Ospa prawdziwa
Patofizjologia i mechanizm

Ospa prawdziwa (variola) to ostra, zakaźna choroba wywoływana przez dwuniciowy wirus DNA z rodziny Poxviridae, replikujący się unikalnie w cytoplazmie komórek gospodarza. Występowały dwie formy: variola major z około 30% śmiertelnością oraz łagodniejsza variola minor z <1% śmiertelnością. Wirus przenosi się głównie drogą kropelkową, a po okresie inkubacji 12-14 dni dochodzi do wtórnej wiremii, manifestującej się gorączką ≥38,3°C i charakterystyczną wysypką. Patogeneza obejmuje replikację w układzie siateczkowo-śródbłonkowym, infekcję leukocytów i lokalizację wirusa w skórze oraz błonach śluzowych, co prowadzi do zmian skórnych i wysokiej zakaźności. Odpowiedź immunologiczna obejmuje produkcję przeciwciał neutralizujących i komórek pamięci T utrzymujących się do 50 lat. Śmierć wynika z toksjemii, hipotensji, koagulopatii i niewydolności wielonarządowej, często związanej z rozsianym wykrzepianiem wewnątrznaczyniowym.

  1. Charakterystyka ogólna ospa prawdziwa
  2. Struktura genomu wirusa ospy prawdziwej
  3. Mechanizm infekcji i rozprzestrzeniania się wirusa
    1. Wnikanie wirusa do komórek gospodarza
  4. Patogeneza zmian skórnych
    1. Rozwój objawów klinicznych
  5. Odpowiedź immunologiczna na zakażenie
    1. Mechanizmy prowadzące do śmierci
  6. Modele zwierzęce w badaniach patogenezy
  7. Nowoczesne badania nad patogenezą ospy prawdziwej
    1. Badania nad lekami przeciwko ospie prawdziwej
  8. Znaczenie w bioterrorizmie
  9. Wnioski
    1. Kolejne rozdziały

Charakterystyka ogólna ospa prawdziwa

Ospa prawdziwa (łac. variola) jest ostrą, zakaźną chorobą wywoływaną przez wirusa ospy prawdziwej (variola virus), należącego do rodzaju Orthopoxvirus w rodzinie Poxviridae. Wirus ospy prawdziwej to duży, cegiełkowaty, dwuniciowy wirus DNA, który replikuje się w cytoplazmie zainfekowanych komórek gospodarza, co odróżnia go od większości wirusów DNA, które namnażają się w jądrze komórkowym.12 Genom wirusa składa się z liniowej, dwuniciowej cząsteczki DNA zawierającej około 186 102 par zasad, która koduje około 10 enzymów regulujących ekspresję genów oraz około 100 nukleobiałek zaangażowanych w transkrypcję DNA.3 Wirusy ospy prawdziwej krzyżowo reagują serologicznie z innymi członkami rodziny pokswirusów, takimi jak ectromeliosis, ospa krowia, ospa małpia, wirus krowianki i wirus ospy wielbłądziej.4

Historycznie występowały dwie formy wirusa ospy prawdziwej: variola major, która była postacią ciężką i najczęstszą, z bardziej rozległą wysypką i wyższą gorączką, prowadzącą do ospy zlewnej o wysokiej śmiertelności (około 30%) oraz variola minor, rzadsza postać, powodująca łagodniejszą chorobę, z historyczną śmiertelnością 1% lub mniej.56 Ospa prawdziwa została eradykowana w skali globalnej w 1980 roku dzięki bezprecedensowej kampanii szczepień, jednak wciąż istnieje potencjalne zagrożenie wykorzystania wirusa jako broni bioterrorystycznej.78

Struktura genomu wirusa ospy prawdziwej

Pokswirusy, w tym wirus ospy prawdziwej, posiadają liniowy, dwuniciowy genom DNA i są wyjątkowe wśród wirusów DNA, ponieważ replikują się w cytoplazmie zamiast w jądrze komórki.910 Genom wirusa ospy prawdziwej koduje wszystkie białka niezbędne do replikacji, co pozwala mu namnażać się w cytoplazmie komórki gospodarza bez konieczności korzystania z aparatu jądrowego.11 Białka kodowane przez wirusa są zlokalizowane głównie w terminalnych regionach DNA wirusa i są odpowiedzialne za patogenność wirusa, umożliwiając mu unikanie odpowiedzi immunologicznej gospodarza.12

Unikalną cechą wirusa ospy prawdziwej, która czyni go tak śmiertelnym, jest to, że nie wymaga on pomocy komórki gospodarza do rozpoczęcia replikacji. Wynika to z faktu, że wirus ospy prawdziwej koduje wszystkie enzymy potrzebne do jego namnażania. Jeden enzym w szczególności, topoizomeraza IB (33 kDa), odpowiada za rozwijanie zapakowanego, superskręconego wirusowego DNA w celu zainicjowania replikacji wirusowej. Następuje to poprzez mechanizm nacięcia-łączenia, w którym nukleofilowa tyrozyna atakuje wiązanie fosfodiesterowe, tworząc wiązanie 3′-fosfotyrozynowe i uwalniając wolną grupę 5′-hydroksylową. Tworzy to nacięcie w DNA, które rozwija się, aby uwolnić superskręcenie. DNA jest następnie ponownie ligowane, tworząc rozluźnione DNA.13

Białko G1R wirusa ospy prawdziwej wiąże się do komórkowego czynnika jądrowego kappa-B (NF-kB), hamując jego funkcję w sygnalizacji komórkowej. Białko G1R jest wysoce konserwowane wśród patogennych ortopokswirusów i jest nieobecne w mniej patogennych szczepach krowianki, co sugeruje, że może ono służyć jako molekularny cel terapeutyczny.1415

Mechanizm infekcji i rozprzestrzeniania się wirusa

Wirus ospy prawdziwej przenosi się z człowieka na człowieka poprzez wdychanie kropel wydzieliny dróg oddechowych lub, mniej skutecznie, przez bezpośredni kontakt.1617 Zakażenie zwykle następuje poprzez wdychanie wirusa znajdującego się w wydzielinach jamy ustnej i gardła osoby zakażonej w pierwszym tygodniu pojawienia się charakterystycznej wysypki.18

Proces infekcji można podzielić na kilka etapów:

  1. Wniknięcie wirusa: Wirus wnika do organizmu przez błony śluzowe jamy ustnej, gardła lub dróg oddechowych. Inne możliwe drogi wniknięcia to skóra, spojówki oraz łożysko.19
  2. Lokalna replikacja: Po wniknięciu do organizmu wirus migruje do regionalnych węzłów chłonnych, gdzie rozpoczyna replikację.20
  3. Pierwotna wiremia: Początkowa wiremia występuje 3-4 dni po zakażeniu, a wirus dalej rozprzestrzenia się do szpiku kostnego, śledziony i dodatkowych łańcuchów węzłów chłonnych.21
  4. Amplifikacja wirusa: Wirus namnaża się w układzie siateczkowo-śródbłonkowym przez 4-14 dni.22
  5. Wtórna wiremia: Wtórna wiremia występuje między 8 a 12 dniem po zakażeniu i zbiega się z wystąpieniem gorączki i klinicznych objawów choroby. Na tym etapie wirus lokalizuje się w błonie śluzowej jamy ustnej i gardła oraz w małych naczyniach krwionośnych skóry, powodując pojawienie się wysypki i zakaźność kliniczną.2324

W trakcie wtórnej wiremii wirus infekuje komórki śluzowe gardła i jamy ustnej oraz śródbłonek naczyń włosowatych skóry właściwej, powodując zmiany skórne.25 Wirus ostatecznie dostaje się do krwi w leukocytach, powodując gorączkę i toksjemię, a następnie przechodzi z leukocytów do sąsiednich komórek w małych naczyniach krwionośnych skóry właściwej i pod błoną śluzową jamy ustno-gardłowej, prowadząc do początkowego pojawienia się enantemu i egzantemu, w którym to momencie (około 14 dnia) pacjent staje się zakaźny.26

Wnikanie wirusa do komórek gospodarza

Wirus ospy prawdziwej wnika do komórek gospodarza poprzez wiązanie się z określonymi receptorami na błonie komórkowej gospodarza. Wiąże się z receptorami komórek gospodarza za pomocą antygenów hemaglutyniny ekspresjonowanych na jego powierzchni zewnętrznej. Dokładny mechanizm wnikania nie jest jeszcze znany.27 Badacze odkryli, że interakcje między polianionowymi lub ujemnie naładowanymi cząsteczkami na powierzchni komórki a glikoproteinami na cząsteczce wirusa powodują niefizygenizacyjne przerwanie zewnętrznej osłonki wirusa, umożliwiając pokswirusowi wniknięcie do komórki.28

Po wniknięciu do komórki gospodarza wirus ospy prawdziwej replikuje się w cytoplazmie, a nie w jądrze, używając wielu własnych enzymów gospodarza do replikacji. Replikacja rozpoczyna się po dotarciu wirionu do cytoplazmy komórki gospodarza. Najpierw cząsteczka informacyjnego RNA jest transkrybowana przez polimerazę RNA i pokrewne enzymy przed odkapsydowaniem genomu. Pierwsze geny, które są transkrybowane, znane jako geny wczesne, kodują białka, które ułatwiają odkapsydowanie genomu wirusowego i inicjują drugą rundę transkrypcji genów pośrednich. Geny pośrednie wytwarzają mRNA, które są translowane na białka umożliwiające transkrypcję klasy genów późnych. Geny późne kodują białka, które tworzą strukturalne i enzymatyczne składniki nowego wirionu.29

Dalsza replikacja tego wirusa prowadzi do ostatecznego wyłączenia syntezy DNA, RNA i białek komórki gospodarza oraz powoduje zmiany w architekturze komórki, umożliwiając wirusowi wykorzystanie aparatu genetycznego komórki gospodarza do reprodukcji.30

Patogeneza zmian skórnych

Zmiany skórne w ospie prawdziwej powstają w wyniku migracji makrofagów do zakażonych obszarów skóry właściwej, prowadząc do obrzęku i martwicy.31 Pierwotnym zdarzeniem, które wyzwala powstawanie ogniskowych zmian w zakażeniach ortopokswirusami, jest lokalizacja cząstek wirusa w małych naczyniach krwionośnych skóry.32

Mechanizmy umożliwiające lokalizację wirusa ospy prawdziwej w skórze i charakterystyczne „odśrodkowe” rozmieszczenie wysypki nie są znane.33 Fakt, że wirus wydaje się podróżować w leukocytach, które specyficznie opuszczają naczynia krwionośne w skórze właściwej brodawkowatej, wskazuje, że wirus ospy prawdziwej preferencyjnie łączy się z leukocytami, które mogą migrować do skóry; alternatywnie, może być tak, że tylko tkanki skóry mogą wspierać kolejne etapy replikacji niezbędne do tworzenia zmian.34

