three days. After the fever and lymphadenectasis, rashes begin to appear on the head and face, and gradually spread throughout the body. The rash evolves from papules to vesicles and pustules, and ultimately forming crusts that heal, leaving behind scars. This progressive rash phase lasts about 2-4 weeks. In the current outbreak of Mpox among men who have sex with men (MSM), some unusual clinical signs have been observed with rashes appearing primarily around the genital or anal area and subsequently spreading throughout the body. Severe cases of Mpox virus infection can lead to complications such as hemorrhagic disease, necrotic disease, obstructive disease, inflammation of vital organs, and septicemia. The case fatality rate of Mpox in non-epidemic regions during 2022 was ~0.04%. Immunocompromised individuals, including children, older adults, and those with immunodeficiencies (such as HIV patients and individuals using immunosuppressive medications), are more susceptible to experiencing these severe manifestations. In addition, immunocompromised individuals are more likely to contribute to the evolution of Mpox, making it increasingly adaptable to human hosts and resulting in widespread transmission.
#13 Advancing the understanding and management of Mpox: insights into epidemiology, disease pathways, prevention, and therapeutic strategies | BMC Infectious Diseases | Full Text
https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-025-10899-2
The incubation stage refers to the period between MPXV entry (through mucous membranes or damaged skin of the host) and the appearance of symptoms. […] During this time the virus is replicating at the infection site before spreading to regional lymph nodes and the bloodstream and causing primary viremia. […] The prodromal stage occurs after the incubation stage, during which the patient experiences flu-like symptoms that signals the onset of infection. […] During this stage the virus continues to spread through the blood stream and lymph nodes leading to secondary viremia and reaching distant organs including the skin. […] In this stage, MPXV deploys immune evasion strategies by binding to type I interferons, delaying immune activation, and suppressing inflammation, which aids in the spread of symptoms and disease.
#14 Mpox – Etiology | BMJ Best Practice US
https://bestpractice.bmj.com/topics/en-us/1611/aetiology
Mpox is caused by the monkeypox virus (MPXV; family Poxviridae; genus Orthopoxvirus), a double-stranded DNA virus. The virus replicates at the site of inoculation (e.g., skin or respiratory route). The virus can infect epithelial cells, dendritic cells, and macrophages in the respiratory tract, or keratinocytes, fibroblasts, Langerhans cells, dendritic cells, and macrophages in the skin. The virus binds to host cell surface glycosaminoglycans and undergoes endocytosis to enter the cell. Infected cells travel to nearby draining lymph nodes (primary viremia). The virus reaches distant lymph nodes and organs via the circulation. This phase of the infection is asymptomatic. During the prodromal stage, secondary viremia occurs from the lymphoid organs to the skin and other organs (e.g., eyes, lungs, gastrointestinal tract, gonads), and nonspecific symptoms develop from the immune system being triggered. Infection of skin and mucosa leads to appearance of pustules and ulcers. […] Data on pathophysiology are limited. A detailed discussion of the pathophysiology is beyond the scope of this topic.
#15 Epidemiology, clinical manifestations, and diagnosis of mpox (formerly monkeypox) – UpToDate
https://www.uptodate.com/contents/epidemiology-clinical-manifestations-and-diagnosis-of-mpox-monkeypox
Using a nonhuman primate model of respiratory MPXV with histopathological examinations at several time points postchallenge, it was demonstrated that during the incubation period, the virus is first seen in respiratory bronchioles and alveoli in the lungs (postchallenge day 4). The virus then spreads to the regional lymph nodes and organs of the reticuloendothelial system (day 6), including the tonsils, spleen, liver, and colon, where it replicates. Virus was ultimately detected in the blood on day 8, and its concentration increased through day 10 along with widespread lesions in the skin. […] Immunology â Mpox infection stimulates an adaptative immune response comprising activated effector CD4+ and CD8+ T-cells; neutralizing antibodies (IgM and IgG); and the production of Th1-inflammatory cytokines (gamma interferon [IFN-Î³], IL-1ra, IL-6, IL-8, and TNF). These immune responses restrict viral replication and induce prolonged immunity in recovering patients. However, it is unknown whether the pauci-symptomatic or localized presentation seen in the multi-country outbreak compared to the disseminated presentation of mpox disease is associated with a lower degree of the immune response following infection.
#16 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
Mpox is a self-limiting disease, and the severity of infection can be influenced by various factors, such as the specific viral strain, individual immune status, and potential complications that may arise. Common early symptoms of Mpox virus infection include pain, fever, fatigue, and lymphadenectasis, with significant inguinal lymphadenectasis often observed. The presence of lymphadenectasis can help to distinguish Mpox virus infection from other orthopoxviruses infection. Furthermore, understanding the transmission mode is essential in establishing effective measures to combat Mpox. Following exposure to the respiratory secretions or body fluids of Mpox patients, the Mpox virus enters nearby tissues through mucous membranes (such as ocular, respiratory, oral, urethral, and rectal) or broken skin. It then spreads throughout the body via tissue-resident immune cells and draining lymph nodes. This constitutes the latent period for Mpox virus infection, which typically lasts up to two weeks. Throughout this period, individuals infected with Mpox are generally asymptomatic and devoid of lesions. Following the latent period, individuals infected with Mpox virus begin to exhibit atypical symptoms, including fever and chills, headache, muscle pain, and lymphadenectasis. These initial prodromal symptoms of Mpox typically last for three days. After the fever and lymphadenectasis, rashes begin to appear on the head and face, and gradually spread throughout the body. The rash evolves from papules to vesicles and pustules, and ultimately forming crusts that heal, leaving behind scars. This progressive rash phase lasts about 2-4 weeks. In the current outbreak of Mpox among men who have sex with men (MSM), some unusual clinical signs have been observed with rashes appearing primarily around the genital or anal area and subsequently spreading throughout the body. Severe cases of Mpox virus infection can lead to complications such as hemorrhagic disease, necrotic disease, obstructive disease, inflammation of vital organs, and septicemia. The case fatality rate of Mpox in non-epidemic regions during 2022 was ~0.04%. Immunocompromised individuals, including children, older adults, and those with immunodeficiencies (such as HIV patients and individuals using immunosuppressive medications), are more susceptible to experiencing these severe manifestations. In addition, immunocompromised individuals are more likely to contribute to the evolution of Mpox, making it increasingly adaptable to human hosts and resulting in widespread transmission.
#17 Advancing the understanding and management of Mpox: insights into epidemiology, disease pathways, prevention, and therapeutic strategies | BMC Infectious Diseases | Full Text
https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-025-10899-2
The incubation stage refers to the period between MPXV entry (through mucous membranes or damaged skin of the host) and the appearance of symptoms. […] During this time the virus is replicating at the infection site before spreading to regional lymph nodes and the bloodstream and causing primary viremia. […] The prodromal stage occurs after the incubation stage, during which the patient experiences flu-like symptoms that signals the onset of infection. […] During this stage the virus continues to spread through the blood stream and lymph nodes leading to secondary viremia and reaching distant organs including the skin. […] In this stage, MPXV deploys immune evasion strategies by binding to type I interferons, delaying immune activation, and suppressing inflammation, which aids in the spread of symptoms and disease.
#18 Epidemiology, clinical manifestations, and diagnosis of mpox (formerly monkeypox) – UpToDate
https://www.uptodate.com/contents/epidemiology-clinical-manifestations-and-diagnosis-of-mpox-monkeypox
Using a nonhuman primate model of respiratory MPXV with histopathological examinations at several time points postchallenge, it was demonstrated that during the incubation period, the virus is first seen in respiratory bronchioles and alveoli in the lungs (postchallenge day 4). The virus then spreads to the regional lymph nodes and organs of the reticuloendothelial system (day 6), including the tonsils, spleen, liver, and colon, where it replicates. Virus was ultimately detected in the blood on day 8, and its concentration increased through day 10 along with widespread lesions in the skin. […] Immunology â Mpox infection stimulates an adaptative immune response comprising activated effector CD4+ and CD8+ T-cells; neutralizing antibodies (IgM and IgG); and the production of Th1-inflammatory cytokines (gamma interferon [IFN-Î³], IL-1ra, IL-6, IL-8, and TNF). These immune responses restrict viral replication and induce prolonged immunity in recovering patients. However, it is unknown whether the pauci-symptomatic or localized presentation seen in the multi-country outbreak compared to the disseminated presentation of mpox disease is associated with a lower degree of the immune response following infection.
#19 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
Mpox is a self-limiting disease, and the severity of infection can be influenced by various factors, such as the specific viral strain, individual immune status, and potential complications that may arise. Common early symptoms of Mpox virus infection include pain, fever, fatigue, and lymphadenectasis, with significant inguinal lymphadenectasis often observed. The presence of lymphadenectasis can help to distinguish Mpox virus infection from other orthopoxviruses infection. Furthermore, understanding the transmission mode is essential in establishing effective measures to combat Mpox. Following exposure to the respiratory secretions or body fluids of Mpox patients, the Mpox virus enters nearby tissues through mucous membranes (such as ocular, respiratory, oral, urethral, and rectal) or broken skin. It then spreads throughout the body via tissue-resident immune cells and draining lymph nodes. This constitutes the latent period for Mpox virus infection, which typically lasts up to two weeks. Throughout this period, individuals infected with Mpox are generally asymptomatic and devoid of lesions. Following the latent period, individuals infected with Mpox virus begin to exhibit atypical symptoms, including fever and chills, headache, muscle pain, and lymphadenectasis. These initial prodromal symptoms of Mpox typically last for three days. After the fever and lymphadenectasis, rashes begin to appear on the head and face, and gradually spread throughout the body. The rash evolves from papules to vesicles and pustules, and ultimately forming crusts that heal, leaving behind scars. This progressive rash phase lasts about 2-4 weeks. In the current outbreak of Mpox among men who have sex with men (MSM), some unusual clinical signs have been observed with rashes appearing primarily around the genital or anal area and subsequently spreading throughout the body. Severe cases of Mpox virus infection can lead to complications such as hemorrhagic disease, necrotic disease, obstructive disease, inflammation of vital organs, and septicemia. The case fatality rate of Mpox in non-epidemic regions during 2022 was ~0.04%. Immunocompromised individuals, including children, older adults, and those with immunodeficiencies (such as HIV patients and individuals using immunosuppressive medications), are more susceptible to experiencing these severe manifestations. In addition, immunocompromised individuals are more likely to contribute to the evolution of Mpox, making it increasingly adaptable to human hosts and resulting in widespread transmission.
#20 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
Mpox is a self-limiting disease, and the severity of infection can be influenced by various factors, such as the specific viral strain, individual immune status, and potential complications that may arise. Common early symptoms of Mpox virus infection include pain, fever, fatigue, and lymphadenectasis, with significant inguinal lymphadenectasis often observed. The presence of lymphadenectasis can help to distinguish Mpox virus infection from other orthopoxviruses infection. Furthermore, understanding the transmission mode is essential in establishing effective measures to combat Mpox. Following exposure to the respiratory secretions or body fluids of Mpox patients, the Mpox virus enters nearby tissues through mucous membranes (such as ocular, respiratory, oral, urethral, and rectal) or broken skin. It then spreads throughout the body via tissue-resident immune cells and draining lymph nodes. This constitutes the latent period for Mpox virus infection, which typically lasts up to two weeks. Throughout this period, individuals infected with Mpox are generally asymptomatic and devoid of lesions. Following the latent period, individuals infected with Mpox virus begin to exhibit atypical symptoms, including fever and chills, headache, muscle pain, and lymphadenectasis. These initial prodromal symptoms of Mpox typically last for three days. After the fever and lymphadenectasis, rashes begin to appear on the head and face, and gradually spread throughout the body. The rash evolves from papules to vesicles and pustules, and ultimately forming crusts that heal, leaving behind scars. This progressive rash phase lasts about 2-4 weeks. In the current outbreak of Mpox among men who have sex with men (MSM), some unusual clinical signs have been observed with rashes appearing primarily around the genital or anal area and subsequently spreading throughout the body. Severe cases of Mpox virus infection can lead to complications such as hemorrhagic disease, necrotic disease, obstructive disease, inflammation of vital organs, and septicemia. The case fatality rate of Mpox in non-epidemic regions during 2022 was ~0.04%. Immunocompromised individuals, including children, older adults, and those with immunodeficiencies (such as HIV patients and individuals using immunosuppressive medications), are more susceptible to experiencing these severe manifestations. In addition, immunocompromised individuals are more likely to contribute to the evolution of Mpox, making it increasingly adaptable to human hosts and resulting in widespread transmission.
#21 Epidemiology, clinical manifestations, and diagnosis of mpox (formerly monkeypox) – UpToDate
https://www.uptodate.com/contents/epidemiology-clinical-manifestations-and-diagnosis-of-mpox-monkeypox
Histopathology â Mpox skin lesions in the vesicular stage consist of epidermal acanthosis and spongiosis with exocytosis of lymphocytes and neutrophils. In the center of the lesion, a vesicle affecting the entire epidermis is formed by ballooning degeneration of keratinocytes and accumulation of intercellular fluid. A mixed inflammatory infiltrate is present at the dermal-epidermal junction at the base of the vesicle composed of lymphocytes, eosinophils, and neutrophils. […] The lesion develops into a pustule containing apoptotic keratinocyte debris, a few viable keratinocytes, and inflammatory cells. Viable keratinocytes may be multinucleated or exhibit cytopathic damage, such as eosinophilic inclusion bodies, prominent nucleoli, and „ground glass” chromatin. A mixed inflammatory infiltrate is also present in the perivascular, perieccrine, and dermal regions. Finally, the pustule becomes desiccated and forms a crust.