Po dotarciu do skóry wirus rozprzestrzenia się w warstwach środkowej i podstawnej, powodując rozszerzające się strefy martwicy, które tworzą pęcherze.35 W nierogowaciejącym nabłonku płaskim jamy ustno-gardłowej ten sam proces odpowiada za tworzenie się owrzodzonych zmian.36 Brak rogowej, keratynizowanej warstwy komórkowej pozwala zmianom na błonach śluzowych na szybkie owrzodzenie po ich powstaniu, uwalniając duże ilości wysoce zakaźnego wirusa do śliny.37

Krosty z otaczającym obrzękiem i rumieniem powstają w wyniku zwiększonej przepuszczalności lokalnych naczyń krwionośnych i późniejszej infiltracji neutrofilów, limfocytów i makrofagów.38 Odpowiedź immunologiczna komórkowa jest warunkiem wstępnym dla ustąpienia zmian.39

Rozwój objawów klinicznych

Po okresie inkubacji trwającym 12-14 dni wirus wnika do krwi w leukocytach, które zasiewają skórę i wytwarzają charakterystyczne zmiany skórne (ospę), podczas gdy większość innych tkanek jest oszczędzona.40 Początkowe objawy podobne są do innych chorób wirusowych, które nadal występują, takich jak grypa i przeziębienie: gorączka co najmniej 38,3°C, bóle mięśni, złe samopoczucie, ból głowy i zmęczenie.41

Zdolność odpowiedzi gospodarza do ograniczenia replikacji wirusa w okresie inkubacji koreluje bezpośrednio z ciężkością choroby.42 Po rozprzestrzenieniu się wirusa objawy ciężkiej choroby, w tym hipotensja i koagulopatia, rozwijają się w wyniku odpowiedzi zapalnej gospodarza.43

Odpowiedź immunologiczna na zakażenie

Odpowiedź układu odpornościowego na wiremię obejmuje aktywację limfocytów T i B oraz jednoczesne wytwarzanie:44

  • Przeciwciał neutralizujących – w pierwszym tygodniu choroby, utrzymujących się przez wiele lat
  • Przeciwciał hamujących hemaglutynację – do 16 dnia zakażenia, zaczynających się zmniejszać po 1 roku
  • Przeciwciał wiążących dopełniacz – do 18 dnia zakażenia, zaczynających się zmniejszać po 1 roku
  • Komórek pamięci T – utrzymujących się przez 50 lat

45

Ludzka odpowiedź immunologiczna na wirusy jest złożonym procesem, o którym wciąż wiele pozostaje do odkrycia.46 Złożona seria reakcji między komórkami prezentującymi antygen a komórkami T służy do ogłoszenia układowi odpornościowemu obecności wewnątrzkomórkowych patogenów, takich jak wirusy.47 Podczas zakażenia wirusem tak złożonym jak ortopokswirusy generowane są przeciwciała specyficzne dla wielu różnych białek wirusowych.48

Najlepsze informacje na temat względnego znaczenia komórkowych i humoralnych odpowiedzi immunologicznych na zakażenia ortopokswirusem u ludzi pochodzą z badań osób w stanach niedoboru odporności, którym następnie podano szczepionkę z wirusem krowianki.4950

Specyficzna dla ortopokswirusów pamięć komórek T i B może być postrzegana jako obejmująca wcześniej indukowane limfocyty, które utrzymują się jako długo żyjące, ale nieaktywowane komórki sekwestrowane w tkance limfoidalnej i w recyrkulacji limfocytów.51 Skuteczność pamięciowych komórek T w zapewnianiu ochronnej odporności przeciwko ortopokswirusom zmniejsza się wraz ze zwiększaniem się odstępu między zakażeniem pierwotnym a wtórnym.52

Mechanizmy prowadzące do śmierci

Śmierć spowodowana ospą prawdziwą była zwykle wynikiem toksjemii, skutkującej:53

  • Hipotensją
  • Koagulopatią
  • Niewydolnością wielonarządową
  • Infekcjami bakteryjnymi

54

Śmierć jest zwykle wynikiem rozsianego wykrzepiania wewnątrznaczyniowego, hipotensji i zapaści sercowo-naczyniowej; są one nasilone przez zaburzenia krzepnięcia w rzadkim krwotocznym typie ospy prawdziwej.55 Komórki śródbłonka wyściełające zatoki wątroby są często obrzęknięte, a czasami proliferujące lub martwicze.56

Dokładny sposób, w jaki zakażenie ospą prawdziwą prowadziło do śmierci pacjenta, pozostaje niejasny. Oxford Textbook of Medicine zauważa, że zakażone osoby mogą rozwinąć objawy prostracji (całkowitego wyczerpania), toksjemii (toksyn we krwi) i hipotensji (niskiego ciśnienia krwi), które wszystkie przyczyniają się do śmierci, ale mechanizmy, przez które ospa prawdziwa powoduje takie objawy, nie są jasne.57

Modele zwierzęce w badaniach patogenezy

Patogeneza ospy prawdziwej była badana na trzy sposoby:5859

  1. Przy użyciu materiału od pacjentów ludzkich
  2. Poprzez przeprowadzanie eksperymentów z zakażeniem wirusem ospy prawdziwej u naczelnych innych niż ludzie
  3. Poprzez przeprowadzanie eksperymentów na modelach zakażeń u myszy, królików i małp z wykorzystaniem pokrewnych ortopokswirusów

W przełomowym badaniu naukowcy wykazali, że małpy cynomolgus eksponowane na wysokie dawki wirusa ospy prawdziwej (variola) umierały na krwotoczną postać ospy prawdziwej w ciągu kilku dni. Dożylne wstrzyknięcie wysokich dawek wirusa ospy prawdziwej wywołało przytłaczającą, krwotoczną postać choroby, kończącą się ostrymi zgonami, zwykle w ciągu 6 dni od inokulacji.60

Zastosowanie dożylnej inokulacji wirusa wyeliminowało etapy inkubacji i prodromalne naturalnej ospy prawdziwej, powodując „natychmiastową wiremię” i skutkując znacznie krótszym przebiegiem klinicznym niż typowy, gdy ospa prawdziwa nadal występowała u ludzi. „Jednak sekwencja zdarzeń u małp jest podobna do ludzkiej krwotocznej ospy prawdziwej, postaci, która była prawie zawsze śmiertelna.”61

Analiza tkanek zainfekowanych małp dostarczyła już pewnych informacji o tym, jak ospa prawdziwa zmienia aktywność genów w komórkach zaatakowanych przez wirusa, dostarczając wskazówek o tym, jak pokonuje ona mechanizmy obronne gospodarza.62

Nowoczesne badania nad patogenezą ospy prawdziwej

W ostatnich latach, ze względu na potencjalne zagrożenie bioterrorystyczne, wzrosło zainteresowanie patogenezą ospy prawdziwej.63 Badacze z Uniwersytetu Florydy odkryli więcej na temat sposobu, w jaki ospa prawdziwa prowadzi swój śmiertelny biznes – odkrycia, które mogą ujawnić tyle samo o ludzkim układzie odpornościowym, co o jednym z najbardziej obawianych patogenów na świecie.64

W wynikach opublikowanych w maju w Proceedings of the National Academy of Sciences, naukowcy opisali, jak przyjrzeli się wszystkim białkom wytwarzanym przez wirusa ospy prawdziwej w połączeniu z białkami ludzkimi i odkryli jedną szczególną interakcję, która wyłącza jeden z pierwszych reagentów organizmu na uraz – zapalenie.65

„Jedną ze strategii wirusa jest hamowanie szlaków zapalnych, a ta interakcja jest inhibitorem ludzkiego zapalenia, jakiego nigdy wcześniej nie widzieliśmy” – powiedział McFadden. „To pomaga wyjaśnić niektóre mechanizmy, które przyczyniają się do patogenezy ospy prawdziwej.”66

Białko G1R wirusa ospy prawdziwej wiąże się do komórkowego czynnika jądrowego kappa-B (NF-kB), hamując jego funkcję w sygnalizacji komórkowej. Białko G1R jest wysoce konserwowane wśród patogennych ortopokswirusów i jest nieobecne w mniej patogennych szczepach krowianki, co sugeruje, że może ono służyć jako molekularny cel terapeutyczny.6768

Badania nad lekami przeciwko ospie prawdziwej

W odpowiedzi na wykrycie wirusa ospy prawdziwej istnieją trzy możliwości kontrolowania każdego wynikającego z tego wybuchu choroby: izolacja i kwarantanna, szczepienia oraz podawanie leków przeciwwirusowych.69 Poczyniono postępy w opracowywaniu leków do leczenia i profilaktyki poekspozycyjnej ospy prawdziwej.70

Lek przeciwwirusowy tekowirymat został zatwierdzony przez amerykańską Agencję ds. Żywności i Leków (FDA) w 2018 roku, a w czerwcu 2021 roku FDA zatwierdziła cidofowir/” title=”brincidofowir” class=”to-tag” data-termid=”89396″>brincidofowir (CMX 001) do leczenia ospy prawdziwej. Oba zatwierdzenia opierały się na badaniach eksperymentalnych i, chociaż ich skuteczność przeciwko ospie prawdziwej u ludzi nie jest znana, w testach laboratoryjnych oba zatrzymały wzrost wirusa, który powoduje ospę prawdziwą i były skuteczne w leczeniu zwierząt, które miały choroby podobne do ospy prawdziwej. Dodatkowo cidofowir, który nie jest zatwierdzony przez FDA do leczenia ospy prawdziwej, mógłby być stosowany podczas wybuchu epidemii w ramach odpowiedniego mechanizmu regulacyjnego.71

Mechanizm działania tekowirymatu polega na hamowaniu białka VP37, zapobiegając prawidłowemu tworzeniu się otoczkowych wirionów.72 Ogólnie rzecz biorąc, tekowirymat łagodził typowe zmiany makroskopowe i histologiczne związane z chorobą wywołaną przez VARV u makaków, gdy zwierzęta były leczone już w 4 dniu po zakażeniu. Możliwość leczenia tak wcześnie, jak to możliwe, w tym przypadku przed rozwojem zmian, może mieć wpływ na przebieg choroby i pozostałą patologię.73

Leczenie ospy prawdziwej jest generalnie wspomagające, z antybiotykami w przypadku wtórnych zakażeń bakteryjnych.74 Chociaż niektóre leki przeciwwirusowe mogą pomóc w leczeniu choroby ospy prawdziwej, nie ma leczenia ospy prawdziwej, które zostało przetestowane u osób chorych na tę chorobę i udowodniono jego skuteczność.75

Znaczenie w bioterrorizmie

Chociaż ospa prawdziwa została eradykowana, istnieje możliwość, że wirus variola mógłby zostać użyty w ataku biologicznym.76 Wirus ospy prawdziwej może zainfekować ludzi poprzez wdychanie, połknięcie lub wstrzyknięcie. Atak ospą prawdziwą prawdopodobnie polegałby na tym, że ofiary wdychałyby Variola poprzez aerozol lub poprzez celowo zakażoną osobę zainfekowaną wirusem.77

Wystąpiły trzy niepokojące przypadki edycji genów pokswirusów w XXI wieku. W 2001 roku Jackson i in. stworzyli zmodyfikowany wirus ospy mysiej, który mógł zainfekować i zabić zaszczepione myszy. Ponieważ ospa mysia jest modelem badań nad ospą prawdziwą, badanie to dostarcza dowodów na to, że variola mogłaby potencjalnie zostać podobnie zmanipulowana, aby obejść szczepienie przeciwko ospie prawdziwej. Te badania pokazują potencjał do tworzenia nowych, bardziej śmiercionośnych wariantów ospy prawdziwej przy użyciu powszechnie dostępnych technik inżynierii genetycznej.78

Wnioski

Patogeneza ospy prawdziwej jest słabo zrozumianą serią zdarzeń, w której wirus najpierw rozprzestrzenia się lokalnie, następnie przez układ limfatyczny, a ostatecznie do skóry bez wpływu na narządy życiowe.7980 Wiele aspektów patogenezy ospy prawdziwej pozostaje nieznanych, w tym mechanizmy umożliwiające lokalizację wirusa ospy prawdziwej w skórze i charakterystyczny „odśrodkowy” rozkład wysypki.81

Lepsza znajomość mechanizmów patogenezy ospy prawdziwej może pomóc w opracowaniu skuteczniejszych metod leczenia i szczepionek, które mogą być wykorzystane w przypadku ponownego pojawienia się choroby, czy to naturalnie, czy jako wynik bioterroryzmu. Badania nad patogenezą ospy prawdziwej mogą również dostarczyć cennych informacji o tym, jak inne ortopokswirusy powodują choroby, co może mieć implikacje dla chorób takich jak ospa małpia, która ostatnio zyskała znaczenie jako choroba zakaźna o potencjale pandemicznym.82

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  1. 11.04.2026
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Materiały źródłowe