#22 Epidemiology, clinical manifestations, and diagnosis of mpox (formerly monkeypox) – UpToDate
https://www.uptodate.com/contents/epidemiology-clinical-manifestations-and-diagnosis-of-mpox-monkeypox
Histopathology â Mpox skin lesions in the vesicular stage consist of epidermal acanthosis and spongiosis with exocytosis of lymphocytes and neutrophils. In the center of the lesion, a vesicle affecting the entire epidermis is formed by ballooning degeneration of keratinocytes and accumulation of intercellular fluid. A mixed inflammatory infiltrate is present at the dermal-epidermal junction at the base of the vesicle composed of lymphocytes, eosinophils, and neutrophils. […] The lesion develops into a pustule containing apoptotic keratinocyte debris, a few viable keratinocytes, and inflammatory cells. Viable keratinocytes may be multinucleated or exhibit cytopathic damage, such as eosinophilic inclusion bodies, prominent nucleoli, and „ground glass” chromatin. A mixed inflammatory infiltrate is also present in the perivascular, perieccrine, and dermal regions. Finally, the pustule becomes desiccated and forms a crust.
#23 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
The process of Mpox virus infection and replication can be summarized into three distinct stages: 1) virus invasion; 2) virus replication and synthesis; 3) virus assembly, maturation and release. Targeting any stage of the Mpox virus lifecycle holds promise for the development of effective antiviral interventions against Mpox virus. In the early stages of Mpox virus infection, two distinct infectious viral particles are present: extracellular enveloped virions (EEV) and intracellular mature virions (IMV). These viral particles vary in surface glycoprotein and envelope membrane composition, with IMV exhibiting a single-membrane structure and EEV possessing a double-membrane structure. IMV are released only upon cell lysis and enters host cells through direct fusion and endocytosis, while EEV enters via membrane fusion. IMV are the most abundant viral particles in terms of quantity, due to the absence of a lipid membrane, which gives them a simpler and more robust structure. This enhances their resistance to external damage, prolonging their survival time outside the host. However, the exposed surface proteins of IMV trigger higher production of neutralizing antibodies and activate complement responses. Additionally, these exposed surface proteins enhance the recognition and inactivation of Mpox virus by immune cells. In contrast, EEV possesses an additional lipid membrane layer on their surface, enabling better intracellular dissemination. The pox virus can utilize lipid rafts on the lipid membrane to enter host cells, and cholesterol is one of the important components responsible for maintain the structure and function of lipid rafts. Amphotericin B, a long-standing antibiotic used for the treatment of fungal infections, can sequester cholesterol within host cell membranes, disrupting the integrity of lipid raft and potentially inhibiting Mpox virus infection. Additionally, cholesterol-lowering drugs such as statins and PCSK9 inhibitors may exhibit antiviral activity by modulating cellular cholesterol levels. Mpox virus attaches to mucous membranes and damaged skin, where a high concentration of glycosaminoglycans (GAGs) are present. GAGs serve as primary attachment receptors for host cells. EEV particles of Mpox virus interact with GAGs and enter host cells. Marine sulfated polysaccharides are natural analogs of GAGs that competitively bind to the host cell membrane surface, thereby preventing the attachment and entry of Mpox virus.
#24 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
The process of Mpox virus infection and replication can be summarized into three distinct stages: 1) virus invasion; 2) virus replication and synthesis; 3) virus assembly, maturation and release. Targeting any stage of the Mpox virus lifecycle holds promise for the development of effective antiviral interventions against Mpox virus. In the early stages of Mpox virus infection, two distinct infectious viral particles are present: extracellular enveloped virions (EEV) and intracellular mature virions (IMV). These viral particles vary in surface glycoprotein and envelope membrane composition, with IMV exhibiting a single-membrane structure and EEV possessing a double-membrane structure. IMV are released only upon cell lysis and enters host cells through direct fusion and endocytosis, while EEV enters via membrane fusion. IMV are the most abundant viral particles in terms of quantity, due to the absence of a lipid membrane, which gives them a simpler and more robust structure. This enhances their resistance to external damage, prolonging their survival time outside the host. However, the exposed surface proteins of IMV trigger higher production of neutralizing antibodies and activate complement responses. Additionally, these exposed surface proteins enhance the recognition and inactivation of Mpox virus by immune cells. In contrast, EEV possesses an additional lipid membrane layer on their surface, enabling better intracellular dissemination. The pox virus can utilize lipid rafts on the lipid membrane to enter host cells, and cholesterol is one of the important components responsible for maintain the structure and function of lipid rafts. Amphotericin B, a long-standing antibiotic used for the treatment of fungal infections, can sequester cholesterol within host cell membranes, disrupting the integrity of lipid raft and potentially inhibiting Mpox virus infection. Additionally, cholesterol-lowering drugs such as statins and PCSK9 inhibitors may exhibit antiviral activity by modulating cellular cholesterol levels. Mpox virus attaches to mucous membranes and damaged skin, where a high concentration of glycosaminoglycans (GAGs) are present. GAGs serve as primary attachment receptors for host cells. EEV particles of Mpox virus interact with GAGs and enter host cells. Marine sulfated polysaccharides are natural analogs of GAGs that competitively bind to the host cell membrane surface, thereby preventing the attachment and entry of Mpox virus.
#25 Core Concepts – Mpox – Self-Study Lessons – National STD Curriculum
https://www.std.uw.edu/go/comprehensive-study/mpox/core-concept/all
The monkeypox virus, the causative agent of mpox disease, is a member of the Orthopoxvirus genus in the family Poxviridae. Orthopoxviruses are characterized by an ovoid brick-shaped morphology as seen on cryo-electron tomography. Monkeypox virus is 360 x 270 x 250 nm in size and contains linear double-stranded DNA of approximately 197 kilobases (kb). This genome encodes more than 200 proteins that are essential for the virus life cycle, virus assembly, and evasion of host immune defenses. Infectious monkeypox virus can exist in two distinct forms: extracellular enveloped virus (EEV, also abbreviated as EV) and intracellular mature virus (IMV, also abbreviated as MV) […] Monkeypox virus infects and replicates within host cells as follows: Virion Entry: Monkeypox virus can attach to and enter a host cell in the form of an extracellular enveloped virus (EEV) or a mature virus (MV). The entry and fusion of the MV envelope with the plasma or endocytic membrane involves multiple viral proteins. Early Transcription and Translation: Some monkeypox DNA is immediately transcribed and translated to produce early proteins, including growth factors, immune response modulators, and factors needed for DNA replication. This early step occurs in the host cell cytoplasm. Uncoating: After cell entry, the uncoating of the viral core occurs, with shedding of the outer membranes and release of the core into the cytoplasm. The uncoating of the core facilitates DNA replication. DNA Replication: Most of the monkeypox DNA replicates to form concatemeric DNA (long continuous DNA molecules that contain the same DNA sequence linked in series). This process occurs in a localized cytoplasmic region denoted as the viral factory. Intermediate Gene Transcription and Translation: Within the viral factory region, the newly replicated (progeny) monkeypox viral DNA can undergo intermediate transcription and translation, generating intermediate proteins that include transcription factors required for late transcription. In addition, late proteins are generated, with some contributing to the viral structure and others playing a role in early transcription and translation. Late Gene Transcription and Translation: Also, within the viral factory region, the progeny monkeypox viral DNA can undergo late transcription and translation, which produces late proteins, including some that contribute to the viral assembly process. Assembly: The monkeypox DNA is resolved into a single genome and packaged into the core along with proteins necessary for early transcription. Morphogenesis: The assembled core is moved out of the viral factory region, where it obtains an outer membrane and becomes a mature virus (MV). The MV generally remains trapped within the cell, except in the rare event of cell lysis. Wrapping: Some portion of the total virus particles produced is further wrapped by trans-Golgi/late endosomal double membranes to form the intracellular enveloped virus (IEV). During this process, the viral p37 protein interacts with the cellular proteins Rab9 GTPase and TIP47, which together stimulate the wrapping of the MV to form the IEV. Exocytosis: The IEV migrates to the cell periphery on microtubules and is released by exocytosis to become cell-associated enveloped virus (CEV). The CEV can infect neighboring cells. Approximately 1% of CEV are released into the extracellular space via motile actin tail formation to become extracellular enveloped virus (EEV). EEV are responsible for long-range dissemination of the virus.
#26 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
The process of Mpox virus infection and replication can be summarized into three distinct stages: 1) virus invasion; 2) virus replication and synthesis; 3) virus assembly, maturation and release. Targeting any stage of the Mpox virus lifecycle holds promise for the development of effective antiviral interventions against Mpox virus. In the early stages of Mpox virus infection, two distinct infectious viral particles are present: extracellular enveloped virions (EEV) and intracellular mature virions (IMV). These viral particles vary in surface glycoprotein and envelope membrane composition, with IMV exhibiting a single-membrane structure and EEV possessing a double-membrane structure. IMV are released only upon cell lysis and enters host cells through direct fusion and endocytosis, while EEV enters via membrane fusion. IMV are the most abundant viral particles in terms of quantity, due to the absence of a lipid membrane, which gives them a simpler and more robust structure. This enhances their resistance to external damage, prolonging their survival time outside the host. However, the exposed surface proteins of IMV trigger higher production of neutralizing antibodies and activate complement responses. Additionally, these exposed surface proteins enhance the recognition and inactivation of Mpox virus by immune cells. In contrast, EEV possesses an additional lipid membrane layer on their surface, enabling better intracellular dissemination. The pox virus can utilize lipid rafts on the lipid membrane to enter host cells, and cholesterol is one of the important components responsible for maintain the structure and function of lipid rafts. Amphotericin B, a long-standing antibiotic used for the treatment of fungal infections, can sequester cholesterol within host cell membranes, disrupting the integrity of lipid raft and potentially inhibiting Mpox virus infection. Additionally, cholesterol-lowering drugs such as statins and PCSK9 inhibitors may exhibit antiviral activity by modulating cellular cholesterol levels. Mpox virus attaches to mucous membranes and damaged skin, where a high concentration of glycosaminoglycans (GAGs) are present. GAGs serve as primary attachment receptors for host cells. EEV particles of Mpox virus interact with GAGs and enter host cells. Marine sulfated polysaccharides are natural analogs of GAGs that competitively bind to the host cell membrane surface, thereby preventing the attachment and entry of Mpox virus.
#27 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
After IMV or EEV enter the host cell, the exposed viral core is transported to the periphery of the cell nucleus through microtubule structures at an average speed of 52m/min. The viral core consists of the central viral genome and an enveloped nucleocapsid. The mechanism of nucleocapsid uncoating involves ubiquitination of the nuclear capsid proteins and degradation by proteasomes. Once uncoating is completed, the Mpox virus genome begins efficient replication, rapidly amplifying like a factory. Currently, researchers are devoted to developing anti-Mpox drugs by interfering with the DNA or RNA synthesis of the viral genome. Nucleoside analogs are chemical compounds that have a similar structure to naturally occurring nucleosides. These drugs competitively bind to the viral DNA or RNA polymerase, disrupting the replication process by causing termination of the DNA or RNA chain synthesis. Due to their ability to inhibit viral replication, these drugs often exhibit broad-spectrum antiviral activity. Cidofovir, a non-cyclic monophosphate nucleoside analog, can be used for the treatment of orthopoxviruses and demonstrate potent antiviral activity in vitro (Mpox virus, effective concentration half maximal (EC50)=2.52g/mL, Selectivity index (SI)=15, in human embryonic lung fibroblasts) and in vivo (Mpox virus, 5mg/kg, cynomolgus macaques, intraperitoneal injection; Mpox virus, 5mg/kg, human, intravenous). Following the Mpox outbreak in 2022, Cidofovir was rapidly employed in clinical trials for the treatment of Mpox. However, Cidofovir is a divalent anion with low bioavailability. In patients with impaired renal function or undergoing renal replacement therapy, its metabolites can accumulate in proximal renal tubular cells, leading to kidney damage. In order to overcome the limitations of Cidofovir, its derivative Brincidofovir has been developed. Brincidofovir has been modified using lipid conjugation technology, resulting in improved cellular uptake and conversion capabilities, it was approved by the FDA in 2021 for the treatment of smallpox. Unlike Cidofovir, Brincidofovir does not require metabolism through the renal anion transport system, thus exhibiting higher bioavailability and no significant nephrotoxicity in vitro (VACV, EC50=0.19M, in vero cells) and in vivo (Mpox virus, 10mg/kg, mice, gastric gavage; Mpox virus, 200mg, human, oral). However, Brincidofovir still presents some adverse reactions such as gastrointestinal reactions and liver function injury. Apart from Brincidofovir, other compounds based on structural modifications of Cidofovir have been developed. For instance, NPP-669 is synthesized by linking a long-chain sulfonate to Cidofovir. This modification improves its solubility in water and affinity for lipid through alkyl chain modification. As a result, this structural modification enhances the metabolic stability and bioavailability while reducing nephrotoxicity. It has shown enhanced antiviral effectiveness in vitro (vaccinia, EC50=8.95M, in HFF cells) and in vivo (cytomegalovirus, 3mg/kg, mice, intraperitoneal injection). Ribavirin, a well-known nucleoside analog, blocks viral nucleotide synthesis and thus inhibits viral replication and transmission. It has broad-spectrum antiviral efficacy against various DNA and RNA viruses, including Mpox virus. Studies have shown that ribavirin can impede the replication of orthopoxviruses in vitro (Mpox virus, EC50=5.9g/mL, in Vero cells) and in vivo (cowpox virus, 50mg/kg, mice, subcutaneous injection). However, further clinical studies are needed to assess its effectiveness in Mpox patients are needed.
#28 Core Concepts – Mpox – Self-Study Lessons – National STD Curriculum
https://www.std.uw.edu/go/comprehensive-study/mpox/core-concept/all
The monkeypox virus, the causative agent of mpox disease, is a member of the Orthopoxvirus genus in the family Poxviridae. Orthopoxviruses are characterized by an ovoid brick-shaped morphology as seen on cryo-electron tomography. Monkeypox virus is 360 x 270 x 250 nm in size and contains linear double-stranded DNA of approximately 197 kilobases (kb). This genome encodes more than 200 proteins that are essential for the virus life cycle, virus assembly, and evasion of host immune defenses. Infectious monkeypox virus can exist in two distinct forms: extracellular enveloped virus (EEV, also abbreviated as EV) and intracellular mature virus (IMV, also abbreviated as MV) […] Monkeypox virus infects and replicates within host cells as follows: Virion Entry: Monkeypox virus can attach to and enter a host cell in the form of an extracellular enveloped virus (EEV) or a mature virus (MV). The entry and fusion of the MV envelope with the plasma or endocytic membrane involves multiple viral proteins. Early Transcription and Translation: Some monkeypox DNA is immediately transcribed and translated to produce early proteins, including growth factors, immune response modulators, and factors needed for DNA replication. This early step occurs in the host cell cytoplasm. Uncoating: After cell entry, the uncoating of the viral core occurs, with shedding of the outer membranes and release of the core into the cytoplasm. The uncoating of the core facilitates DNA replication. DNA Replication: Most of the monkeypox DNA replicates to form concatemeric DNA (long continuous DNA molecules that contain the same DNA sequence linked in series). This process occurs in a localized cytoplasmic region denoted as the viral factory. Intermediate Gene Transcription and Translation: Within the viral factory region, the newly replicated (progeny) monkeypox viral DNA can undergo intermediate transcription and translation, generating intermediate proteins that include transcription factors required for late transcription. In addition, late proteins are generated, with some contributing to the viral structure and others playing a role in early transcription and translation. Late Gene Transcription and Translation: Also, within the viral factory region, the progeny monkeypox viral DNA can undergo late transcription and translation, which produces late proteins, including some that contribute to the viral assembly process. Assembly: The monkeypox DNA is resolved into a single genome and packaged into the core along with proteins necessary for early transcription. Morphogenesis: The assembled core is moved out of the viral factory region, where it obtains an outer membrane and becomes a mature virus (MV). The MV generally remains trapped within the cell, except in the rare event of cell lysis. Wrapping: Some portion of the total virus particles produced is further wrapped by trans-Golgi/late endosomal double membranes to form the intracellular enveloped virus (IEV). During this process, the viral p37 protein interacts with the cellular proteins Rab9 GTPase and TIP47, which together stimulate the wrapping of the MV to form the IEV. Exocytosis: The IEV migrates to the cell periphery on microtubules and is released by exocytosis to become cell-associated enveloped virus (CEV). The CEV can infect neighboring cells. Approximately 1% of CEV are released into the extracellular space via motile actin tail formation to become extracellular enveloped virus (EEV). EEV are responsible for long-range dissemination of the virus.
#29 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
The DNA-dependent RNA polymerase (DdRp) plays a crucial role in catalyzing the replication process of DNA viruses in the cytoplasm. Due to its biological significance, DdRp is considered a potential therapeutic target for Mpox virus. Through computer modeling of DdRp, along with techniques such as molecular dynamics simulations, docking, and computational screening, potential inhibitors of DdRp can be efficiently identified. Several small molecule compounds with inhibitory activity against DdRp have been discovered through computer-assisted drug design. However, further researches are needed to validate these identified candidate compounds, evaluate their safety and effectiveness, and ultimately progress them to the clinical application stage. The endoplasmic reticulum (ER) plays a crucial role in enveloping and stabilizing the viral genome. Electron microscopy observations have shown that the replication factory is surrounded by a significant amount of ER membrane. The ER plays a key role in the synthesis of viral membrane proteins. Subsequently, these membrane proteins, together with other viral structure proteins, enter into the viral factory, encapsulate the core genes, forming crescent-shaped structures. Moreover, the presence of the ER is important for maintaining the stability of the viral genome. Studies have indicated that ionomycin disrupts the integrity of ER in vitro, resulting in the inability of ER membrane proteins to enclose the exposed genome. This exposure triggers an immune response, leading to the degradation of viral DNA and significantly impacting VACV DNA replication. This discovery highlights the essential role of the ER in maintaining Mpox virus genome stability and facilitating viral replication. Based on these findings, compounds that effectively inhibit the formation of ER membrane proteins could also serve as potential antiviral drugs against Mpox virus.
#30
https://journals.lww.com/imd/fulltext/2024/06000/from_entry_to_evasion__a_comprehensive_analysis_of.2.aspx
The entry-fusion processes of MPXV and VACV exhibit similarities owing to their substantial homology within the Poxviridae family. […] Upon binding, viruses penetrate the host cell either through fusion with the cellular membrane or via endocytosis. […] Replication of MPXV presents an intricate mechanism, yet it is frequently conjectured to mirror replication patterns observed in various other poxviruses. […] The DNA-dependent RNA polymerase enzyme of poxviruses is a critical factor that enables replication of the poxvirus within the cytoplasm. […] Recent investigations using small interfering RNA knockdown revealed a dependence on cellular DNA ligase I, which is utilized in the viral DNA factories located in the cytoplasm. […] Therefore, by inhibiting this factor, B1R kinase plays an important role in VACV DNA replication and escape from host immune responses.
#31 Mpox: a better understanding of tecovirimat resistance | Institut Pasteur
https://www.pasteur.fr/en/press-area/press-documents/mpox-better-understanding-tecovirimat-resistance
Previously, it had been observed that treatment-resistant mpox variants all had mutations in phospholipase F13, a key enzyme in the formation of the viral particle’s outer envelope. […] The hypothesis was therefore that tecovirimat interacts with the F13 enzyme to block infection, which is impossible when the F13 enzyme is mutated. […] „We have shown that tecovirimat acts as a kind of glue that binds two F13 phospholipases together, preventing it from fulfilling its role in spreading viral particles,” he says. […] This basic research has enabled us to explain the drugs mechanism of action, and to understand why variants carrying these mutations render antiviral treatment ineffective. […] This understanding is essential for the development of new therapeutic approaches effective across all mpox strains.
#32 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
The DNA-dependent RNA polymerase (DdRp) plays a crucial role in catalyzing the replication process of DNA viruses in the cytoplasm. Due to its biological significance, DdRp is considered a potential therapeutic target for Mpox virus. Through computer modeling of DdRp, along with techniques such as molecular dynamics simulations, docking, and computational screening, potential inhibitors of DdRp can be efficiently identified. Several small molecule compounds with inhibitory activity against DdRp have been discovered through computer-assisted drug design. However, further researches are needed to validate these identified candidate compounds, evaluate their safety and effectiveness, and ultimately progress them to the clinical application stage. The endoplasmic reticulum (ER) plays a crucial role in enveloping and stabilizing the viral genome. Electron microscopy observations have shown that the replication factory is surrounded by a significant amount of ER membrane. The ER plays a key role in the synthesis of viral membrane proteins. Subsequently, these membrane proteins, together with other viral structure proteins, enter into the viral factory, encapsulate the core genes, forming crescent-shaped structures. Moreover, the presence of the ER is important for maintaining the stability of the viral genome. Studies have indicated that ionomycin disrupts the integrity of ER in vitro, resulting in the inability of ER membrane proteins to enclose the exposed genome. This exposure triggers an immune response, leading to the degradation of viral DNA and significantly impacting VACV DNA replication. This discovery highlights the essential role of the ER in maintaining Mpox virus genome stability and facilitating viral replication. Based on these findings, compounds that effectively inhibit the formation of ER membrane proteins could also serve as potential antiviral drugs against Mpox virus.
#33 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
Within the replication factory, these crescent-shaped structures develop into ellipsoidal or spherical shapes, representing immature virion (IV) particles. IV particles undergo the proteolytic cleavage of several capsid proteins and the condensation of the core, resulting in the formation of mature virus particles known as IMV. These IMV are abundant within the host cells. As IMV proliferate, they cause the lysis of the host cells, subsequently releasing IMV viral particles. Additionally, a portion of the IMV exits the virus factory through the microtubule organizing center and becomes enveloped by the trans-Golgi network (TGN) or the nuclear membranes, forming intracellular enveloped virus (IEV). Compared to the single-layered membrane structure of IMV, IEV possesses a three-layered membrane structure. During the early stage of infection, a majority of IMV are enveloped to form IEV. However, in the later stages of infection, IMV become the predominant form, possibly due to the depletion of TGN and nuclear membranes. Once IEV reach the peripheral region of the cell, the viral envelope fuses with the host cell membrane, forming cell-associated enveloped viruses (CEV) through the process of exocytosis. Virus particles remaining on the surface of the host cell are referred to as CEV, whereas those released into the extracellular environment are referred to as EEV. The ratio of EEV to CEV depends on the specific virus strain and host cell type. While the mechanism by which EEV released from infected cells further infect neighboring cells is not fully understood, researchers have discovered that the actin tails can form and extend a long distance outside the cell. EEV can utilize actin tails to enter adjacent cells, establishing bridges between the actin tails and neighboring cells, thereby facilitating efficient viral spread. In order to reach the cellular plasma membrane, the release of viruses requires the involvement of the actin cytoskeleton. Currently, two mechanisms have been proposed to explain how IEV traverse the actin cytoskeleton. The first mechanism is actin polymerization-induced assembly. Upon viral infection, host cells trigger the polymerization of actin, resulting in the formation of filamentous structures known as actin tails. Failure to form actin tails hinders virus migration, adhesion, and intercellular spread. Several studies suggest that tyrosine phosphorylation plays a pivotal role in the formation of actin tails. The second mechanism is microtubule transport. IEV reach the cell surface through microtubule-mediated transport. Studies conducted by Hollinshead et al. observed the movement trajectory of viral particles labeled with green fluorescent protein. They found that viral particles co-localized with microtubules and exhibited an average velocity of 60m/min, consistent with the speed of microtubule transport. This speed far exceeds the transport rate of actin tails. The movement of viral particles to the cell surface can be hampered by the microtubule-depolymerizing drug nocodazole in vitro. Based on this evidence, it is evident that microtubule transport plays a crucial role in the externalization of IEV to the cell surface. Disruption of microtubule structures may contribute to reducing the export of virus particles and inhibiting the spread of infection.
#34 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
Within the replication factory, these crescent-shaped structures develop into ellipsoidal or spherical shapes, representing immature virion (IV) particles. IV particles undergo the proteolytic cleavage of several capsid proteins and the condensation of the core, resulting in the formation of mature virus particles known as IMV. These IMV are abundant within the host cells. As IMV proliferate, they cause the lysis of the host cells, subsequently releasing IMV viral particles. Additionally, a portion of the IMV exits the virus factory through the microtubule organizing center and becomes enveloped by the trans-Golgi network (TGN) or the nuclear membranes, forming intracellular enveloped virus (IEV). Compared to the single-layered membrane structure of IMV, IEV possesses a three-layered membrane structure. During the early stage of infection, a majority of IMV are enveloped to form IEV. However, in the later stages of infection, IMV become the predominant form, possibly due to the depletion of TGN and nuclear membranes. Once IEV reach the peripheral region of the cell, the viral envelope fuses with the host cell membrane, forming cell-associated enveloped viruses (CEV) through the process of exocytosis. Virus particles remaining on the surface of the host cell are referred to as CEV, whereas those released into the extracellular environment are referred to as EEV. The ratio of EEV to CEV depends on the specific virus strain and host cell type. While the mechanism by which EEV released from infected cells further infect neighboring cells is not fully understood, researchers have discovered that the actin tails can form and extend a long distance outside the cell. EEV can utilize actin tails to enter adjacent cells, establishing bridges between the actin tails and neighboring cells, thereby facilitating efficient viral spread. In order to reach the cellular plasma membrane, the release of viruses requires the involvement of the actin cytoskeleton. Currently, two mechanisms have been proposed to explain how IEV traverse the actin cytoskeleton. The first mechanism is actin polymerization-induced assembly. Upon viral infection, host cells trigger the polymerization of actin, resulting in the formation of filamentous structures known as actin tails. Failure to form actin tails hinders virus migration, adhesion, and intercellular spread. Several studies suggest that tyrosine phosphorylation plays a pivotal role in the formation of actin tails. The second mechanism is microtubule transport. IEV reach the cell surface through microtubule-mediated transport. Studies conducted by Hollinshead et al. observed the movement trajectory of viral particles labeled with green fluorescent protein. They found that viral particles co-localized with microtubules and exhibited an average velocity of 60m/min, consistent with the speed of microtubule transport. This speed far exceeds the transport rate of actin tails. The movement of viral particles to the cell surface can be hampered by the microtubule-depolymerizing drug nocodazole in vitro. Based on this evidence, it is evident that microtubule transport plays a crucial role in the externalization of IEV to the cell surface. Disruption of microtubule structures may contribute to reducing the export of virus particles and inhibiting the spread of infection.