  • #1 Smallpox: Background, Etiology, Epidemiology
    https://emedicine.medscape.com/article/237229-overview
    Smallpox is an acute, contagious disease caused by the variola virus, a member of the genus Orthopoxvirus, in the Poxviridae family. […] Poxviridae are linear, double-stranded deoxyribonucleic acid (DNA) viruses that replicate in the cytoplasm. […] The variola virus is a large, brick-shaped, double-stranded DNA virus that serologically cross-reacts with other members of the poxvirus family, including ectromelia, cowpox, monkeypox, vaccinia, and camelpox. Unlike other DNA viruses, the variola virus multiplies in the cytoplasm of parasitized host cells. […] Because of potential bioterrorism, interest in smallpox pathogenesis has increased. Protein analysis indicates that the variola virus G1R protein binds to cellular nuclear factor kappa-B (NF-kB), thereby inhibiting its function in cell signalling.
  • #2 Smallpox – StatPearls – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK470418/
    Smallpox is a member of the viral family poxvirus, genus orthopoxvirus, and species variola virus. […] The poxviruses possess a linear, double-stranded DNA genome, and are unique in that their genetic makeup encodes all the proteins necessary for replication allowing them to replicate in the host cell cytoplasm. […] After viral entry through the oropharynx or nasopharynx, the virus migrates to regional lymph nodes where it begins replication. An initial viremia occurs on day 3 to 4 after infection, and the virus further disseminates to the bone marrow, spleen, and additional lymph node chains. A secondary viremia occurs between day 8 to 12 after infection and coincides with the onset of fever and clinical evidence of illness. At this stage, the virus becomes localized in the oropharyngeal mucosa and small blood vessels of the dermis, resulting in the onset of rash and clinical infectiousness.
  • #3 Smallpox (Variola Virus) – Topoisomerase 1B – Proteopedia, life in 3D
    https://proteopedia.org/wiki/index.php/Smallpox_%28Variola_Virus%29_-_Topoisomerase_1B
    Smallpox is caused by the Variola virus, a member of the genus Orthopoxvirus. Its genome consists of a single, linear double-stranded DNA molecule made up of 186,102 base pairs. There are 10 enzymes that regulate gene expression, as well as about 100 nucleoproteins involved in transcription of the DNA. The smallpox virus invades host cells by binding to specific receptors on the host cell membrane. The virus binds to host cell receptors via hemagglutinin antigens expressed on its outer surface. The exact mechanism of entry is not yet known. Upon invasion of a host cell, the smallpox virus replicates in the host cytoplasm, rather than the host nucleus, using many of the host’s own enzymes to replicate. Replication begins once the virion has reached the cytoplasm of the host cell. First, a messenger RNA molecule is transcribed by RNA polymerase and related enzymes before the genome is uncoated. The first genes that are transcribed, known as early genes, code for proteins that facilitate the uncoating of the viral genome and initiate a second round of transcription of intermediate genes. The intermediate genes produce mRNA, which are translated into proteins that allow the transcription of the late class of genes. The late class genes encode proteins, which make up the structural and enzymatic components of a new virion. Further replication of this virus leads to the eventual shutdown of the host cells DNA, RNA, and protein synthesis, and causes changes to the cells architecture to allow the virus to use the host cells genetic machinery for reproduction. One characteristic that makes the Variola virus so deadly is that it doesn’t require any help from the host cell to begin replication. The reason for this is that the Variola virus codes for all the enzymes needed for its proliferation. One enzyme in particular, the type IB topoisomerase is responsible for unwinding the packaged, supercoiled, viral DNA to initiate viral replication. This is accomplished through a nick-joining mechanism, in which a tyrosine nucleophile attacks a phosphodiester bond to form a 3 phosphotyrosine linkage and releases a free 5 hydroxyl group. This creates a nick in the DNA, which unwinds to relieve supercoiling. The DNA is then re-ligated to form relaxed DNA. Most mechanisms involving DNA including replication, transcription, and repair induce a certain degree of positive supercoiling. Tension due to the positive supercoiling buildup can be relieved by the enzymes topoisomerase. The variola topoisomerase 1B is an unusual topoisomerase. It is by far the smallest topoisomerase (33Kda) and only acts at specific sites that contain the sequence 5-(T/C)CCTT-3 in the variola genome. The topoisomerase 1B is made up of two domains that wrap around this recognition sequence forming a clamp around the DNA. The smaller N-terminal domain is responsible for interactions with the DNA sequence, whereas the larger C-terminal domain contains the active site and is the area responsible for all enzymatic activity. The type 1B topoisomerase can relieve negative or positive supercoiling without the use of ATP. As long as there’s torsional strain on the DNA strand from the supercoiling, this is enough potential energy to drive the uncoiling of the strand. The viral topoisomerase 1B enzymes contain a highly conserved region consisting of five common amino acid residues. These residues are Tyr, Arg, Arg, Lys, His/Asp. Type IB topoisomerase is a key target for research against the spread of smallpox because it is integral for the virus’s replication process. The replication of smallpox is complicated since it doesn’t hijack the host’s genetic machinery to reproduce, this makes the disease highly virulent, and hard to specifically target for elimination by antiviral drugs.
  • #4 Smallpox: Background, Etiology, Epidemiology
    https://emedicine.medscape.com/article/237229-overview
    Smallpox is an acute, contagious disease caused by the variola virus, a member of the genus Orthopoxvirus, in the Poxviridae family. […] Poxviridae are linear, double-stranded deoxyribonucleic acid (DNA) viruses that replicate in the cytoplasm. […] The variola virus is a large, brick-shaped, double-stranded DNA virus that serologically cross-reacts with other members of the poxvirus family, including ectromelia, cowpox, monkeypox, vaccinia, and camelpox. Unlike other DNA viruses, the variola virus multiplies in the cytoplasm of parasitized host cells. […] Because of potential bioterrorism, interest in smallpox pathogenesis has increased. Protein analysis indicates that the variola virus G1R protein binds to cellular nuclear factor kappa-B (NF-kB), thereby inhibiting its function in cell signalling.
  • #5 SMALLPOX ( Pathophysiology and Health Education Presentation ) | PPT
    https://www.slideshare.net/slideshow/smallpox-pathophysiology-and-health-education-presentation/233047577
    Smallpox is a devastating disease caused by the variola virus a member of the orthopoxvirus family. […] Smallpox is a contagious, disfiguring and often deadly disease that has affected humans for thousands of years. Naturally occurring smallpox was eradicated worldwide by 1980 the result of an unprecedented global immunization campaign. […] POXVIRUSES ARE UNIQUE AMONG DNA VIRUSES THAT THEY REPLICATE IN THE CYTOPLASM OF THE CELL RATHER THAN THE NUCLEUS. […] VARIOLA CELL STRUCTURE […] VIRUS EXITS HOST CELL AFTER USING REPLICATION MACHINERY OF HOST CELL TO INFECT OTHER CELLS. […] There were two forms of the smallpox virus. Variola major was the severe and most common form, with a more extensive rash and higher fever, which can result in confluent smallpox, which had a high death rate. Variola minor was a less common presentation, causing a less severe disease, typically discrete smallpox, with historical death rates of one percent or less.
  • #6 SMALLPOX ( Pathophysiology and Health Education Presentation ) | PPT
    https://www.slideshare.net/slideshow/smallpox-pathophysiology-and-health-education-presentation/233047577
    The initial symptoms were similar to other viral diseases that are still extant, such as influenza and the common cold: fever of at least 38.3 C (101 F), muscle pain, malaise, headache and fatigue. […] The more dangerous form, variola major, led to smallpox disease that killed about 30% of people who were infected. Variola minor caused a less deadly type that killed about 1% of those who got it. […] HEMORRHAGIC SMALLPOX (MOST SEVERE FORM) […] Hemorrhagic smallpox was a severe form accompanied by extensive bleeding into the skin, mucous membranes, and gastrointestinal tract. This form developed in approximately 2 percent of infections and occurred mostly in adults.
  • #7 About Smallpox | Smallpox | CDC
    https://www.cdc.gov/smallpox/about/index.html
    Smallpox was an infectious disease caused by the variola virus. […] Variola virus, a virus from Orthopoxviridae family that causes smallpox, highly contagious disease eradicated by vaccination. […] Before smallpox was eradicated, it was a serious infectious disease caused by the variola virus. It was contagious meaning, it spread from one person to another. […] While some antiviral drugs may help treat smallpox disease, there is no treatment for smallpox that has been tested in people who are sick with the disease and proven effective. […] Although smallpox has been eradicated, it is possible that variola virus could be used in a biological attack.
  • #8 What is mpox? A microbiologist explains what’s known about this smallpox cousin
    https://theconversation.com/what-is-mpox-a-microbiologist-explains-whats-known-about-this-smallpox-cousin-236857
    Mpox is caused by the monkeypox virus, which belongs to a subset of the Poxviridae family of viruses called Orthopoxvirus. This subset includes the smallpox, vaccinia and cowpox viruses. […] Because mpox is closely related to smallpox, the smallpox vaccine can provide protection against infection from both viruses. […] After the virus enters the body, it starts to replicate and spread through the body via the bloodstream. […] Mpox produces smallpox-like skin lesions, but symptoms are usually milder than those of smallpox. […] While mpox is rare and usually nonfatal, one version of the disease kills around 10% of infected people. The form of the virus currently circulating is thought to be milder, with a fatality rate of less than 1%. […] Evidence suggests that the smallpox vaccine can help prevent mpox infections and decrease the severity of the symptoms.
  • #9 SMALLPOX ( Pathophysiology and Health Education Presentation ) | PPT
    https://www.slideshare.net/slideshow/smallpox-pathophysiology-and-health-education-presentation/233047577
    Smallpox is a devastating disease caused by the variola virus a member of the orthopoxvirus family. […] Smallpox is a contagious, disfiguring and often deadly disease that has affected humans for thousands of years. Naturally occurring smallpox was eradicated worldwide by 1980 the result of an unprecedented global immunization campaign. […] POXVIRUSES ARE UNIQUE AMONG DNA VIRUSES THAT THEY REPLICATE IN THE CYTOPLASM OF THE CELL RATHER THAN THE NUCLEUS. […] VARIOLA CELL STRUCTURE […] VIRUS EXITS HOST CELL AFTER USING REPLICATION MACHINERY OF HOST CELL TO INFECT OTHER CELLS. […] There were two forms of the smallpox virus. Variola major was the severe and most common form, with a more extensive rash and higher fever, which can result in confluent smallpox, which had a high death rate. Variola minor was a less common presentation, causing a less severe disease, typically discrete smallpox, with historical death rates of one percent or less.
  • #10 Smallpox – StatPearls – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK470418/
    Smallpox is a member of the viral family poxvirus, genus orthopoxvirus, and species variola virus. […] The poxviruses possess a linear, double-stranded DNA genome, and are unique in that their genetic makeup encodes all the proteins necessary for replication allowing them to replicate in the host cell cytoplasm. […] After viral entry through the oropharynx or nasopharynx, the virus migrates to regional lymph nodes where it begins replication. An initial viremia occurs on day 3 to 4 after infection, and the virus further disseminates to the bone marrow, spleen, and additional lymph node chains. A secondary viremia occurs between day 8 to 12 after infection and coincides with the onset of fever and clinical evidence of illness. At this stage, the virus becomes localized in the oropharyngeal mucosa and small blood vessels of the dermis, resulting in the onset of rash and clinical infectiousness.
  • #11 Smallpox (Variola Virus) – Topoisomerase 1B – Proteopedia, life in 3D
    https://proteopedia.org/wiki/index.php/Smallpox_(Variola_Virus)_-_Topoisomerase_1B