#35 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
Within the replication factory, these crescent-shaped structures develop into ellipsoidal or spherical shapes, representing immature virion (IV) particles. IV particles undergo the proteolytic cleavage of several capsid proteins and the condensation of the core, resulting in the formation of mature virus particles known as IMV. These IMV are abundant within the host cells. As IMV proliferate, they cause the lysis of the host cells, subsequently releasing IMV viral particles. Additionally, a portion of the IMV exits the virus factory through the microtubule organizing center and becomes enveloped by the trans-Golgi network (TGN) or the nuclear membranes, forming intracellular enveloped virus (IEV). Compared to the single-layered membrane structure of IMV, IEV possesses a three-layered membrane structure. During the early stage of infection, a majority of IMV are enveloped to form IEV. However, in the later stages of infection, IMV become the predominant form, possibly due to the depletion of TGN and nuclear membranes. Once IEV reach the peripheral region of the cell, the viral envelope fuses with the host cell membrane, forming cell-associated enveloped viruses (CEV) through the process of exocytosis. Virus particles remaining on the surface of the host cell are referred to as CEV, whereas those released into the extracellular environment are referred to as EEV. The ratio of EEV to CEV depends on the specific virus strain and host cell type. While the mechanism by which EEV released from infected cells further infect neighboring cells is not fully understood, researchers have discovered that the actin tails can form and extend a long distance outside the cell. EEV can utilize actin tails to enter adjacent cells, establishing bridges between the actin tails and neighboring cells, thereby facilitating efficient viral spread. In order to reach the cellular plasma membrane, the release of viruses requires the involvement of the actin cytoskeleton. Currently, two mechanisms have been proposed to explain how IEV traverse the actin cytoskeleton. The first mechanism is actin polymerization-induced assembly. Upon viral infection, host cells trigger the polymerization of actin, resulting in the formation of filamentous structures known as actin tails. Failure to form actin tails hinders virus migration, adhesion, and intercellular spread. Several studies suggest that tyrosine phosphorylation plays a pivotal role in the formation of actin tails. The second mechanism is microtubule transport. IEV reach the cell surface through microtubule-mediated transport. Studies conducted by Hollinshead et al. observed the movement trajectory of viral particles labeled with green fluorescent protein. They found that viral particles co-localized with microtubules and exhibited an average velocity of 60m/min, consistent with the speed of microtubule transport. This speed far exceeds the transport rate of actin tails. The movement of viral particles to the cell surface can be hampered by the microtubule-depolymerizing drug nocodazole in vitro. Based on this evidence, it is evident that microtubule transport plays a crucial role in the externalization of IEV to the cell surface. Disruption of microtubule structures may contribute to reducing the export of virus particles and inhibiting the spread of infection.
#36 Epidemiology, clinical manifestations, and diagnosis of mpox (formerly monkeypox) – UpToDate
https://www.uptodate.com/contents/epidemiology-clinical-manifestations-and-diagnosis-of-mpox-monkeypox
Using a nonhuman primate model of respiratory MPXV with histopathological examinations at several time points postchallenge, it was demonstrated that during the incubation period, the virus is first seen in respiratory bronchioles and alveoli in the lungs (postchallenge day 4). The virus then spreads to the regional lymph nodes and organs of the reticuloendothelial system (day 6), including the tonsils, spleen, liver, and colon, where it replicates. Virus was ultimately detected in the blood on day 8, and its concentration increased through day 10 along with widespread lesions in the skin. […] Immunology â Mpox infection stimulates an adaptative immune response comprising activated effector CD4+ and CD8+ T-cells; neutralizing antibodies (IgM and IgG); and the production of Th1-inflammatory cytokines (gamma interferon [IFN-Î³], IL-1ra, IL-6, IL-8, and TNF). These immune responses restrict viral replication and induce prolonged immunity in recovering patients. However, it is unknown whether the pauci-symptomatic or localized presentation seen in the multi-country outbreak compared to the disseminated presentation of mpox disease is associated with a lower degree of the immune response following infection.
#37 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
Mpox virus enters the human body through mucous membranes or compromised skin, resulting in infection of resident immune cells and antigen-presenting cells in the tissues. Subsequently, Mpox virus rapidly replicates in draining lymph nodes and disseminates through the lymphatic system, explaining the characteristic lymph node enlargement observed in Mpox virus infections. Innate immune cells act as the first line of defense against viral infections and are primary targets for viral assault. During the early stages of Mpox virus infection, monocytes are recruited to the infection site and become early targets for viral infection. The level of Mpox virus antigens detected in monocytes can serve as an indicator of infection severity and prognosis. Additionally, natural killer (NK) cells play a crucial role in generating a robust immune response following Mpox virus infection. Despite an increase in the abundance of NK cells in Mpox virus-infected individuals, their migration, degranulation, and effector molecule release capabilities are significantly impaired.
#38 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
The response of immune effector molecules during Mpox virus infection plays a crucial role in disease progression and severity. At the beginning of infection, the Mpox virus can suppress the expression of chemokines, resulting in a decrease in effector molecule expression like IFN- and TNF-. This inhibition in T-cell activation hinders the initiation of humoral immune response, allowing the virus to evade the immune system much easier. However, severe Mpox infection often leads to a cytokine storm in later stages. This results in an increase in Th2-associated cytokines and a decrease in Th1-associated cytokines, characterized by increased expression of IL-2, IL-4, and IL-8 and a reduction in TNF-, IL-2, and IL-12. By regulating these immune effectors, Mpox virus suppresses the antiviral immune response and disrupts the host immunity.
#39 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
The response of immune effector molecules during Mpox virus infection plays a crucial role in disease progression and severity. At the beginning of infection, the Mpox virus can suppress the expression of chemokines, resulting in a decrease in effector molecule expression like IFN- and TNF-. This inhibition in T-cell activation hinders the initiation of humoral immune response, allowing the virus to evade the immune system much easier. However, severe Mpox infection often leads to a cytokine storm in later stages. This results in an increase in Th2-associated cytokines and a decrease in Th1-associated cytokines, characterized by increased expression of IL-2, IL-4, and IL-8 and a reduction in TNF-, IL-2, and IL-12. By regulating these immune effectors, Mpox virus suppresses the antiviral immune response and disrupts the host immunity.
#40 Mpox: An Overview of Pathogenesis, Diagnosis, and – ProQuest
https://www.proquest.com/docview/3046919612?pq-origsite=primo
MPXV has evolved sophisticated strategies to evade immune detection and establish persistent infection within the host. These evasion tactics target various components of the host immune response, allowing the virus to subvert antiviral defenses and promote its survival and dissemination. One strategy employed by MPXV involves the modulation of host innate immune signaling pathways. Upon infection, the virus encodes a range of immunomodulatory proteins that interfere with the production and signaling of host antiviral cytokines, including interferons (IFNs) and proinflammatory cytokines. For instance, MPXV produces soluble cytokine decoy receptors, which competitively bind to host cytokines, preventing their interaction with cellular receptors and dampening the immune response. Additionally, the virus secretes proteins that disrupt downstream signaling pathways activated by cytokine receptor engagement, thereby inhibiting the expression of antiviral genes and promoting viral replication. Furthermore, MPXV can evade immune detection by modulating host cell signaling pathways involved in antigen presentation and recognition. The virus interferes with major histocompatibility complex (MHC) class I antigen presentation, either by downregulating MHC class I expression on infected cells or by inhibiting the processing and presentation of viral antigens. This impairs the recognition of infected cells by cytotoxic T lymphocytes (CTLs), allowing MPXV to evade immune surveillance and establish persistent infection. Moreover, MPXV can inhibit the expression of co-stimulatory molecules on antigen-presenting cells, impairing T cell activation and proliferation in response to viral antigens. Additionally, MPXV has evolved mechanisms to evade detection by the host adaptive immune system. The virus can undergo antigenic variation, generating diverse viral variants with altered antigenic profiles that evade recognition by neutralizing antibodies and T cells. This antigenic diversity enables MPXV to escape immune surveillance and persist in the host population. Furthermore, the virus can modulate the expression of viral antigens on the surface of infected cells, either by downregulating antigen presentation machinery or by masking antigenic epitopes with viral proteins. This reduces the susceptibility of infected cells to recognition and elimination by immune effectors, allowing MPXV to establish persistent infection within the host. Moreover, MPXV has developed mechanisms to evade host cell apoptosis, prolonging the survival of infected cells and facilitating viral replication and dissemination. The virus encodes proteins that inhibit apoptosis, either by interfering with the activation of proapoptotic signaling pathways or by directly blocking the execution of apoptotic cell death. This prolongs the lifespan of infected cells, allowing MPXV to replicate to high levels and spread to neighboring cells without triggering immune-mediated clearance. Overall, the evasion strategies employed by MPXV underscore the virus’s remarkable ability to subvert host immune defenses and establish persistent infection. Understanding the molecular mechanisms underlying immune evasion is crucial for the development of effective countermeasures against MPXV infection. By elucidating the interplay between the virus and the host immune system, researchers can identify novel targets for therapeutic intervention and devise strategies to enhance host immunity and control viral spread. Moreover, insights into MPXV immune evasion mechanisms may inform the design of next-generation vaccines capable of eliciting robust and durable immune responses against this emerging infectious disease. Continued research into the immunopathogenesis of MPXV infection will be essential for advancing our understanding of virus-host interactions and improving clinical outcomes for infected individuals.
#41 Plant-derived molecules in monkeypox management: insight and alternative therapeutic strategies | Beni-Suef University Journal of Basic and Applied Sciences | Full Text
https://bjbas.springeropen.com/articles/10.1186/s43088-025-00603-3
Additionally, research shows that antibodies directed against the L1R protein, found in the outer membrane of MV, can stop the virus from infecting cells, indicating that L1R may be involved in the initial stage of viral entry. […] MPXV primarily infects skin and mucosal cells, leading to lesions and systemic symptoms such as fever and lymphadenopathy. MPXV can modulate the immune response, affecting natural killer cells, macrophages, and cytokine production, which may contribute to severe disease in immunocompromised individuals. […] The MPXV strategies of immune evasion can be used in therapeutic and vaccine development by targeting either the viral protein used in the immune evasion or by enhancing the targeted host immune cells so that they can respond without interference. […] MPXV can hide their DNA molecules from cellular DNA sensors which hinder the activation of signal transduction pathways.
#42 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
Mpox virus infection induces immune responses while also regulating cellular signal transduction. One example is the presence of a Mpox virus-encoded Bcl-2-like protein, which regulates the intrinsic apoptotic pathway. Additionally, the SPI-2 protein, encoded by the B12R gene, inhibits both caspase-1 and caspase-8, thereby disrupting the pyroptosis or apoptosis pathway, respectively. However, active induction of pyroptosis can be achieved by using nigericin, an inflammasome activator and pyroptosis inducer, as a strategy against Mpox infection. The findings demonstrated that Nigericin effectively reduced the viral titers and showed a stronger antiviral effect and lower EC50 values compared to the control group treated with Cidofovir. Protein kinases play a key role in regulating signal transduction pathways. Raghav et al. conducted an analysis to explore the interactions between Mpox virus and host proteins in order to further investigate the defense mechanisms triggered by Mpox infection. Their findings show the important role of the mitogen-activated protein kinase (MAPK) signaling pathway in the response to Mpox infection. Inhibition of the thymidine kinase enzyme, which is activated by MAPK, led to a significant reduction in viral replication. This evidence supports the potential of targeted therapies against MAPK signaling pathway as a promising strategy to combat Mpox.
#43 Plant-derived molecules in monkeypox management: insight and alternative therapeutic strategies | Beni-Suef University Journal of Basic and Applied Sciences | Full Text
https://bjbas.springeropen.com/articles/10.1186/s43088-025-00603-3
MPXV is recognized for its ability to encode a multitude of viral proteins that play a crucial role in circumventing host immune responses. […] Another key strategy for MPXV to evade the immune system is by inhibiting the type I interferon response which is very important to the antiviral innate immunity. […] The virus produces proteins that block the activation of interferon-stimulating genes (ISGs) while targeting signaling molecules such as STAT1 and STAT2, which are crucial for IFN-mediated antiviral response; therefore, the innate immune response becomes weak in the early stage of the infection and allows the virus to replicate freely. […] The MPXV M2 protein interacts with human B7.1 and B7.2 and prevents the binding of CD28 and CTLA4 to their ligand B7.1/2, respectively, which affects the activation and proliferation of T cells.
#44 Plant-derived molecules in monkeypox management: insight and alternative therapeutic strategies | Beni-Suef University Journal of Basic and Applied Sciences | Full Text
https://bjbas.springeropen.com/articles/10.1186/s43088-025-00603-3
MPXV is recognized for its ability to encode a multitude of viral proteins that play a crucial role in circumventing host immune responses. […] Another key strategy for MPXV to evade the immune system is by inhibiting the type I interferon response which is very important to the antiviral innate immunity. […] The virus produces proteins that block the activation of interferon-stimulating genes (ISGs) while targeting signaling molecules such as STAT1 and STAT2, which are crucial for IFN-mediated antiviral response; therefore, the innate immune response becomes weak in the early stage of the infection and allows the virus to replicate freely. […] The MPXV M2 protein interacts with human B7.1 and B7.2 and prevents the binding of CD28 and CTLA4 to their ligand B7.1/2, respectively, which affects the activation and proliferation of T cells.
#45 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
Mpox virus, a member of the genus orthopoxvirus in the family Poxviridae, is characterized by its brick-shaped or oval morphology with a diameter of ~200-250nm. Its genome consists of a linear, double-stranded DNA with a length of ~197kb and encoding about 180 proteins. Additionally, Mpox virus possesses dumbbell-shaped nucleocapsid enveloped by ovoid lipid-containing particles. The genomic structure of Mpox virus closely resembles that of other orthopoxviruses, characterized by a highly conserved central core region, variable regions at the left and right ends, and a tandemly repeated inverted terminal repeat. The central core region of Mpox virus shares more than 90% sequence homology with other orthopoxviruses, particularly within the open reading frame (ORF) located between C10L and A25R. Species and strain-specific characteristics of orthopoxviruses are often found in the variable regions at the ends of the genome. A better understanding about these ORFs may provide insights into its host tropism, pathogenesis, and differences in immune regulation. Based on a genomic and phylogenetic analysis conducted in 2022, the prevalent strain of Mpox virus was identified as belonging to the B.1 lineage of the West African clade. The B.1 lineage exhibits multiple mutations in genes associated with virulence, host recognition, and immune evasion. In comparison to previously obtained complete genome sequences of Mpox virus isolated in Nigeria from 2017 to 2018, the Mpox virus strains that emerged in 2022 exhibited a higher number of single nucleotide polymorphisms (SNPs). The Mpox virus strain isolated in 2022 exhibit ~50 SNPs, indicating an approximately 6-12-fold increase in the predicted substitution rate of Mpox virus compared to the strains isolated from 2018-2019. The functional significance of these mutations is yet to be fully understood, but this high mutation rate may help explain the sudden appearance and heightened transmissibility of Mpox virus in non-endemic regions.
#46 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
Mpox virus, a member of the genus orthopoxvirus in the family Poxviridae, is characterized by its brick-shaped or oval morphology with a diameter of ~200-250nm. Its genome consists of a linear, double-stranded DNA with a length of ~197kb and encoding about 180 proteins. Additionally, Mpox virus possesses dumbbell-shaped nucleocapsid enveloped by ovoid lipid-containing particles. The genomic structure of Mpox virus closely resembles that of other orthopoxviruses, characterized by a highly conserved central core region, variable regions at the left and right ends, and a tandemly repeated inverted terminal repeat. The central core region of Mpox virus shares more than 90% sequence homology with other orthopoxviruses, particularly within the open reading frame (ORF) located between C10L and A25R. Species and strain-specific characteristics of orthopoxviruses are often found in the variable regions at the ends of the genome. A better understanding about these ORFs may provide insights into its host tropism, pathogenesis, and differences in immune regulation. Based on a genomic and phylogenetic analysis conducted in 2022, the prevalent strain of Mpox virus was identified as belonging to the B.1 lineage of the West African clade. The B.1 lineage exhibits multiple mutations in genes associated with virulence, host recognition, and immune evasion. In comparison to previously obtained complete genome sequences of Mpox virus isolated in Nigeria from 2017 to 2018, the Mpox virus strains that emerged in 2022 exhibited a higher number of single nucleotide polymorphisms (SNPs). The Mpox virus strain isolated in 2022 exhibit ~50 SNPs, indicating an approximately 6-12-fold increase in the predicted substitution rate of Mpox virus compared to the strains isolated from 2018-2019. The functional significance of these mutations is yet to be fully understood, but this high mutation rate may help explain the sudden appearance and heightened transmissibility of Mpox virus in non-endemic regions.
#47 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
Mpox virus, a member of the genus orthopoxvirus in the family Poxviridae, is characterized by its brick-shaped or oval morphology with a diameter of ~200-250nm. Its genome consists of a linear, double-stranded DNA with a length of ~197kb and encoding about 180 proteins. Additionally, Mpox virus possesses dumbbell-shaped nucleocapsid enveloped by ovoid lipid-containing particles. The genomic structure of Mpox virus closely resembles that of other orthopoxviruses, characterized by a highly conserved central core region, variable regions at the left and right ends, and a tandemly repeated inverted terminal repeat. The central core region of Mpox virus shares more than 90% sequence homology with other orthopoxviruses, particularly within the open reading frame (ORF) located between C10L and A25R. Species and strain-specific characteristics of orthopoxviruses are often found in the variable regions at the ends of the genome. A better understanding about these ORFs may provide insights into its host tropism, pathogenesis, and differences in immune regulation. Based on a genomic and phylogenetic analysis conducted in 2022, the prevalent strain of Mpox virus was identified as belonging to the B.1 lineage of the West African clade. The B.1 lineage exhibits multiple mutations in genes associated with virulence, host recognition, and immune evasion. In comparison to previously obtained complete genome sequences of Mpox virus isolated in Nigeria from 2017 to 2018, the Mpox virus strains that emerged in 2022 exhibited a higher number of single nucleotide polymorphisms (SNPs). The Mpox virus strain isolated in 2022 exhibit ~50 SNPs, indicating an approximately 6-12-fold increase in the predicted substitution rate of Mpox virus compared to the strains isolated from 2018-2019. The functional significance of these mutations is yet to be fully understood, but this high mutation rate may help explain the sudden appearance and heightened transmissibility of Mpox virus in non-endemic regions.
#48 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
Mpox virus, a member of the genus orthopoxvirus in the family Poxviridae, is characterized by its brick-shaped or oval morphology with a diameter of ~200-250nm. Its genome consists of a linear, double-stranded DNA with a length of ~197kb and encoding about 180 proteins. Additionally, Mpox virus possesses dumbbell-shaped nucleocapsid enveloped by ovoid lipid-containing particles. The genomic structure of Mpox virus closely resembles that of other orthopoxviruses, characterized by a highly conserved central core region, variable regions at the left and right ends, and a tandemly repeated inverted terminal repeat. The central core region of Mpox virus shares more than 90% sequence homology with other orthopoxviruses, particularly within the open reading frame (ORF) located between C10L and A25R. Species and strain-specific characteristics of orthopoxviruses are often found in the variable regions at the ends of the genome. A better understanding about these ORFs may provide insights into its host tropism, pathogenesis, and differences in immune regulation. Based on a genomic and phylogenetic analysis conducted in 2022, the prevalent strain of Mpox virus was identified as belonging to the B.1 lineage of the West African clade. The B.1 lineage exhibits multiple mutations in genes associated with virulence, host recognition, and immune evasion. In comparison to previously obtained complete genome sequences of Mpox virus isolated in Nigeria from 2017 to 2018, the Mpox virus strains that emerged in 2022 exhibited a higher number of single nucleotide polymorphisms (SNPs). The Mpox virus strain isolated in 2022 exhibit ~50 SNPs, indicating an approximately 6-12-fold increase in the predicted substitution rate of Mpox virus compared to the strains isolated from 2018-2019. The functional significance of these mutations is yet to be fully understood, but this high mutation rate may help explain the sudden appearance and heightened transmissibility of Mpox virus in non-endemic regions.
#49 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
Mpox is a self-limiting disease, and the severity of infection can be influenced by various factors, such as the specific viral strain, individual immune status, and potential complications that may arise. Common early symptoms of Mpox virus infection include pain, fever, fatigue, and lymphadenectasis, with significant inguinal lymphadenectasis often observed. The presence of lymphadenectasis can help to distinguish Mpox virus infection from other orthopoxviruses infection. Furthermore, understanding the transmission mode is essential in establishing effective measures to combat Mpox. Following exposure to the respiratory secretions or body fluids of Mpox patients, the Mpox virus enters nearby tissues through mucous membranes (such as ocular, respiratory, oral, urethral, and rectal) or broken skin. It then spreads throughout the body via tissue-resident immune cells and draining lymph nodes. This constitutes the latent period for Mpox virus infection, which typically lasts up to two weeks. Throughout this period, individuals infected with Mpox are generally asymptomatic and devoid of lesions. Following the latent period, individuals infected with Mpox virus begin to exhibit atypical symptoms, including fever and chills, headache, muscle pain, and lymphadenectasis. These initial prodromal symptoms of Mpox typically last for three days. After the fever and lymphadenectasis, rashes begin to appear on the head and face, and gradually spread throughout the body. The rash evolves from papules to vesicles and pustules, and ultimately forming crusts that heal, leaving behind scars. This progressive rash phase lasts about 2-4 weeks. In the current outbreak of Mpox among men who have sex with men (MSM), some unusual clinical signs have been observed with rashes appearing primarily around the genital or anal area and subsequently spreading throughout the body. Severe cases of Mpox virus infection can lead to complications such as hemorrhagic disease, necrotic disease, obstructive disease, inflammation of vital organs, and septicemia. The case fatality rate of Mpox in non-epidemic regions during 2022 was ~0.04%. Immunocompromised individuals, including children, older adults, and those with immunodeficiencies (such as HIV patients and individuals using immunosuppressive medications), are more susceptible to experiencing these severe manifestations. In addition, immunocompromised individuals are more likely to contribute to the evolution of Mpox, making it increasingly adaptable to human hosts and resulting in widespread transmission.
#50 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
Mpox is a self-limiting disease, and the severity of infection can be influenced by various factors, such as the specific viral strain, individual immune status, and potential complications that may arise. Common early symptoms of Mpox virus infection include pain, fever, fatigue, and lymphadenectasis, with significant inguinal lymphadenectasis often observed. The presence of lymphadenectasis can help to distinguish Mpox virus infection from other orthopoxviruses infection. Furthermore, understanding the transmission mode is essential in establishing effective measures to combat Mpox. Following exposure to the respiratory secretions or body fluids of Mpox patients, the Mpox virus enters nearby tissues through mucous membranes (such as ocular, respiratory, oral, urethral, and rectal) or broken skin. It then spreads throughout the body via tissue-resident immune cells and draining lymph nodes. This constitutes the latent period for Mpox virus infection, which typically lasts up to two weeks. Throughout this period, individuals infected with Mpox are generally asymptomatic and devoid of lesions. Following the latent period, individuals infected with Mpox virus begin to exhibit atypical symptoms, including fever and chills, headache, muscle pain, and lymphadenectasis. These initial prodromal symptoms of Mpox typically last for three days. After the fever and lymphadenectasis, rashes begin to appear on the head and face, and gradually spread throughout the body. The rash evolves from papules to vesicles and pustules, and ultimately forming crusts that heal, leaving behind scars. This progressive rash phase lasts about 2-4 weeks. In the current outbreak of Mpox among men who have sex with men (MSM), some unusual clinical signs have been observed with rashes appearing primarily around the genital or anal area and subsequently spreading throughout the body. Severe cases of Mpox virus infection can lead to complications such as hemorrhagic disease, necrotic disease, obstructive disease, inflammation of vital organs, and septicemia. The case fatality rate of Mpox in non-epidemic regions during 2022 was ~0.04%. Immunocompromised individuals, including children, older adults, and those with immunodeficiencies (such as HIV patients and individuals using immunosuppressive medications), are more susceptible to experiencing these severe manifestations. In addition, immunocompromised individuals are more likely to contribute to the evolution of Mpox, making it increasingly adaptable to human hosts and resulting in widespread transmission.
#51 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
Mpox is a self-limiting disease, and the severity of infection can be influenced by various factors, such as the specific viral strain, individual immune status, and potential complications that may arise. Common early symptoms of Mpox virus infection include pain, fever, fatigue, and lymphadenectasis, with significant inguinal lymphadenectasis often observed. The presence of lymphadenectasis can help to distinguish Mpox virus infection from other orthopoxviruses infection. Furthermore, understanding the transmission mode is essential in establishing effective measures to combat Mpox. Following exposure to the respiratory secretions or body fluids of Mpox patients, the Mpox virus enters nearby tissues through mucous membranes (such as ocular, respiratory, oral, urethral, and rectal) or broken skin. It then spreads throughout the body via tissue-resident immune cells and draining lymph nodes. This constitutes the latent period for Mpox virus infection, which typically lasts up to two weeks. Throughout this period, individuals infected with Mpox are generally asymptomatic and devoid of lesions. Following the latent period, individuals infected with Mpox virus begin to exhibit atypical symptoms, including fever and chills, headache, muscle pain, and lymphadenectasis. These initial prodromal symptoms of Mpox typically last for three days. After the fever and lymphadenectasis, rashes begin to appear on the head and face, and gradually spread throughout the body. The rash evolves from papules to vesicles and pustules, and ultimately forming crusts that heal, leaving behind scars. This progressive rash phase lasts about 2-4 weeks. In the current outbreak of Mpox among men who have sex with men (MSM), some unusual clinical signs have been observed with rashes appearing primarily around the genital or anal area and subsequently spreading throughout the body. Severe cases of Mpox virus infection can lead to complications such as hemorrhagic disease, necrotic disease, obstructive disease, inflammation of vital organs, and septicemia. The case fatality rate of Mpox in non-epidemic regions during 2022 was ~0.04%. Immunocompromised individuals, including children, older adults, and those with immunodeficiencies (such as HIV patients and individuals using immunosuppressive medications), are more susceptible to experiencing these severe manifestations. In addition, immunocompromised individuals are more likely to contribute to the evolution of Mpox, making it increasingly adaptable to human hosts and resulting in widespread transmission.
#52 Factsheet for health professionals on mpox
https://www.ecdc.europa.eu/en/all-topics-z/monkeypox/factsheet-health-professionals
However, in PLWHA with CD4 cell counts of 100 cells per mm, severe complications were more common than in those with CD4 cell counts between 300 and 350 cells per mm, including necrotising skin lesions, lung involvement and secondary infections with sepsis. […] Emerging evidence indicates that infected people may transit MPXV up to four days prior to symptom onset. […] The infectious period lasts until all skin lesions have scabbed over and re-epithelialisation has occurred. […] Asymptomatic mpox infections have been reported as well.
#53 Clinical Treatment of Mpox | Mpox | CDC
https://www.cdc.gov/mpox/hcp/clinical-care/index.html
People with advanced HIV who contract MPXV have an increased risk of severe manifestations of mpox and mortality from mpox. […] The goal of the study is to determine why some patients experience severe mpox manifestations and to increase understanding of mpox pathogenesis.
#54 Pathogenicity and virulence of monkeypox at the human-animal-ecology interface
https://pmc.ncbi.nlm.nih.gov/articles/PMC10012937/
Monkeypox (Mpox) was mostly limited to Central and Western Africa, but recently it has been reported globally. […] The origin, reservoir(s) and the sylvatic cycle of the virus in the natural ecosystem are yet to be confirmed. […] The major drivers of disease transmission include trapping, hunting, bushmeat consumption, animal trade, and travel to endemic countries. […] However, in the 2022 epidemic, the majority of the infected humans in non-endemic countries had a history of direct contact with clinical or asymptomatic persons through sexual activity. […] The prevention and control strategies should include deterring misinformation and stigma, promoting appropriate social and behavioural changes, including healthy life practices, instituting contact tracing and management, and using the smallpox vaccine for high-risk people.
#55 Pathogenicity and virulence of monkeypox at the human-animal-ecology interface
https://pmc.ncbi.nlm.nih.gov/articles/PMC10012937/
Monkeypox (Mpox) was mostly limited to Central and Western Africa, but recently it has been reported globally. […] The origin, reservoir(s) and the sylvatic cycle of the virus in the natural ecosystem are yet to be confirmed. […] The major drivers of disease transmission include trapping, hunting, bushmeat consumption, animal trade, and travel to endemic countries. […] However, in the 2022 epidemic, the majority of the infected humans in non-endemic countries had a history of direct contact with clinical or asymptomatic persons through sexual activity. […] The prevention and control strategies should include deterring misinformation and stigma, promoting appropriate social and behavioural changes, including healthy life practices, instituting contact tracing and management, and using the smallpox vaccine for high-risk people.