    Smallpox is caused by the Variola virus, a member of the genus Orthopoxvirus. Its genome consists of a single, linear double-stranded DNA molecule made up of 186,102 base pairs. There are 10 enzymes that regulate gene expression, as well as about 100 nucleoproteins involved in transcription of the DNA. The smallpox virus invades host cells by binding to specific receptors on the host cell membrane. The virus binds to host cell receptors via hemagglutinin antigens expressed on its outer surface. The exact mechanism of entry is not yet known. Upon invasion of a host cell, the smallpox virus replicates in the host cytoplasm, rather than the host nucleus, using many of the host’s own enzymes to replicate. Replication begins once the virion has reached the cytoplasm of the host cell. First, a messenger RNA molecule is transcribed by RNA polymerase and related enzymes before the genome is uncoated. The first genes that are transcribed, known as early genes, code for proteins that facilitate the uncoating of the viral genome and initiate a second round of transcription of intermediate genes. The intermediate genes produce mRNA, which are translated into proteins that allow the transcription of the late class of genes. The late class genes encode proteins, which make up the structural and enzymatic components of a new virion. Further replication of this virus leads to the eventual shutdown of the host cells DNA, RNA, and protein synthesis, and causes changes to the cells architecture to allow the virus to use the host cells genetic machinery for reproduction. One characteristic that makes the Variola virus so deadly is that it doesn’t require any help from the host cell to begin replication. The reason for this is that the Variola virus codes for all the enzymes needed for its proliferation. One enzyme in particular, the type IB topoisomerase is responsible for unwinding the packaged, supercoiled, viral DNA to initiate viral replication. This is accomplished through a nick-joining mechanism, in which a tyrosine nucleophile attacks a phosphodiester bond to form a 3 phosphotyrosine linkage and releases a free 5 hydroxyl group. This creates a nick in the DNA, which unwinds to relieve supercoiling. The DNA is then re-ligated to form relaxed DNA. Most mechanisms involving DNA including replication, transcription, and repair induce a certain degree of positive supercoiling. Tension due to the positive supercoiling buildup can be relieved by the enzymes topoisomerase. The variola topoisomerase 1B is an unusual topoisomerase. It is by far the smallest topoisomerase (33Kda) and only acts at specific sites that contain the sequence 5-(T/C)CCTT-3 in the variola genome. The topoisomerase 1B is made up of two domains that wrap around this recognition sequence forming a clamp around the DNA. The smaller N-terminal domain is responsible for interactions with the DNA sequence, whereas the larger C-terminal domain contains the active site and is the area responsible for all enzymatic activity. The type 1B topoisomerase can relieve negative or positive supercoiling without the use of ATP. As long as there’s torsional strain on the DNA strand from the supercoiling, this is enough potential energy to drive the uncoiling of the strand. The viral topoisomerase 1B enzymes contain a highly conserved sequence consisting of five common amino acid residues. These residues are Tyr, Arg, Arg, Lys, His/Asp. Type IB topoisomerase is a key target for research against the spread of smallpox because it is integral for the viruses replication process. The replication of smallpox is complicated since it doesn’t hijack the hosts genetic machinery to reproduce, this makes the disease highly virulent, and hard to specifically target for elimination by antiviral drugs.
  • #12 Smallpox pathophysiology – wikidoc
    https://www.wikidoc.org/index.php/Smallpox_pathophysiology
    Smallpox pathogenicity is due to its ability to evade the host’s immune system. Most proteins responsible for the pathogenesis of the virus are located at the terminal DNA regions of the virus. […] The smallpox virus commonly enters the body through the upper respiratory tract, invading the oropharyngeal and respiratory mucosa. Other possible ports of entry include: skin, conjunctiva as well as through the placenta. […] Once in the respiratory mucosa, the infection commonly progresses as: Asymptomatic respiratory mucosa infection, Viral replication within respiratory epithelium, Transient primary asymptomatic viraemia, Virus enters macrophages and spreads to lymph nodes and reticuloendothelial system, where it replicates during 4 – 14 days, Exuberant secondary viraemia, leading to symptom onset.
  • #13 Smallpox (Variola Virus) – Topoisomerase 1B – Proteopedia, life in 3D
    https://proteopedia.org/wiki/index.php/Smallpox_(Variola_Virus)_-_Topoisomerase_1B
    Smallpox is caused by the Variola virus, a member of the genus Orthopoxvirus. Its genome consists of a single, linear double-stranded DNA molecule made up of 186,102 base pairs. There are 10 enzymes that regulate gene expression, as well as about 100 nucleoproteins involved in transcription of the DNA. The smallpox virus invades host cells by binding to specific receptors on the host cell membrane. The virus binds to host cell receptors via hemagglutinin antigens expressed on its outer surface. The exact mechanism of entry is not yet known. Upon invasion of a host cell, the smallpox virus replicates in the host cytoplasm, rather than the host nucleus, using many of the host’s own enzymes to replicate. Replication begins once the virion has reached the cytoplasm of the host cell. First, a messenger RNA molecule is transcribed by RNA polymerase and related enzymes before the genome is uncoated. The first genes that are transcribed, known as early genes, code for proteins that facilitate the uncoating of the viral genome and initiate a second round of transcription of intermediate genes. The intermediate genes produce mRNA, which are translated into proteins that allow the transcription of the late class of genes. The late class genes encode proteins, which make up the structural and enzymatic components of a new virion. Further replication of this virus leads to the eventual shutdown of the host cells DNA, RNA, and protein synthesis, and causes changes to the cells architecture to allow the virus to use the host cells genetic machinery for reproduction. One characteristic that makes the Variola virus so deadly is that it doesn’t require any help from the host cell to begin replication. The reason for this is that the Variola virus codes for all the enzymes needed for its proliferation. One enzyme in particular, the type IB topoisomerase is responsible for unwinding the packaged, supercoiled, viral DNA to initiate viral replication. This is accomplished through a nick-joining mechanism, in which a tyrosine nucleophile attacks a phosphodiester bond to form a 3 phosphotyrosine linkage and releases a free 5 hydroxyl group. This creates a nick in the DNA, which unwinds to relieve supercoiling. The DNA is then re-ligated to form relaxed DNA. Most mechanisms involving DNA including replication, transcription, and repair induce a certain degree of positive supercoiling. Tension due to the positive supercoiling buildup can be relieved by the enzymes topoisomerase. The variola topoisomerase 1B is an unusual topoisomerase. It is by far the smallest topoisomerase (33Kda) and only acts at specific sites that contain the sequence 5-(T/C)CCTT-3 in the variola genome. The topoisomerase 1B is made up of two domains that wrap around this recognition sequence forming a clamp around the DNA. The smaller N-terminal domain is responsible for interactions with the DNA sequence, whereas the larger C-terminal domain contains the active site and is the area responsible for all enzymatic activity. The type 1B topoisomerase can relieve negative or positive supercoiling without the use of ATP. As long as there’s torsional strain on the DNA strand from the supercoiling, this is enough potential energy to drive the uncoiling of the strand. The viral topoisomerase 1B enzymes contain a highly conserved sequence consisting of five common amino acid residues. These residues are Tyr, Arg, Arg, Lys, His/Asp. Type IB topoisomerase is a key target for research against the spread of smallpox because it is integral for the viruses replication process. The replication of smallpox is complicated since it doesn’t hijack the hosts genetic machinery to reproduce, this makes the disease highly virulent, and hard to specifically target for elimination by antiviral drugs.
  • #14 Smallpox: Background, Etiology, Epidemiology
    https://emedicine.medscape.com/article/237229-overview
    Smallpox is an acute, contagious disease caused by the variola virus, a member of the genus Orthopoxvirus, in the Poxviridae family. […] Poxviridae are linear, double-stranded deoxyribonucleic acid (DNA) viruses that replicate in the cytoplasm. […] The variola virus is a large, brick-shaped, double-stranded DNA virus that serologically cross-reacts with other members of the poxvirus family, including ectromelia, cowpox, monkeypox, vaccinia, and camelpox. Unlike other DNA viruses, the variola virus multiplies in the cytoplasm of parasitized host cells. […] Because of potential bioterrorism, interest in smallpox pathogenesis has increased. Protein analysis indicates that the variola virus G1R protein binds to cellular nuclear factor kappa-B (NF-kB), thereby inhibiting its function in cell signalling.
  • #15 Smallpox: Background, Etiology, Epidemiology
    https://emedicine.medscape.com/article/237229-overview
    The G1R protein is highly conserved among pathogenic orthopoxviruses and is absent from the less-pathogenic vaccinia strains, thus suggesting that it may serve as a molecular therapeutic target. […] Other studies developed a method of reliably classifying species of variola virus into major and minor species by genotype using novel real-time polymerase chain reaction (PCR) assay probes. […] Implantation of just a few virions of smallpox into the oropharynx or respiratory tracts can cause infection. The virus infects macrophages during the first 72 hours of the incubation phase. The virus migrates and multiplies in the regional lymph nodes, resulting in asymptomatic viremia by the fourth day. The virus multiplies in the spleen, bone marrow, and lymph nodes, resulting in a symptomatic secondary viremia (ie, fever, toxemia) by the eighth day.
  • #16 Smallpox – Infectious Diseases – Merck Manual Professional Edition
    https://www.merckmanuals.com/professional/infectious-diseases/pox-viruses/smallpox
    Smallpox is transmitted from person to person by inhalation of respiratory droplets or, less efficiently, by direct contact. […] The virus invades the oropharyngeal or respiratory mucosa and multiplies in regional lymph nodes, causing subsequent viremia. It eventually localizes in small blood vessels of the dermis and the oropharyngeal mucosa. Other organs are seldom clinically involved, except for occasionally the central nervous system, with encephalitis. Secondary bacterial infection of the skin, lungs, and bones may develop. […] The antiviral drug tecovirimat was approved by the US Food and Drug Administration (FDA) in 2018 and, in June 2021, the FDA approved brincidofovir (CMX 001) for treatment of smallpox. Both approvals were based on experimental studies and, although their effectiveness against smallpox in humans is unknown, in laboratory tests, both stopped the growth of the virus that causes smallpox and were effective in treating animals that had diseases similar to smallpox. Additionally, cidofovir, which is not FDA-approved for treatment of smallpox, could be used during an outbreak under an appropriate regulatory mechanism. […] Treatment of smallpox is generally supportive, with antibiotics for secondary bacterial infections.
  • #17 Smallpox – Symptoms and causes – Mayo Clinic
    https://www.mayoclinic.org/diseases-conditions/smallpox/symptoms-causes/syc-20353027
    Smallpox is caused by the variola virus. The virus can spread: […] Directly from person to person. You can catch the smallpox virus by being around someone who has it. An infected person can spread the virus when they cough, sneeze or talk. […] Smallpox can also spread through contact with contaminated clothing and bedding. But getting smallpox this way is less likely. […] Using smallpox as a weapon is an unlikely threat. But because releasing the virus could spread the disease quickly, governments are preparing for this possibility.
  • #18
    https://virus.stanford.edu/pox/2000/smallpox.html
    Infection usually occurred by inhalation of virus found in the oropharyngeal secretions of an infected individual during the first week that the characteristic rash appeared. […] Upon infection, early viral replication took place in the lymphoid organs: the spleen, bone marrow, and lymph nodes. The cell-associated virions, and infected macrophages, became localized in small vessels of the dermis. Infected macrophages would then migrate from these vessels into the epidermis, where they would in turn infect nearby cells of the basal layer. Necrosis and edema followed, with obstruction of the dermis. […] The first components of the immune system to become manifest upon mounting an immune response, were cytotoxic T cells. These cells promptly destroyed many infected cells before they produced virions by reacting with antigens in the cell membranes. In cases in which an early cell-mediated immune response occurred, replication of the virus was inhibited and the skin lesions were restricted. However, in immunocompromised individuals, hemorrhagic smallpox usually occurred. […] The outcome of infection was either death or recovery with immunity. Variola virus did not persist in the body after recovery. Blindness was a rare complication, usually occurring in cases where there was malnutrition and/or a secondary bacterial infection.
  • #19 Smallpox pathophysiology – wikidoc
    https://www.wikidoc.org/index.php/Smallpox_pathophysiology
    Smallpox pathogenicity is due to its ability to evade the host’s immune system. Most proteins responsible for the pathogenesis of the virus are located at the terminal DNA regions of the virus. […] The smallpox virus commonly enters the body through the upper respiratory tract, invading the oropharyngeal and respiratory mucosa. Other possible ports of entry include: skin, conjunctiva as well as through the placenta. […] Once in the respiratory mucosa, the infection commonly progresses as: Asymptomatic respiratory mucosa infection, Viral replication within respiratory epithelium, Transient primary asymptomatic viraemia, Virus enters macrophages and spreads to lymph nodes and reticuloendothelial system, where it replicates during 4 – 14 days, Exuberant secondary viraemia, leading to symptom onset.
  • #20 Smallpox – StatPearls – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK470418/
    Smallpox is a member of the viral family poxvirus, genus orthopoxvirus, and species variola virus. […] The poxviruses possess a linear, double-stranded DNA genome, and are unique in that their genetic makeup encodes all the proteins necessary for replication allowing them to replicate in the host cell cytoplasm. […] After viral entry through the oropharynx or nasopharynx, the virus migrates to regional lymph nodes where it begins replication. An initial viremia occurs on day 3 to 4 after infection, and the virus further disseminates to the bone marrow, spleen, and additional lymph node chains. A secondary viremia occurs between day 8 to 12 after infection and coincides with the onset of fever and clinical evidence of illness. At this stage, the virus becomes localized in the oropharyngeal mucosa and small blood vessels of the dermis, resulting in the onset of rash and clinical infectiousness.