#56 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
With the global cessation of smallpox vaccination administration, the proportion of individuals with cross-immune protection against Mpox virus has rapidly declined, rendering Mpox a potential bioterrorism threat. While a few anti-Mpox drugs, such as Tecovirimat, have been clinically proven to be effective, relying solely on them would be unwise. Despite Mpox virus belonging to the DNA virus family, it exhibits significantly higher genomic variability due to increased nucleotide polymorphism. The rapid population mobility and increased international travel have facilitated the continuous spread of Mpox virus among populations, further increasing its potential for mutation. These factors contribute to increased variability, drug resistance, and the emergence of multidrug-resistant strains of Mpox virus. Moreover, currently available drugs face certain limitations that impede their clinical applications. For example, Cidofovir has low bioavailability and carries the risk of renal damage, while Cidofovir and Brincidofovir pose potential threats to hematopoietic and liver functions. There is an urgent need to develop novel anti-Mpox virus drugs.
#57 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
After IMV or EEV enter the host cell, the exposed viral core is transported to the periphery of the cell nucleus through microtubule structures at an average speed of 52m/min. The viral core consists of the central viral genome and an enveloped nucleocapsid. The mechanism of nucleocapsid uncoating involves ubiquitination of the nuclear capsid proteins and degradation by proteasomes. Once uncoating is completed, the Mpox virus genome begins efficient replication, rapidly amplifying like a factory. Currently, researchers are devoted to developing anti-Mpox drugs by interfering with the DNA or RNA synthesis of the viral genome. Nucleoside analogs are chemical compounds that have a similar structure to naturally occurring nucleosides. These drugs competitively bind to the viral DNA or RNA polymerase, disrupting the replication process by causing termination of the DNA or RNA chain synthesis. Due to their ability to inhibit viral replication, these drugs often exhibit broad-spectrum antiviral activity. Cidofovir, a non-cyclic monophosphate nucleoside analog, can be used for the treatment of orthopoxviruses and demonstrate potent antiviral activity in vitro (Mpox virus, effective concentration half maximal (EC50)=2.52g/mL, Selectivity index (SI)=15, in human embryonic lung fibroblasts) and in vivo (Mpox virus, 5mg/kg, cynomolgus macaques, intraperitoneal injection; Mpox virus, 5mg/kg, human, intravenous). Following the Mpox outbreak in 2022, Cidofovir was rapidly employed in clinical trials for the treatment of Mpox. However, Cidofovir is a divalent anion with low bioavailability. In patients with impaired renal function or undergoing renal replacement therapy, its metabolites can accumulate in proximal renal tubular cells, leading to kidney damage. In order to overcome the limitations of Cidofovir, its derivative Brincidofovir has been developed. Brincidofovir has been modified using lipid conjugation technology, resulting in improved cellular uptake and conversion capabilities, it was approved by the FDA in 2021 for the treatment of smallpox. Unlike Cidofovir, Brincidofovir does not require metabolism through the renal anion transport system, thus exhibiting higher bioavailability and no significant nephrotoxicity in vitro (VACV, EC50=0.19M, in vero cells) and in vivo (Mpox virus, 10mg/kg, mice, gastric gavage; Mpox virus, 200mg, human, oral). However, Brincidofovir still presents some adverse reactions such as gastrointestinal reactions and liver function injury. Apart from Brincidofovir, other compounds based on structural modifications of Cidofovir have been developed. For instance, NPP-669 is synthesized by linking a long-chain sulfonate to Cidofovir. This modification improves its solubility in water and affinity for lipid through alkyl chain modification. As a result, this structural modification enhances the metabolic stability and bioavailability while reducing nephrotoxicity. It has shown enhanced antiviral effectiveness in vitro (vaccinia, EC50=8.95M, in HFF cells) and in vivo (cytomegalovirus, 3mg/kg, mice, intraperitoneal injection). Ribavirin, a well-known nucleoside analog, blocks viral nucleotide synthesis and thus inhibits viral replication and transmission. It has broad-spectrum antiviral efficacy against various DNA and RNA viruses, including Mpox virus. Studies have shown that ribavirin can impede the replication of orthopoxviruses in vitro (Mpox virus, EC50=5.9g/mL, in Vero cells) and in vivo (cowpox virus, 50mg/kg, mice, subcutaneous injection). However, further clinical studies are needed to assess its effectiveness in Mpox patients are needed.
#58 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
After IMV or EEV enter the host cell, the exposed viral core is transported to the periphery of the cell nucleus through microtubule structures at an average speed of 52m/min. The viral core consists of the central viral genome and an enveloped nucleocapsid. The mechanism of nucleocapsid uncoating involves ubiquitination of the nuclear capsid proteins and degradation by proteasomes. Once uncoating is completed, the Mpox virus genome begins efficient replication, rapidly amplifying like a factory. Currently, researchers are devoted to developing anti-Mpox drugs by interfering with the DNA or RNA synthesis of the viral genome. Nucleoside analogs are chemical compounds that have a similar structure to naturally occurring nucleosides. These drugs competitively bind to the viral DNA or RNA polymerase, disrupting the replication process by causing termination of the DNA or RNA chain synthesis. Due to their ability to inhibit viral replication, these drugs often exhibit broad-spectrum antiviral activity. Cidofovir, a non-cyclic monophosphate nucleoside analog, can be used for the treatment of orthopoxviruses and demonstrate potent antiviral activity in vitro (Mpox virus, effective concentration half maximal (EC50)=2.52g/mL, Selectivity index (SI)=15, in human embryonic lung fibroblasts) and in vivo (Mpox virus, 5mg/kg, cynomolgus macaques, intraperitoneal injection; Mpox virus, 5mg/kg, human, intravenous). Following the Mpox outbreak in 2022, Cidofovir was rapidly employed in clinical trials for the treatment of Mpox. However, Cidofovir is a divalent anion with low bioavailability. In patients with impaired renal function or undergoing renal replacement therapy, its metabolites can accumulate in proximal renal tubular cells, leading to kidney damage. In order to overcome the limitations of Cidofovir, its derivative Brincidofovir has been developed. Brincidofovir has been modified using lipid conjugation technology, resulting in improved cellular uptake and conversion capabilities, it was approved by the FDA in 2021 for the treatment of smallpox. Unlike Cidofovir, Brincidofovir does not require metabolism through the renal anion transport system, thus exhibiting higher bioavailability and no significant nephrotoxicity in vitro (VACV, EC50=0.19M, in vero cells) and in vivo (Mpox virus, 10mg/kg, mice, gastric gavage; Mpox virus, 200mg, human, oral). However, Brincidofovir still presents some adverse reactions such as gastrointestinal reactions and liver function injury. Apart from Brincidofovir, other compounds based on structural modifications of Cidofovir have been developed. For instance, NPP-669 is synthesized by linking a long-chain sulfonate to Cidofovir. This modification improves its solubility in water and affinity for lipid through alkyl chain modification. As a result, this structural modification enhances the metabolic stability and bioavailability while reducing nephrotoxicity. It has shown enhanced antiviral effectiveness in vitro (vaccinia, EC50=8.95M, in HFF cells) and in vivo (cytomegalovirus, 3mg/kg, mice, intraperitoneal injection). Ribavirin, a well-known nucleoside analog, blocks viral nucleotide synthesis and thus inhibits viral replication and transmission. It has broad-spectrum antiviral efficacy against various DNA and RNA viruses, including Mpox virus. Studies have shown that ribavirin can impede the replication of orthopoxviruses in vitro (Mpox virus, EC50=5.9g/mL, in Vero cells) and in vivo (cowpox virus, 50mg/kg, mice, subcutaneous injection). However, further clinical studies are needed to assess its effectiveness in Mpox patients are needed.
#59 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
After IMV or EEV enter the host cell, the exposed viral core is transported to the periphery of the cell nucleus through microtubule structures at an average speed of 52m/min. The viral core consists of the central viral genome and an enveloped nucleocapsid. The mechanism of nucleocapsid uncoating involves ubiquitination of the nuclear capsid proteins and degradation by proteasomes. Once uncoating is completed, the Mpox virus genome begins efficient replication, rapidly amplifying like a factory. Currently, researchers are devoted to developing anti-Mpox drugs by interfering with the DNA or RNA synthesis of the viral genome. Nucleoside analogs are chemical compounds that have a similar structure to naturally occurring nucleosides. These drugs competitively bind to the viral DNA or RNA polymerase, disrupting the replication process by causing termination of the DNA or RNA chain synthesis. Due to their ability to inhibit viral replication, these drugs often exhibit broad-spectrum antiviral activity. Cidofovir, a non-cyclic monophosphate nucleoside analog, can be used for the treatment of orthopoxviruses and demonstrate potent antiviral activity in vitro (Mpox virus, effective concentration half maximal (EC50)=2.52g/mL, Selectivity index (SI)=15, in human embryonic lung fibroblasts) and in vivo (Mpox virus, 5mg/kg, cynomolgus macaques, intraperitoneal injection; Mpox virus, 5mg/kg, human, intravenous). Following the Mpox outbreak in 2022, Cidofovir was rapidly employed in clinical trials for the treatment of Mpox. However, Cidofovir is a divalent anion with low bioavailability. In patients with impaired renal function or undergoing renal replacement therapy, its metabolites can accumulate in proximal renal tubular cells, leading to kidney damage. In order to overcome the limitations of Cidofovir, its derivative Brincidofovir has been developed. Brincidofovir has been modified using lipid conjugation technology, resulting in improved cellular uptake and conversion capabilities, it was approved by the FDA in 2021 for the treatment of smallpox. Unlike Cidofovir, Brincidofovir does not require metabolism through the renal anion transport system, thus exhibiting higher bioavailability and no significant nephrotoxicity in vitro (VACV, EC50=0.19M, in vero cells) and in vivo (Mpox virus, 10mg/kg, mice, gastric gavage; Mpox virus, 200mg, human, oral). However, Brincidofovir still presents some adverse reactions such as gastrointestinal reactions and liver function injury. Apart from Brincidofovir, other compounds based on structural modifications of Cidofovir have been developed. For instance, NPP-669 is synthesized by linking a long-chain sulfonate to Cidofovir. This modification improves its solubility in water and affinity for lipid through alkyl chain modification. As a result, this structural modification enhances the metabolic stability and bioavailability while reducing nephrotoxicity. It has shown enhanced antiviral effectiveness in vitro (vaccinia, EC50=8.95M, in HFF cells) and in vivo (cytomegalovirus, 3mg/kg, mice, intraperitoneal injection). Ribavirin, a well-known nucleoside analog, blocks viral nucleotide synthesis and thus inhibits viral replication and transmission. It has broad-spectrum antiviral efficacy against various DNA and RNA viruses, including Mpox virus. Studies have shown that ribavirin can impede the replication of orthopoxviruses in vitro (Mpox virus, EC50=5.9g/mL, in Vero cells) and in vivo (cowpox virus, 50mg/kg, mice, subcutaneous injection). However, further clinical studies are needed to assess its effectiveness in Mpox patients are needed.
#60 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
After IMV or EEV enter the host cell, the exposed viral core is transported to the periphery of the cell nucleus through microtubule structures at an average speed of 52m/min. The viral core consists of the central viral genome and an enveloped nucleocapsid. The mechanism of nucleocapsid uncoating involves ubiquitination of the nuclear capsid proteins and degradation by proteasomes. Once uncoating is completed, the Mpox virus genome begins efficient replication, rapidly amplifying like a factory. Currently, researchers are devoted to developing anti-Mpox drugs by interfering with the DNA or RNA synthesis of the viral genome. Nucleoside analogs are chemical compounds that have a similar structure to naturally occurring nucleosides. These drugs competitively bind to the viral DNA or RNA polymerase, disrupting the replication process by causing termination of the DNA or RNA chain synthesis. Due to their ability to inhibit viral replication, these drugs often exhibit broad-spectrum antiviral activity. Cidofovir, a non-cyclic monophosphate nucleoside analog, can be used for the treatment of orthopoxviruses and demonstrate potent antiviral activity in vitro (Mpox virus, effective concentration half maximal (EC50)=2.52g/mL, Selectivity index (SI)=15, in human embryonic lung fibroblasts) and in vivo (Mpox virus, 5mg/kg, cynomolgus macaques, intraperitoneal injection; Mpox virus, 5mg/kg, human, intravenous). Following the Mpox outbreak in 2022, Cidofovir was rapidly employed in clinical trials for the treatment of Mpox. However, Cidofovir is a divalent anion with low bioavailability. In patients with impaired renal function or undergoing renal replacement therapy, its metabolites can accumulate in proximal renal tubular cells, leading to kidney damage. In order to overcome the limitations of Cidofovir, its derivative Brincidofovir has been developed. Brincidofovir has been modified using lipid conjugation technology, resulting in improved cellular uptake and conversion capabilities, it was approved by the FDA in 2021 for the treatment of smallpox. Unlike Cidofovir, Brincidofovir does not require metabolism through the renal anion transport system, thus exhibiting higher bioavailability and no significant nephrotoxicity in vitro (VACV, EC50=0.19M, in vero cells) and in vivo (Mpox virus, 10mg/kg, mice, gastric gavage; Mpox virus, 200mg, human, oral). However, Brincidofovir still presents some adverse reactions such as gastrointestinal reactions and liver function injury. Apart from Brincidofovir, other compounds based on structural modifications of Cidofovir have been developed. For instance, NPP-669 is synthesized by linking a long-chain sulfonate to Cidofovir. This modification improves its solubility in water and affinity for lipid through alkyl chain modification. As a result, this structural modification enhances the metabolic stability and bioavailability while reducing nephrotoxicity. It has shown enhanced antiviral effectiveness in vitro (vaccinia, EC50=8.95M, in HFF cells) and in vivo (cytomegalovirus, 3mg/kg, mice, intraperitoneal injection). Ribavirin, a well-known nucleoside analog, blocks viral nucleotide synthesis and thus inhibits viral replication and transmission. It has broad-spectrum antiviral efficacy against various DNA and RNA viruses, including Mpox virus. Studies have shown that ribavirin can impede the replication of orthopoxviruses in vitro (Mpox virus, EC50=5.9g/mL, in Vero cells) and in vivo (cowpox virus, 50mg/kg, mice, subcutaneous injection). However, further clinical studies are needed to assess its effectiveness in Mpox patients are needed.