  • #21 Smallpox – StatPearls – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK470418/
    Smallpox is a member of the viral family poxvirus, genus orthopoxvirus, and species variola virus. […] The poxviruses possess a linear, double-stranded DNA genome, and are unique in that their genetic makeup encodes all the proteins necessary for replication allowing them to replicate in the host cell cytoplasm. […] After viral entry through the oropharynx or nasopharynx, the virus migrates to regional lymph nodes where it begins replication. An initial viremia occurs on day 3 to 4 after infection, and the virus further disseminates to the bone marrow, spleen, and additional lymph node chains. A secondary viremia occurs between day 8 to 12 after infection and coincides with the onset of fever and clinical evidence of illness. At this stage, the virus becomes localized in the oropharyngeal mucosa and small blood vessels of the dermis, resulting in the onset of rash and clinical infectiousness.
  • #22 Smallpox pathophysiology – wikidoc
    https://www.wikidoc.org/index.php/Smallpox_pathophysiology
    Smallpox pathogenicity is due to its ability to evade the host’s immune system. Most proteins responsible for the pathogenesis of the virus are located at the terminal DNA regions of the virus. […] The smallpox virus commonly enters the body through the upper respiratory tract, invading the oropharyngeal and respiratory mucosa. Other possible ports of entry include: skin, conjunctiva as well as through the placenta. […] Once in the respiratory mucosa, the infection commonly progresses as: Asymptomatic respiratory mucosa infection, Viral replication within respiratory epithelium, Transient primary asymptomatic viraemia, Virus enters macrophages and spreads to lymph nodes and reticuloendothelial system, where it replicates during 4 – 14 days, Exuberant secondary viraemia, leading to symptom onset.
  • #23 Smallpox – StatPearls – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK470418/
    Smallpox is a member of the viral family poxvirus, genus orthopoxvirus, and species variola virus. […] The poxviruses possess a linear, double-stranded DNA genome, and are unique in that their genetic makeup encodes all the proteins necessary for replication allowing them to replicate in the host cell cytoplasm. […] After viral entry through the oropharynx or nasopharynx, the virus migrates to regional lymph nodes where it begins replication. An initial viremia occurs on day 3 to 4 after infection, and the virus further disseminates to the bone marrow, spleen, and additional lymph node chains. A secondary viremia occurs between day 8 to 12 after infection and coincides with the onset of fever and clinical evidence of illness. At this stage, the virus becomes localized in the oropharyngeal mucosa and small blood vessels of the dermis, resulting in the onset of rash and clinical infectiousness.
  • #24 Smallpox: Background, Etiology, Epidemiology
    https://emedicine.medscape.com/article/237229-overview
    Finally, the virus reenters the blood in leukocytes, producing fever and toxemia, and then passes from leukocytes to adjacent cells in small blood vessels of the dermis and beneath the oropharyngeal mucosa, leading to the initial onset of the enanthem and exanthem, at which point (approximately day 14) the patient becomes infectious. […] Patients exposed to smallpox through routes other than the person-to-person respiratory route also have shorter incubation periods. Prior immunization, vaccinia immunoglobulin (VIG), and, possibly, antiviral chemotherapy may extend the incubation period. […] Because of potential bioterrorism, interest in smallpox pathogenesis has increased. Protein analysis indicates that the variola virus G1R protein binds to cellular nuclear factor kappa-B (NF-kB), thereby inhibiting its function in cell signalling.
  • #25 Smallpox pathophysiology – wikidoc
    https://www.wikidoc.org/index.php/Smallpox_pathophysiology
    During secondary viraemia the virus infects mucous cells of the pharynx and mouth, and endothelium of the capillaries of the dermis, causing skin lesions. […] Skin lesions develop due to migration of macrophages to the infected areas of the dermis, leading to edema and necrosis. […] The immune system responds to the viremia with activation of lymphocytes T and B and concomitant production of: Neutralizing antibodies, during first week of disease, remaining for many years, Hemagglutination-inhibition antibodies, by the 16th day of infection, beginning to decrease after 1 year, Complement-fixation antibodies, by the 18th day of infection, beginning to decrease after 1 year, Memory T cells, remaining for 50 years. […] Death by smallpox was commonly due to toxemia, following: Hypotension, Coagulopathy, Multiorgan failure, Bacterial infections.
  • #26 Smallpox: Background, Etiology, Epidemiology
    https://emedicine.medscape.com/article/237229-overview
    Finally, the virus reenters the blood in leukocytes, producing fever and toxemia, and then passes from leukocytes to adjacent cells in small blood vessels of the dermis and beneath the oropharyngeal mucosa, leading to the initial onset of the enanthem and exanthem, at which point (approximately day 14) the patient becomes infectious. […] Patients exposed to smallpox through routes other than the person-to-person respiratory route also have shorter incubation periods. Prior immunization, vaccinia immunoglobulin (VIG), and, possibly, antiviral chemotherapy may extend the incubation period. […] Because of potential bioterrorism, interest in smallpox pathogenesis has increased. Protein analysis indicates that the variola virus G1R protein binds to cellular nuclear factor kappa-B (NF-kB), thereby inhibiting its function in cell signalling.
  • #27 Smallpox (Variola Virus) – Topoisomerase 1B – Proteopedia, life in 3D
    https://proteopedia.org/wiki/index.php/Smallpox_%28Variola_Virus%29_-_Topoisomerase_1B
    Smallpox is caused by the Variola virus, a member of the genus Orthopoxvirus. Its genome consists of a single, linear double-stranded DNA molecule made up of 186,102 base pairs. There are 10 enzymes that regulate gene expression, as well as about 100 nucleoproteins involved in transcription of the DNA. The smallpox virus invades host cells by binding to specific receptors on the host cell membrane. The virus binds to host cell receptors via hemagglutinin antigens expressed on its outer surface. The exact mechanism of entry is not yet known. Upon invasion of a host cell, the smallpox virus replicates in the host cytoplasm, rather than the host nucleus, using many of the host’s own enzymes to replicate. Replication begins once the virion has reached the cytoplasm of the host cell. First, a messenger RNA molecule is transcribed by RNA polymerase and related enzymes before the genome is uncoated. The first genes that are transcribed, known as early genes, code for proteins that facilitate the uncoating of the viral genome and initiate a second round of transcription of intermediate genes. The intermediate genes produce mRNA, which are translated into proteins that allow the transcription of the late class of genes. The late class genes encode proteins, which make up the structural and enzymatic components of a new virion. Further replication of this virus leads to the eventual shutdown of the host cells DNA, RNA, and protein synthesis, and causes changes to the cells architecture to allow the virus to use the host cells genetic machinery for reproduction. One characteristic that makes the Variola virus so deadly is that it doesn’t require any help from the host cell to begin replication. The reason for this is that the Variola virus codes for all the enzymes needed for its proliferation. One enzyme in particular, the type IB topoisomerase is responsible for unwinding the packaged, supercoiled, viral DNA to initiate viral replication. This is accomplished through a nick-joining mechanism, in which a tyrosine nucleophile attacks a phosphodiester bond to form a 3 phosphotyrosine linkage and releases a free 5 hydroxyl group. This creates a nick in the DNA, which unwinds to relieve supercoiling. The DNA is then re-ligated to form relaxed DNA. Most mechanisms involving DNA including replication, transcription, and repair induce a certain degree of positive supercoiling. Tension due to the positive supercoiling buildup can be relieved by the enzymes topoisomerase. The variola topoisomerase 1B is an unusual topoisomerase. It is by far the smallest topoisomerase (33Kda) and only acts at specific sites that contain the sequence 5-(T/C)CCTT-3 in the variola genome. The topoisomerase 1B is made up of two domains that wrap around this recognition sequence forming a clamp around the DNA. The smaller N-terminal domain is responsible for interactions with the DNA sequence, whereas the larger C-terminal domain contains the active site and is the area responsible for all enzymatic activity. The type 1B topoisomerase can relieve negative or positive supercoiling without the use of ATP. As long as there’s torsional strain on the DNA strand from the supercoiling, this is enough potential energy to drive the uncoiling of the strand. The viral topoisomerase 1B enzymes contain a highly conserved region consisting of five common amino acid residues. These residues are Tyr, Arg, Arg, Lys, His/Asp. Type IB topoisomerase is a key target for research against the spread of smallpox because it is integral for the virus’s replication process. The replication of smallpox is complicated since it doesn’t hijack the host’s genetic machinery to reproduce, this makes the disease highly virulent, and hard to specifically target for elimination by antiviral drugs.
  • #28 Novel virus entry mechanism could lead to new drugs against poxviruses | ScienceDaily
    https://www.sciencedaily.com/releases/2006/04/060412222250.htm
    Scientists working with Vaccinia virus, the smallpox vaccine, have discovered a novel mechanism that allows poxviruses to enter cells and cause infection. […] The mechanism is unique in virology and paves the way for development of new antiviral drugs. […] The researchers found that interactions between polyanionic or negatively charged molecules on the cell surface and glycoproteins on the virus particle caused a non-fusogenic disruption of the virus outer envelope, allowing the poxvirus to enter the cell. […] Disrupting the outer membrane with polyanionic compounds exposes the virus, allowing antiviral antibodies to be more effective. […] It increases our understanding of how viruses can manipulate biological membranes and will help the development of new drugs against poxviruses, such as variola virus, the cause of smallpox.
  • #29 Smallpox (Variola Virus) – Topoisomerase 1B – Proteopedia, life in 3D
    https://proteopedia.org/wiki/index.php/Smallpox_%28Variola_Virus%29_-_Topoisomerase_1B
    Smallpox is caused by the Variola virus, a member of the genus Orthopoxvirus. Its genome consists of a single, linear double-stranded DNA molecule made up of 186,102 base pairs. There are 10 enzymes that regulate gene expression, as well as about 100 nucleoproteins involved in transcription of the DNA. The smallpox virus invades host cells by binding to specific receptors on the host cell membrane. The virus binds to host cell receptors via hemagglutinin antigens expressed on its outer surface. The exact mechanism of entry is not yet known. Upon invasion of a host cell, the smallpox virus replicates in the host cytoplasm, rather than the host nucleus, using many of the host’s own enzymes to replicate. Replication begins once the virion has reached the cytoplasm of the host cell. First, a messenger RNA molecule is transcribed by RNA polymerase and related enzymes before the genome is uncoated. The first genes that are transcribed, known as early genes, code for proteins that facilitate the uncoating of the viral genome and initiate a second round of transcription of intermediate genes. The intermediate genes produce mRNA, which are translated into proteins that allow the transcription of the late class of genes. The late class genes encode proteins, which make up the structural and enzymatic components of a new virion. Further replication of this virus leads to the eventual shutdown of the host cells DNA, RNA, and protein synthesis, and causes changes to the cells architecture to allow the virus to use the host cells genetic machinery for reproduction. One characteristic that makes the Variola virus so deadly is that it doesn’t require any help from the host cell to begin replication. The reason for this is that the Variola virus codes for all the enzymes needed for its proliferation. One enzyme in particular, the type IB topoisomerase is responsible for unwinding the packaged, supercoiled, viral DNA to initiate viral replication. This is accomplished through a nick-joining mechanism, in which a tyrosine nucleophile attacks a phosphodiester bond to form a 3 phosphotyrosine linkage and releases a free 5 hydroxyl group. This creates a nick in the DNA, which unwinds to relieve supercoiling. The DNA is then re-ligated to form relaxed DNA. Most mechanisms involving DNA including replication, transcription, and repair induce a certain degree of positive supercoiling. Tension due to the positive supercoiling buildup can be relieved by the enzymes topoisomerase. The variola topoisomerase 1B is an unusual topoisomerase. It is by far the smallest topoisomerase (33Kda) and only acts at specific sites that contain the sequence 5-(T/C)CCTT-3 in the variola genome. The topoisomerase 1B is made up of two domains that wrap around this recognition sequence forming a clamp around the DNA. The smaller N-terminal domain is responsible for interactions with the DNA sequence, whereas the larger C-terminal domain contains the active site and is the area responsible for all enzymatic activity. The type 1B topoisomerase can relieve negative or positive supercoiling without the use of ATP. As long as there’s torsional strain on the DNA strand from the supercoiling, this is enough potential energy to drive the uncoiling of the strand. The viral topoisomerase 1B enzymes contain a highly conserved region consisting of five common amino acid residues. These residues are Tyr, Arg, Arg, Lys, His/Asp. Type IB topoisomerase is a key target for research against the spread of smallpox because it is integral for the virus’s replication process. The replication of smallpox is complicated since it doesn’t hijack the host’s genetic machinery to reproduce, this makes the disease highly virulent, and hard to specifically target for elimination by antiviral drugs.
  • #30 Smallpox (Variola Virus) – Topoisomerase 1B – Proteopedia, life in 3D
    https://proteopedia.org/wiki/index.php/Smallpox_%28Variola_Virus%29_-_Topoisomerase_1B
    Smallpox is caused by the Variola virus, a member of the genus Orthopoxvirus. Its genome consists of a single, linear double-stranded DNA molecule made up of 186,102 base pairs. There are 10 enzymes that regulate gene expression, as well as about 100 nucleoproteins involved in transcription of the DNA. The smallpox virus invades host cells by binding to specific receptors on the host cell membrane. The virus binds to host cell receptors via hemagglutinin antigens expressed on its outer surface. The exact mechanism of entry is not yet known. Upon invasion of a host cell, the smallpox virus replicates in the host cytoplasm, rather than the host nucleus, using many of the host’s own enzymes to replicate. Replication begins once the virion has reached the cytoplasm of the host cell. First, a messenger RNA molecule is transcribed by RNA polymerase and related enzymes before the genome is uncoated. The first genes that are transcribed, known as early genes, code for proteins that facilitate the uncoating of the viral genome and initiate a second round of transcription of intermediate genes. The intermediate genes produce mRNA, which are translated into proteins that allow the transcription of the late class of genes. The late class genes encode proteins, which make up the structural and enzymatic components of a new virion. Further replication of this virus leads to the eventual shutdown of the host cells DNA, RNA, and protein synthesis, and causes changes to the cells architecture to allow the virus to use the host cells genetic machinery for reproduction. One characteristic that makes the Variola virus so deadly is that it doesn’t require any help from the host cell to begin replication. The reason for this is that the Variola virus codes for all the enzymes needed for its proliferation. One enzyme in particular, the type IB topoisomerase is responsible for unwinding the packaged, supercoiled, viral DNA to initiate viral replication. This is accomplished through a nick-joining mechanism, in which a tyrosine nucleophile attacks a phosphodiester bond to form a 3 phosphotyrosine linkage and releases a free 5 hydroxyl group. This creates a nick in the DNA, which unwinds to relieve supercoiling. The DNA is then re-ligated to form relaxed DNA. Most mechanisms involving DNA including replication, transcription, and repair induce a certain degree of positive supercoiling. Tension due to the positive supercoiling buildup can be relieved by the enzymes topoisomerase. The variola topoisomerase 1B is an unusual topoisomerase. It is by far the smallest topoisomerase (33Kda) and only acts at specific sites that contain the sequence 5-(T/C)CCTT-3 in the variola genome. The topoisomerase 1B is made up of two domains that wrap around this recognition sequence forming a clamp around the DNA. The smaller N-terminal domain is responsible for interactions with the DNA sequence, whereas the larger C-terminal domain contains the active site and is the area responsible for all enzymatic activity. The type 1B topoisomerase can relieve negative or positive supercoiling without the use of ATP. As long as there’s torsional strain on the DNA strand from the supercoiling, this is enough potential energy to drive the uncoiling of the strand. The viral topoisomerase 1B enzymes contain a highly conserved region consisting of five common amino acid residues. These residues are Tyr, Arg, Arg, Lys, His/Asp. Type IB topoisomerase is a key target for research against the spread of smallpox because it is integral for the virus’s replication process. The replication of smallpox is complicated since it doesn’t hijack the host’s genetic machinery to reproduce, this makes the disease highly virulent, and hard to specifically target for elimination by antiviral drugs.
  • #31 Smallpox pathophysiology – wikidoc
    https://www.wikidoc.org/index.php/Smallpox_pathophysiology
    During secondary viraemia the virus infects mucous cells of the pharynx and mouth, and endothelium of the capillaries of the dermis, causing skin lesions. […] Skin lesions develop due to migration of macrophages to the infected areas of the dermis, leading to edema and necrosis. […] The immune system responds to the viremia with activation of lymphocytes T and B and concomitant production of: Neutralizing antibodies, during first week of disease, remaining for many years, Hemagglutination-inhibition antibodies, by the 16th day of infection, beginning to decrease after 1 year, Complement-fixation antibodies, by the 18th day of infection, beginning to decrease after 1 year, Memory T cells, remaining for 50 years. […] Death by smallpox was commonly due to toxemia, following: Hypotension, Coagulopathy, Multiorgan failure, Bacterial infections.
  • #32 Clinical Features of Smallpox – Assessment of Future Scientific Needs for Live Variola Virus – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK230904/
    The term pathogenesis is used to describe the mechanisms involved in the production of disease, from the spread of infection through the body to the molecular and physiological responses of host cells to a pathogen. […] The pathogenesis of smallpox has been studied in three ways: (1) by using material from human patients; (2) by conducting experiments with variola virus infection of nonhuman primates; and (3) by conducting experiments with model infections in mice, rabbits, and monkeys using related orthopoxviruses. […] Smallpox pathogenesis is a poorly understood series of events in which the virus first disseminates locally, then through the lymphatic system, and finally to the skin without affecting vital organs. […] The primary event that triggers the production of focal lesions in orthopoxvirus infections is the localization of virus particles in the small dermal blood vessels.
  • #33 Clinical Features of Smallpox – Assessment of Future Scientific Needs for Live Variola Virus – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK230904/
    The mechanisms that allow the localization of variola virus in the skin and the characteristic „centrifugal’ distribution of the rash are not known. […] The lack of a homy, keratinized cell layer permits the lesions on the mucous membranes to ulcerate soon afar their formation, releasing large amounts of highly infectious virus into the saliva. […] Death is usually the result of disseminated intravascular coagulation, hypotension, and cardiovascular collapse; these are exacerbated by clotting defects in the rare hemorrhagic type of smallpox. […] The endothelial cells lining the sinusoids of the liver are often swollen and occasionally proliferating or necrotic. […] The best information on the relative importance of cell-mediated and humoral immune responses to orthopoxvirus infections in humans comes from studies of human subjects in immune-deficient states who are subsequently vaccinated with vaccinia virus. […] The effectiveness of memory T cells in providing protective immunity against orthopoxviruses decreases as the interval between primary and secondary infection increases.
  • #34 Variola virus
    https://www.ufrgs.br/imunovet/molecular_immunology/pathoviruses_variola.html
    Pathogenesis : typically enters the host through the oropharynx, invades the mucosal epithelium, and migrates to regional lymph nodes = asymptomatic viremia = multiplication of virus in the spleen, the bone marrow and other lymph nodes, where viral replication occurs = secondary viremia. […] After an incubation period of 1214 days, virus enters the blood within leukocytes, which seed the skin and produce the characteristic skin lesions (pox), whereas most other tissues are spared. […] The fact that virus seems to travel in leukocytes that specifically exit blood vessels in the papillary dermis indicates that variola virus preferentially associates with leukocytes that can home to skin; alternatively, it might be that only skin tissues can support the subsequent replication steps that are required for lesion formation.
  • #35 Azthena logo with the word Azthena
    https://www.news-medical.net/health/What-is-Smallpox.aspx
    Inhalation of the variola virus initiates foci of mucosal infection in the upper airway without causing symptoms or apparent lesions. […] According to the mousepox model, replication at the point of entry is followed by infection of mononuclear phagocytic cells in regional lymph nodes, with the potential further spread through the bloodstream to similar cells in the liver, spleen, and other tissues. […] After reaching the skin, the virus spreads in the middle and basal layers, causing expanding zones of necrosis that form vesicles. […] In the nonkeratinized squamous epithelium of the oropharynx, the same process is responsible for the formation of ulcerated lesions. […] Pustules with surrounding edema and erythema are produced as a result of increased permeability of local blood vessels and the subsequent infiltration of neutrophils, lymphocytes, and macrophages.
  • #36 Azthena logo with the word Azthena
    https://www.news-medical.net/health/What-is-Smallpox.aspx
    Inhalation of the variola virus initiates foci of mucosal infection in the upper airway without causing symptoms or apparent lesions. […] According to the mousepox model, replication at the point of entry is followed by infection of mononuclear phagocytic cells in regional lymph nodes, with the potential further spread through the bloodstream to similar cells in the liver, spleen, and other tissues. […] After reaching the skin, the virus spreads in the middle and basal layers, causing expanding zones of necrosis that form vesicles. […] In the nonkeratinized squamous epithelium of the oropharynx, the same process is responsible for the formation of ulcerated lesions. […] Pustules with surrounding edema and erythema are produced as a result of increased permeability of local blood vessels and the subsequent infiltration of neutrophils, lymphocytes, and macrophages.
  • #37 Clinical Features of Smallpox – Assessment of Future Scientific Needs for Live Variola Virus – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK230904/
    The mechanisms that allow the localization of variola virus in the skin and the characteristic „centrifugal’ distribution of the rash are not known. […] The lack of a homy, keratinized cell layer permits the lesions on the mucous membranes to ulcerate soon afar their formation, releasing large amounts of highly infectious virus into the saliva. […] Death is usually the result of disseminated intravascular coagulation, hypotension, and cardiovascular collapse; these are exacerbated by clotting defects in the rare hemorrhagic type of smallpox. […] The endothelial cells lining the sinusoids of the liver are often swollen and occasionally proliferating or necrotic. […] The best information on the relative importance of cell-mediated and humoral immune responses to orthopoxvirus infections in humans comes from studies of human subjects in immune-deficient states who are subsequently vaccinated with vaccinia virus. […] The effectiveness of memory T cells in providing protective immunity against orthopoxviruses decreases as the interval between primary and secondary infection increases.
  • #38 Azthena logo with the word Azthena
    https://www.news-medical.net/health/What-is-Smallpox.aspx
    Inhalation of the variola virus initiates foci of mucosal infection in the upper airway without causing symptoms or apparent lesions. […] According to the mousepox model, replication at the point of entry is followed by infection of mononuclear phagocytic cells in regional lymph nodes, with the potential further spread through the bloodstream to similar cells in the liver, spleen, and other tissues. […] After reaching the skin, the virus spreads in the middle and basal layers, causing expanding zones of necrosis that form vesicles. […] In the nonkeratinized squamous epithelium of the oropharynx, the same process is responsible for the formation of ulcerated lesions. […] Pustules with surrounding edema and erythema are produced as a result of increased permeability of local blood vessels and the subsequent infiltration of neutrophils, lymphocytes, and macrophages.
  • #39 Azthena logo with the word Azthena
    https://www.news-medical.net/health/What-is-Smallpox.aspx
    The cell-mediated immune response is a prerequisite for lesion resolution. […] The ability of host responses to limit viral replication during the incubation period correlates directly with disease severity. […] Once viral dissemination has occurred, manifestations of severe illness, including hypotension and coagulopathy, develop due to host inflammatory responses. […] Thus, differences in host responses are responsible for a spectrum of diseases.
  • #40 Variola virus
    https://www.ufrgs.br/imunovet/molecular_immunology/pathoviruses_variola.html
    Pathogenesis : typically enters the host through the oropharynx, invades the mucosal epithelium, and migrates to regional lymph nodes = asymptomatic viremia = multiplication of virus in the spleen, the bone marrow and other lymph nodes, where viral replication occurs = secondary viremia. […] After an incubation period of 1214 days, virus enters the blood within leukocytes, which seed the skin and produce the characteristic skin lesions (pox), whereas most other tissues are spared. […] The fact that virus seems to travel in leukocytes that specifically exit blood vessels in the papillary dermis indicates that variola virus preferentially associates with leukocytes that can home to skin; alternatively, it might be that only skin tissues can support the subsequent replication steps that are required for lesion formation.