#61 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
After IMV or EEV enter the host cell, the exposed viral core is transported to the periphery of the cell nucleus through microtubule structures at an average speed of 52m/min. The viral core consists of the central viral genome and an enveloped nucleocapsid. The mechanism of nucleocapsid uncoating involves ubiquitination of the nuclear capsid proteins and degradation by proteasomes. Once uncoating is completed, the Mpox virus genome begins efficient replication, rapidly amplifying like a factory. Currently, researchers are devoted to developing anti-Mpox drugs by interfering with the DNA or RNA synthesis of the viral genome. Nucleoside analogs are chemical compounds that have a similar structure to naturally occurring nucleosides. These drugs competitively bind to the viral DNA or RNA polymerase, disrupting the replication process by causing termination of the DNA or RNA chain synthesis. Due to their ability to inhibit viral replication, these drugs often exhibit broad-spectrum antiviral activity. Cidofovir, a non-cyclic monophosphate nucleoside analog, can be used for the treatment of orthopoxviruses and demonstrate potent antiviral activity in vitro (Mpox virus, effective concentration half maximal (EC50)=2.52g/mL, Selectivity index (SI)=15, in human embryonic lung fibroblasts) and in vivo (Mpox virus, 5mg/kg, cynomolgus macaques, intraperitoneal injection; Mpox virus, 5mg/kg, human, intravenous). Following the Mpox outbreak in 2022, Cidofovir was rapidly employed in clinical trials for the treatment of Mpox. However, Cidofovir is a divalent anion with low bioavailability. In patients with impaired renal function or undergoing renal replacement therapy, its metabolites can accumulate in proximal renal tubular cells, leading to kidney damage. In order to overcome the limitations of Cidofovir, its derivative Brincidofovir has been developed. Brincidofovir has been modified using lipid conjugation technology, resulting in improved cellular uptake and conversion capabilities, it was approved by the FDA in 2021 for the treatment of smallpox. Unlike Cidofovir, Brincidofovir does not require metabolism through the renal anion transport system, thus exhibiting higher bioavailability and no significant nephrotoxicity in vitro (VACV, EC50=0.19M, in vero cells) and in vivo (Mpox virus, 10mg/kg, mice, gastric gavage; Mpox virus, 200mg, human, oral). However, Brincidofovir still presents some adverse reactions such as gastrointestinal reactions and liver function injury. Apart from Brincidofovir, other compounds based on structural modifications of Cidofovir have been developed. For instance, NPP-669 is synthesized by linking a long-chain sulfonate to Cidofovir. This modification improves its solubility in water and affinity for lipid through alkyl chain modification. As a result, this structural modification enhances the metabolic stability and bioavailability while reducing nephrotoxicity. It has shown enhanced antiviral effectiveness in vitro (vaccinia, EC50=8.95M, in HFF cells) and in vivo (cytomegalovirus, 3mg/kg, mice, intraperitoneal injection). Ribavirin, a well-known nucleoside analog, blocks viral nucleotide synthesis and thus inhibits viral replication and transmission. It has broad-spectrum antiviral efficacy against various DNA and RNA viruses, including Mpox virus. Studies have shown that ribavirin can impede the replication of orthopoxviruses in vitro (Mpox virus, EC50=5.9g/mL, in Vero cells) and in vivo (cowpox virus, 50mg/kg, mice, subcutaneous injection). However, further clinical studies are needed to assess its effectiveness in Mpox patients are needed.
#62 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
After IMV or EEV enter the host cell, the exposed viral core is transported to the periphery of the cell nucleus through microtubule structures at an average speed of 52m/min. The viral core consists of the central viral genome and an enveloped nucleocapsid. The mechanism of nucleocapsid uncoating involves ubiquitination of the nuclear capsid proteins and degradation by proteasomes. Once uncoating is completed, the Mpox virus genome begins efficient replication, rapidly amplifying like a factory. Currently, researchers are devoted to developing anti-Mpox drugs by interfering with the DNA or RNA synthesis of the viral genome. Nucleoside analogs are chemical compounds that have a similar structure to naturally occurring nucleosides. These drugs competitively bind to the viral DNA or RNA polymerase, disrupting the replication process by causing termination of the DNA or RNA chain synthesis. Due to their ability to inhibit viral replication, these drugs often exhibit broad-spectrum antiviral activity. Cidofovir, a non-cyclic monophosphate nucleoside analog, can be used for the treatment of orthopoxviruses and demonstrate potent antiviral activity in vitro (Mpox virus, effective concentration half maximal (EC50)=2.52g/mL, Selectivity index (SI)=15, in human embryonic lung fibroblasts) and in vivo (Mpox virus, 5mg/kg, cynomolgus macaques, intraperitoneal injection; Mpox virus, 5mg/kg, human, intravenous). Following the Mpox outbreak in 2022, Cidofovir was rapidly employed in clinical trials for the treatment of Mpox. However, Cidofovir is a divalent anion with low bioavailability. In patients with impaired renal function or undergoing renal replacement therapy, its metabolites can accumulate in proximal renal tubular cells, leading to kidney damage. In order to overcome the limitations of Cidofovir, its derivative Brincidofovir has been developed. Brincidofovir has been modified using lipid conjugation technology, resulting in improved cellular uptake and conversion capabilities, it was approved by the FDA in 2021 for the treatment of smallpox. Unlike Cidofovir, Brincidofovir does not require metabolism through the renal anion transport system, thus exhibiting higher bioavailability and no significant nephrotoxicity in vitro (VACV, EC50=0.19M, in vero cells) and in vivo (Mpox virus, 10mg/kg, mice, gastric gavage; Mpox virus, 200mg, human, oral). However, Brincidofovir still presents some adverse reactions such as gastrointestinal reactions and liver function injury. Apart from Brincidofovir, other compounds based on structural modifications of Cidofovir have been developed. For instance, NPP-669 is synthesized by linking a long-chain sulfonate to Cidofovir. This modification improves its solubility in water and affinity for lipid through alkyl chain modification. As a result, this structural modification enhances the metabolic stability and bioavailability while reducing nephrotoxicity. It has shown enhanced antiviral effectiveness in vitro (vaccinia, EC50=8.95M, in HFF cells) and in vivo (cytomegalovirus, 3mg/kg, mice, intraperitoneal injection). Ribavirin, a well-known nucleoside analog, blocks viral nucleotide synthesis and thus inhibits viral replication and transmission. It has broad-spectrum antiviral efficacy against various DNA and RNA viruses, including Mpox virus. Studies have shown that ribavirin can impede the replication of orthopoxviruses in vitro (Mpox virus, EC50=5.9g/mL, in Vero cells) and in vivo (cowpox virus, 50mg/kg, mice, subcutaneous injection). However, further clinical studies are needed to assess its effectiveness in Mpox patients are needed.
#63 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
After IMV or EEV enter the host cell, the exposed viral core is transported to the periphery of the cell nucleus through microtubule structures at an average speed of 52m/min. The viral core consists of the central viral genome and an enveloped nucleocapsid. The mechanism of nucleocapsid uncoating involves ubiquitination of the nuclear capsid proteins and degradation by proteasomes. Once uncoating is completed, the Mpox virus genome begins efficient replication, rapidly amplifying like a factory. Currently, researchers are devoted to developing anti-Mpox drugs by interfering with the DNA or RNA synthesis of the viral genome. Nucleoside analogs are chemical compounds that have a similar structure to naturally occurring nucleosides. These drugs competitively bind to the viral DNA or RNA polymerase, disrupting the replication process by causing termination of the DNA or RNA chain synthesis. Due to their ability to inhibit viral replication, these drugs often exhibit broad-spectrum antiviral activity. Cidofovir, a non-cyclic monophosphate nucleoside analog, can be used for the treatment of orthopoxviruses and demonstrate potent antiviral activity in vitro (Mpox virus, effective concentration half maximal (EC50)=2.52g/mL, Selectivity index (SI)=15, in human embryonic lung fibroblasts) and in vivo (Mpox virus, 5mg/kg, cynomolgus macaques, intraperitoneal injection; Mpox virus, 5mg/kg, human, intravenous). Following the Mpox outbreak in 2022, Cidofovir was rapidly employed in clinical trials for the treatment of Mpox. However, Cidofovir is a divalent anion with low bioavailability. In patients with impaired renal function or undergoing renal replacement therapy, its metabolites can accumulate in proximal renal tubular cells, leading to kidney damage. In order to overcome the limitations of Cidofovir, its derivative Brincidofovir has been developed. Brincidofovir has been modified using lipid conjugation technology, resulting in improved cellular uptake and conversion capabilities, it was approved by the FDA in 2021 for the treatment of smallpox. Unlike Cidofovir, Brincidofovir does not require metabolism through the renal anion transport system, thus exhibiting higher bioavailability and no significant nephrotoxicity in vitro (VACV, EC50=0.19M, in vero cells) and in vivo (Mpox virus, 10mg/kg, mice, gastric gavage; Mpox virus, 200mg, human, oral). However, Brincidofovir still presents some adverse reactions such as gastrointestinal reactions and liver function injury. Apart from Brincidofovir, other compounds based on structural modifications of Cidofovir have been developed. For instance, NPP-669 is synthesized by linking a long-chain sulfonate to Cidofovir. This modification improves its solubility in water and affinity for lipid through alkyl chain modification. As a result, this structural modification enhances the metabolic stability and bioavailability while reducing nephrotoxicity. It has shown enhanced antiviral effectiveness in vitro (vaccinia, EC50=8.95M, in HFF cells) and in vivo (cytomegalovirus, 3mg/kg, mice, intraperitoneal injection). Ribavirin, a well-known nucleoside analog, blocks viral nucleotide synthesis and thus inhibits viral replication and transmission. It has broad-spectrum antiviral efficacy against various DNA and RNA viruses, including Mpox virus. Studies have shown that ribavirin can impede the replication of orthopoxviruses in vitro (Mpox virus, EC50=5.9g/mL, in Vero cells) and in vivo (cowpox virus, 50mg/kg, mice, subcutaneous injection). However, further clinical studies are needed to assess its effectiveness in Mpox patients are needed.
#64 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
Mpox virus-induced immunopathology leads to adverse outcomes in clinical, and immunotherapy for Mpox has the potential to reduce severe cases. Antibody-based therapeutics, immune cell, Immune effector molecules, and Modulation of cellular signal transduction are potential immunotherapies. Combination antiviral drugs with immunotherapy may be more effective and provide greater clinical benefit than single antiviral therapy alone. Antibody-based therapeutics have shown significant progress in treating certain infectious diseases and currently being actively explored. Immune globulin, convalescent plasma, and neutralizing antibodies offer promising options as adjunctive treatments for cases with insufficient antiviral drug efficacy in severe patients. Notably, individuals who have been previously vaccinated with the smallpox vaccine produce more neutralizing antibodies that may be cross-protective against Mpox virus infection. Thus, some countries have approved the intravenous administration of vaccinia immune globulin (VIGIV) for managing complications associated with smallpox vaccination. For individuals with severe T cell functional immunodeficiency due to contraindications to smallpox vaccination, VIGIV can be considered as a prophylactic measure in vitro and in vivo and in one clinical case.
#65 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
Mpox virus-induced immunopathology leads to adverse outcomes in clinical, and immunotherapy for Mpox has the potential to reduce severe cases. Antibody-based therapeutics, immune cell, Immune effector molecules, and Modulation of cellular signal transduction are potential immunotherapies. Combination antiviral drugs with immunotherapy may be more effective and provide greater clinical benefit than single antiviral therapy alone. Antibody-based therapeutics have shown significant progress in treating certain infectious diseases and currently being actively explored. Immune globulin, convalescent plasma, and neutralizing antibodies offer promising options as adjunctive treatments for cases with insufficient antiviral drug efficacy in severe patients. Notably, individuals who have been previously vaccinated with the smallpox vaccine produce more neutralizing antibodies that may be cross-protective against Mpox virus infection. Thus, some countries have approved the intravenous administration of vaccinia immune globulin (VIGIV) for managing complications associated with smallpox vaccination. For individuals with severe T cell functional immunodeficiency due to contraindications to smallpox vaccination, VIGIV can be considered as a prophylactic measure in vitro and in vivo and in one clinical case.
#66 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
Mpox virus-induced immunopathology leads to adverse outcomes in clinical, and immunotherapy for Mpox has the potential to reduce severe cases. Antibody-based therapeutics, immune cell, Immune effector molecules, and Modulation of cellular signal transduction are potential immunotherapies. Combination antiviral drugs with immunotherapy may be more effective and provide greater clinical benefit than single antiviral therapy alone. Antibody-based therapeutics have shown significant progress in treating certain infectious diseases and currently being actively explored. Immune globulin, convalescent plasma, and neutralizing antibodies offer promising options as adjunctive treatments for cases with insufficient antiviral drug efficacy in severe patients. Notably, individuals who have been previously vaccinated with the smallpox vaccine produce more neutralizing antibodies that may be cross-protective against Mpox virus infection. Thus, some countries have approved the intravenous administration of vaccinia immune globulin (VIGIV) for managing complications associated with smallpox vaccination. For individuals with severe T cell functional immunodeficiency due to contraindications to smallpox vaccination, VIGIV can be considered as a prophylactic measure in vitro and in vivo and in one clinical case.
#67 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
Mpox virus-induced immunopathology leads to adverse outcomes in clinical, and immunotherapy for Mpox has the potential to reduce severe cases. Antibody-based therapeutics, immune cell, Immune effector molecules, and Modulation of cellular signal transduction are potential immunotherapies. Combination antiviral drugs with immunotherapy may be more effective and provide greater clinical benefit than single antiviral therapy alone. Antibody-based therapeutics have shown significant progress in treating certain infectious diseases and currently being actively explored. Immune globulin, convalescent plasma, and neutralizing antibodies offer promising options as adjunctive treatments for cases with insufficient antiviral drug efficacy in severe patients. Notably, individuals who have been previously vaccinated with the smallpox vaccine produce more neutralizing antibodies that may be cross-protective against Mpox virus infection. Thus, some countries have approved the intravenous administration of vaccinia immune globulin (VIGIV) for managing complications associated with smallpox vaccination. For individuals with severe T cell functional immunodeficiency due to contraindications to smallpox vaccination, VIGIV can be considered as a prophylactic measure in vitro and in vivo and in one clinical case.
#68 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
The development of multi-omics technologies and HTS techniques has enabled precise identification and characterization of various molecular targets of Mpox virus, which is crucial for the development of novel anti-Mpox virus drugs targeting new mechanisms. Furthermore, multi-omics technologies have revealed the gene expression patterns during Mpox infection and identified specific receptors and pathways regulated during Mpox progression. By precisely modulating these receptors and pathways, it is possible to develop drugs for Mpox therapy. This study contributes to optimizing the chemical structure of drugs, enhancing their delivery and targeting, thereby improving treatment precision and reducing drug side effects. […] In addition to the development of systemic anti-infective drugs, exploring local therapies for Mpox is crucial. Mpox infections can cause severe physiological and psychological trauma to the skin and eyes. This damage is often visibly evident and difficult to conceal. Skin lesions, for example, are a hallmark of Mpox infection and inflict immense pain on patients. The psychological trauma resulting from these skin injuries and subsequent scarring may surpass the physical harm. A distressing incident reported in 2017 highlighted the tragic suicide of a 34-year-old Mpox patient due to the psychological trauma endured post-infection. Therefore, addressing skin lesions during the course of Mpox infection is essential. Notably, the topical cream imiquimod has demonstrated particular efficacy in treating Mpox-induced skin lesions. The exact mechanism of action of imiquimod in the treatment of Mpox infections is not fully understood, although several potential mechanisms have been proposed. Imiquimod acts as an agonist for Toll-like receptor 7 (TLR-7) and Toll-like receptor 8 (TLR-8), triggering the nuclear translocation and transcriptional activity of nuclear factor B (NF-B). This activation leads to the release of downstream pro-inflammatory cytokines, enhancing the immune response against Mpox. Additionally, imiquimod acts as a direct local immune stimulant by stimulating the production of various cytokines, including IFN-, TNF-, IL-1, and IL-6. These cytokines play a crucial role in activating the innate immune system and promoting a localized immune response. Studies have shown that imiquimod can recruit plasmacytoid dendritic cells to the site of infection, thereby enhancing the antigen presentation process.
#69 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
The development of multi-omics technologies and HTS techniques has enabled precise identification and characterization of various molecular targets of Mpox virus, which is crucial for the development of novel anti-Mpox virus drugs targeting new mechanisms. Furthermore, multi-omics technologies have revealed the gene expression patterns during Mpox infection and identified specific receptors and pathways regulated during Mpox progression. By precisely modulating these receptors and pathways, it is possible to develop drugs for Mpox therapy. This study contributes to optimizing the chemical structure of drugs, enhancing their delivery and targeting, thereby improving treatment precision and reducing drug side effects. […] In addition to the development of systemic anti-infective drugs, exploring local therapies for Mpox is crucial. Mpox infections can cause severe physiological and psychological trauma to the skin and eyes. This damage is often visibly evident and difficult to conceal. Skin lesions, for example, are a hallmark of Mpox infection and inflict immense pain on patients. The psychological trauma resulting from these skin injuries and subsequent scarring may surpass the physical harm. A distressing incident reported in 2017 highlighted the tragic suicide of a 34-year-old Mpox patient due to the psychological trauma endured post-infection. Therefore, addressing skin lesions during the course of Mpox infection is essential. Notably, the topical cream imiquimod has demonstrated particular efficacy in treating Mpox-induced skin lesions. The exact mechanism of action of imiquimod in the treatment of Mpox infections is not fully understood, although several potential mechanisms have been proposed. Imiquimod acts as an agonist for Toll-like receptor 7 (TLR-7) and Toll-like receptor 8 (TLR-8), triggering the nuclear translocation and transcriptional activity of nuclear factor B (NF-B). This activation leads to the release of downstream pro-inflammatory cytokines, enhancing the immune response against Mpox. Additionally, imiquimod acts as a direct local immune stimulant by stimulating the production of various cytokines, including IFN-, TNF-, IL-1, and IL-6. These cytokines play a crucial role in activating the innate immune system and promoting a localized immune response. Studies have shown that imiquimod can recruit plasmacytoid dendritic cells to the site of infection, thereby enhancing the antigen presentation process.
#70 Exploration of drug repurposing for Mpox outbreaks targeting gene signatures and host-pathogen interactions | Research Communities by Springer Nature
https://communities.springernature.com/posts/exploration-of-drug-repurposing-for-mpox-outbreaks-targeting-gene-signatures-and-host-pathogen-interactions
The motivation behind this paper comes from the need to better understand the molecular mechanisms and HPI driving Mpox pathogenesis, especially given its growing threat to global health. […] This study fills that gap by combining Weighted Gene Co-expression Network Analysis (WGCNA) with HPI analysis, offering a novel approach to studying Mpox. […] WGCNA identifies key gene modules and regulatory hubs impacted by Mpox infection, while HPI analysis reveals how viral proteins interact with host components to alter cellular processes. […] Together, these methods provide a systems-level view of how Mpox reshapes host molecular networks, focusing on the transcriptional and signaling regulators involved in immune evasion and viral persistence. […] Our findings not only deepen the understanding of Mpox immunopathogenesis but also identify potential therapeutic targets, such as kinase inhibitors, hormone-based therapies, and agents that influence PI3K/AKT and STAT3 signaling.
#71 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
While some progress has been made in the development of drugs against Mpox, it is crucial to expedite the research progress. This will enable us to effectively combat potential long-term outbreaks and the emergence of drug-resistant Mpox virus strains. In the development of drugs against Mpox, the following aspects should be given priority: Firstly, improving the specificity and delivery efficiency of drugs is essential to ensure accurate targeting of the Mpox and efficient transmission to the infection site. Secondly, development anti-Mpox drugs that are less prone to resistance is necessary to prevent the gradual emergence of drug-resistant strains and ensuring sustained efficacy of treatment. Additionally, exploring the development of sequential and combination drug therapies should enhance effectiveness against different stages of Mpox infections and their variants. Lastly, attention should be paid to drug modifications to mitigate or eliminate toxicity, minimizing the adverse impact on patients during the treatment process. The early investment in drug development against Mpox is crucial in tackling the ongoing global Mpox outbreak. Accelerating progress in the development of effective anti-Mpox drugs will help prepare for future challenges and provide more reliable protection for public health.
#72 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
The lengthy and costly nature of drug development, combined with numerous uncertainties, has led to the exploration of drug repurposing strategies as a more efficient and economical approach. High-throughput screening of marketed drugs or clinically established medications has the potential to expedite the identification of antiviral agents, thus saving valuable time. For instance, the potential antiviral drug ribavirin has demonstrated therapeutic effectiveness against Mpox infection. Similarly, the widely used EGFR inhibitor gefitinib has shown promising antiviral activity against Mpox virus in addition to its approved indication for late-stage non-small cell lung cancer. However, drug repurposing efforts still heavily rely on serendipitous discoveries. Historically, drug development has been predominantly confined to laboratory settings. However, advances in computer science and computational drug design have significantly accelerated the discoveries in drug repurposing. Computer-aided drug discovery (CADD) techniques encompass the following three main directions: 1) High-throughput library screening of small molecule libraries, such as the discovery and development of Tecovirimat based on the VP37 protein. 2) Structural optimization based on existing drugs, such as NPP669, which involves alkyl chain modifications based on Cidofovir, resulting in overall improved pharmacological properties compared to Cidofovir. 3) Directly targeting functional sites for novel drug design, such as DdRp, which usually serves as a target for antiviral CADD.
#73 Exploration of drug repurposing for Mpox outbreaks targeting gene signatures and host-pathogen interactions | Research Communities by Springer Nature
https://communities.springernature.com/posts/exploration-of-drug-repurposing-for-mpox-outbreaks-targeting-gene-signatures-and-host-pathogen-interactions
In this in silico study, we constructed a HPI network by utilizing experimentally validated protein-protein interaction data from publicly available repositories such as STRING, BioGRID, and IntAct, alongside virus-host interaction databases specific to orthopoxviruses. […] Centrality analysis of the network revealed hub proteins, including EGFR, TRAF6, and CASP8, which appear to play significant roles in immune regulation. […] Specifically, EGFR was found to be involved in viral entry and immune suppression, while TRAF6 and CASP8 were linked to inflammatory responses and apoptosis pathways. […] These findings highlight potential targets for immunomodulatory therapies aimed at mitigating the effects of Mpox infection. […] We predicted 11 kinases, including JAK1, TYK2, and MAPK1, as potential regulatory targets involved in Mpox pathogenesis.
#74 Exploration of drug repurposing for Mpox outbreaks targeting gene signatures and host-pathogen interactions | Research Communities by Springer Nature
https://communities.springernature.com/posts/exploration-of-drug-repurposing-for-mpox-outbreaks-targeting-gene-signatures-and-host-pathogen-interactions
In this in silico study, we constructed a HPI network by utilizing experimentally validated protein-protein interaction data from publicly available repositories such as STRING, BioGRID, and IntAct, alongside virus-host interaction databases specific to orthopoxviruses. […] Centrality analysis of the network revealed hub proteins, including EGFR, TRAF6, and CASP8, which appear to play significant roles in immune regulation. […] Specifically, EGFR was found to be involved in viral entry and immune suppression, while TRAF6 and CASP8 were linked to inflammatory responses and apoptosis pathways. […] These findings highlight potential targets for immunomodulatory therapies aimed at mitigating the effects of Mpox infection. […] We predicted 11 kinases, including JAK1, TYK2, and MAPK1, as potential regulatory targets involved in Mpox pathogenesis.
#75 Exploration of drug repurposing for Mpox outbreaks targeting gene signatures and host-pathogen interactions | Research Communities by Springer Nature
https://communities.springernature.com/posts/exploration-of-drug-repurposing-for-mpox-outbreaks-targeting-gene-signatures-and-host-pathogen-interactions
Additionally, we identified 15 transcription factors, such as IRF7, STAT1, and NFKB1, which play a critical role in driving antiviral gene expression. […] These transcription factors are essential for regulating immune responses during infection. […] Several candidate drugs were proposed, including Ruxolitinib, a JAK1/2 inhibitor, to suppress hyperinflammatory responses, Ribavirin and Favipiravir as antiviral agents targeting the viral replication machinery, and Baricitinib as an immunomodulator to mitigate cytokine storms. […] This study paves the way for future research by integrating multi-omics data to provide a deeper understanding of Mpox pathogenesis. […] Expanding beyond transcriptomics, it includes proteomics and epigenomics, offering a more comprehensive view of how the virus interacts with the host. […] These approaches collectively aim to advance our understanding of Mpox and lead to the development of targeted therapies and vaccines.
#76 Mpox (formerly monkeypox): pathogenesis, prevention and treatment | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-023-01675-2
Mpox virus infection induces immune responses while also regulating cellular signal transduction. One example is the presence of a Mpox virus-encoded Bcl-2-like protein, which regulates the intrinsic apoptotic pathway. Additionally, the SPI-2 protein, encoded by the B12R gene, inhibits both caspase-1 and caspase-8, thereby disrupting the pyroptosis or apoptosis pathway, respectively. However, active induction of pyroptosis can be achieved by using nigericin, an inflammasome activator and pyroptosis inducer, as a strategy against Mpox infection. The findings demonstrated that Nigericin effectively reduced the viral titers and showed a stronger antiviral effect and lower EC50 values compared to the control group treated with Cidofovir. Protein kinases play a key role in regulating signal transduction pathways. Raghav et al. conducted an analysis to explore the interactions between Mpox virus and host proteins in order to further investigate the defense mechanisms triggered by Mpox infection. Their findings show the important role of the mitogen-activated protein kinase (MAPK) signaling pathway in the response to Mpox infection. Inhibition of the thymidine kinase enzyme, which is activated by MAPK, led to a significant reduction in viral replication. This evidence supports the potential of targeted therapies against MAPK signaling pathway as a promising strategy to combat Mpox.
#77 Advancing the understanding and management of Mpox: insights into epidemiology, disease pathways, prevention, and therapeutic strategies | BMC Infectious Diseases | Full Text
https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-025-10899-2
In the quest for effective treatments for Mpox, identifying viral and host proteins that facilitate virus-host interactions is crucial. […] These proteins play essential roles in the virus’s life cycle, making them promising targets for drug discovery. […] By focusing on these putative targets, researchers can develop novel therapeutic strategies aimed at disrupting the mechanisms through which the virus replicates and spreads.
#78 Advancing the understanding and management of Mpox: insights into epidemiology, disease pathways, prevention, and therapeutic strategies | BMC Infectious Diseases | Full Text
https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-025-10899-2
In the quest for effective treatments for Mpox, identifying viral and host proteins that facilitate virus-host interactions is crucial. […] These proteins play essential roles in the virus’s life cycle, making them promising targets for drug discovery. […] By focusing on these putative targets, researchers can develop novel therapeutic strategies aimed at disrupting the mechanisms through which the virus replicates and spreads.