  • #41 SMALLPOX ( Pathophysiology and Health Education Presentation ) | PPT
    https://www.slideshare.net/slideshow/smallpox-pathophysiology-and-health-education-presentation/233047577
    The initial symptoms were similar to other viral diseases that are still extant, such as influenza and the common cold: fever of at least 38.3 C (101 F), muscle pain, malaise, headache and fatigue. […] The more dangerous form, variola major, led to smallpox disease that killed about 30% of people who were infected. Variola minor caused a less deadly type that killed about 1% of those who got it. […] HEMORRHAGIC SMALLPOX (MOST SEVERE FORM) […] Hemorrhagic smallpox was a severe form accompanied by extensive bleeding into the skin, mucous membranes, and gastrointestinal tract. This form developed in approximately 2 percent of infections and occurred mostly in adults.
  • #42 Azthena logo with the word Azthena
    https://www.news-medical.net/health/What-is-Smallpox.aspx
    The cell-mediated immune response is a prerequisite for lesion resolution. […] The ability of host responses to limit viral replication during the incubation period correlates directly with disease severity. […] Once viral dissemination has occurred, manifestations of severe illness, including hypotension and coagulopathy, develop due to host inflammatory responses. […] Thus, differences in host responses are responsible for a spectrum of diseases.
  • #43 Azthena logo with the word Azthena
    https://www.news-medical.net/health/What-is-Smallpox.aspx
    The cell-mediated immune response is a prerequisite for lesion resolution. […] The ability of host responses to limit viral replication during the incubation period correlates directly with disease severity. […] Once viral dissemination has occurred, manifestations of severe illness, including hypotension and coagulopathy, develop due to host inflammatory responses. […] Thus, differences in host responses are responsible for a spectrum of diseases.
  • #44 Smallpox pathophysiology – wikidoc
    https://www.wikidoc.org/index.php/Smallpox_pathophysiology
    During secondary viraemia the virus infects mucous cells of the pharynx and mouth, and endothelium of the capillaries of the dermis, causing skin lesions. […] Skin lesions develop due to migration of macrophages to the infected areas of the dermis, leading to edema and necrosis. […] The immune system responds to the viremia with activation of lymphocytes T and B and concomitant production of: Neutralizing antibodies, during first week of disease, remaining for many years, Hemagglutination-inhibition antibodies, by the 16th day of infection, beginning to decrease after 1 year, Complement-fixation antibodies, by the 18th day of infection, beginning to decrease after 1 year, Memory T cells, remaining for 50 years. […] Death by smallpox was commonly due to toxemia, following: Hypotension, Coagulopathy, Multiorgan failure, Bacterial infections.
  • #45 Smallpox pathophysiology – wikidoc
    https://www.wikidoc.org/index.php/Smallpox_pathophysiology
    During secondary viraemia the virus infects mucous cells of the pharynx and mouth, and endothelium of the capillaries of the dermis, causing skin lesions. […] Skin lesions develop due to migration of macrophages to the infected areas of the dermis, leading to edema and necrosis. […] The immune system responds to the viremia with activation of lymphocytes T and B and concomitant production of: Neutralizing antibodies, during first week of disease, remaining for many years, Hemagglutination-inhibition antibodies, by the 16th day of infection, beginning to decrease after 1 year, Complement-fixation antibodies, by the 18th day of infection, beginning to decrease after 1 year, Memory T cells, remaining for 50 years. […] Death by smallpox was commonly due to toxemia, following: Hypotension, Coagulopathy, Multiorgan failure, Bacterial infections.
  • #46 3 Clinical Features of Smallpox | Assessment of Future Scientific Needs for Live Variola Virus | The National Academies Press
    https://nap.nationalacademies.org/read/6445/chapter/7
    The mechanisms that allow the localization of variola virus in the skin and the characteristic „centrifugal’ distribution of the rash are not known. […] The lack of a homy, keratinized cell layer permits the lesions on the mucous membranes to ulcerate soon afar their formation, releasing large amounts of highly infectious virus into the saliva. […] The endothelial cells lining the sinusoids of the liver are often swollen and occasionally proliferating or necrotic. […] The human immune response to viruses is a complicated process about which much has yet to be discovered. […] The complicated series of reactions between antigen-presenting and T cells serves to announce to the immune system the presence of intracellular pathogens such as viruses. […] During infection with a virus as complex as an orthopoxvirus, antibodies specific to many different viral proteins are generated.
  • #47 3 Clinical Features of Smallpox | Assessment of Future Scientific Needs for Live Variola Virus | The National Academies Press
    https://nap.nationalacademies.org/read/6445/chapter/7
    The mechanisms that allow the localization of variola virus in the skin and the characteristic „centrifugal’ distribution of the rash are not known. […] The lack of a homy, keratinized cell layer permits the lesions on the mucous membranes to ulcerate soon afar their formation, releasing large amounts of highly infectious virus into the saliva. […] The endothelial cells lining the sinusoids of the liver are often swollen and occasionally proliferating or necrotic. […] The human immune response to viruses is a complicated process about which much has yet to be discovered. […] The complicated series of reactions between antigen-presenting and T cells serves to announce to the immune system the presence of intracellular pathogens such as viruses. […] During infection with a virus as complex as an orthopoxvirus, antibodies specific to many different viral proteins are generated.
  • #48 3 Clinical Features of Smallpox | Assessment of Future Scientific Needs for Live Variola Virus | The National Academies Press
    https://nap.nationalacademies.org/read/6445/chapter/7
    The mechanisms that allow the localization of variola virus in the skin and the characteristic „centrifugal’ distribution of the rash are not known. […] The lack of a homy, keratinized cell layer permits the lesions on the mucous membranes to ulcerate soon afar their formation, releasing large amounts of highly infectious virus into the saliva. […] The endothelial cells lining the sinusoids of the liver are often swollen and occasionally proliferating or necrotic. […] The human immune response to viruses is a complicated process about which much has yet to be discovered. […] The complicated series of reactions between antigen-presenting and T cells serves to announce to the immune system the presence of intracellular pathogens such as viruses. […] During infection with a virus as complex as an orthopoxvirus, antibodies specific to many different viral proteins are generated.
  • #49 Clinical Features of Smallpox – Assessment of Future Scientific Needs for Live Variola Virus – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK230904/
    The mechanisms that allow the localization of variola virus in the skin and the characteristic „centrifugal’ distribution of the rash are not known. […] The lack of a homy, keratinized cell layer permits the lesions on the mucous membranes to ulcerate soon afar their formation, releasing large amounts of highly infectious virus into the saliva. […] Death is usually the result of disseminated intravascular coagulation, hypotension, and cardiovascular collapse; these are exacerbated by clotting defects in the rare hemorrhagic type of smallpox. […] The endothelial cells lining the sinusoids of the liver are often swollen and occasionally proliferating or necrotic. […] The best information on the relative importance of cell-mediated and humoral immune responses to orthopoxvirus infections in humans comes from studies of human subjects in immune-deficient states who are subsequently vaccinated with vaccinia virus. […] The effectiveness of memory T cells in providing protective immunity against orthopoxviruses decreases as the interval between primary and secondary infection increases.
  • #50 3 Clinical Features of Smallpox | Assessment of Future Scientific Needs for Live Variola Virus | The National Academies Press
    https://nap.nationalacademies.org/read/6445/chapter/7
    The best information on the relative importance of cell-mediated and humoral immune responses to orthopoxvirus infections in humans comes from studies of human subjects in immune-deficient states who are subsequently vaccinated with vaccinia virus. […] Orthopoxvirus-specific T cell and B cell memory can be thought of as involving previously induced lymphocytes that persist as long-lived but nonactivated cells sequestered in lymphoid tissue and in the recirculating pool of lymphocytes. […] All orthopoxviruses induce cross-protective immunity in susceptible laboratory animals. […] The process of inoculating smallpox material is called variolation to distinguish it from vaccination, which uses cowpox or vaccinia virus. […] Modern vaccination against smallpox consists of abrading the skin with vaccinia virus, which may subsequently spread to the lymph nodes and spleen, organs heavily involved in initiating the immune response. […] Active immunity, whether elicited by vaccination or the disease, provokes the complete range of cell-mediated and humoral immune responses, whereas passive immunization provides only the antibodies present in the source of the sera.
  • #51 3 Clinical Features of Smallpox | Assessment of Future Scientific Needs for Live Variola Virus | The National Academies Press
    https://nap.nationalacademies.org/read/6445/chapter/7
    The best information on the relative importance of cell-mediated and humoral immune responses to orthopoxvirus infections in humans comes from studies of human subjects in immune-deficient states who are subsequently vaccinated with vaccinia virus. […] Orthopoxvirus-specific T cell and B cell memory can be thought of as involving previously induced lymphocytes that persist as long-lived but nonactivated cells sequestered in lymphoid tissue and in the recirculating pool of lymphocytes. […] All orthopoxviruses induce cross-protective immunity in susceptible laboratory animals. […] The process of inoculating smallpox material is called variolation to distinguish it from vaccination, which uses cowpox or vaccinia virus. […] Modern vaccination against smallpox consists of abrading the skin with vaccinia virus, which may subsequently spread to the lymph nodes and spleen, organs heavily involved in initiating the immune response. […] Active immunity, whether elicited by vaccination or the disease, provokes the complete range of cell-mediated and humoral immune responses, whereas passive immunization provides only the antibodies present in the source of the sera.
  • #52 Clinical Features of Smallpox – Assessment of Future Scientific Needs for Live Variola Virus – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK230904/
    The mechanisms that allow the localization of variola virus in the skin and the characteristic „centrifugal’ distribution of the rash are not known. […] The lack of a homy, keratinized cell layer permits the lesions on the mucous membranes to ulcerate soon afar their formation, releasing large amounts of highly infectious virus into the saliva. […] Death is usually the result of disseminated intravascular coagulation, hypotension, and cardiovascular collapse; these are exacerbated by clotting defects in the rare hemorrhagic type of smallpox. […] The endothelial cells lining the sinusoids of the liver are often swollen and occasionally proliferating or necrotic. […] The best information on the relative importance of cell-mediated and humoral immune responses to orthopoxvirus infections in humans comes from studies of human subjects in immune-deficient states who are subsequently vaccinated with vaccinia virus. […] The effectiveness of memory T cells in providing protective immunity against orthopoxviruses decreases as the interval between primary and secondary infection increases.
  • #53 Smallpox pathophysiology – wikidoc
    https://www.wikidoc.org/index.php/Smallpox_pathophysiology
    During secondary viraemia the virus infects mucous cells of the pharynx and mouth, and endothelium of the capillaries of the dermis, causing skin lesions. […] Skin lesions develop due to migration of macrophages to the infected areas of the dermis, leading to edema and necrosis. […] The immune system responds to the viremia with activation of lymphocytes T and B and concomitant production of: Neutralizing antibodies, during first week of disease, remaining for many years, Hemagglutination-inhibition antibodies, by the 16th day of infection, beginning to decrease after 1 year, Complement-fixation antibodies, by the 18th day of infection, beginning to decrease after 1 year, Memory T cells, remaining for 50 years. […] Death by smallpox was commonly due to toxemia, following: Hypotension, Coagulopathy, Multiorgan failure, Bacterial infections.
  • #54 Smallpox pathophysiology – wikidoc
    https://www.wikidoc.org/index.php/Smallpox_pathophysiology
    During secondary viraemia the virus infects mucous cells of the pharynx and mouth, and endothelium of the capillaries of the dermis, causing skin lesions. […] Skin lesions develop due to migration of macrophages to the infected areas of the dermis, leading to edema and necrosis. […] The immune system responds to the viremia with activation of lymphocytes T and B and concomitant production of: Neutralizing antibodies, during first week of disease, remaining for many years, Hemagglutination-inhibition antibodies, by the 16th day of infection, beginning to decrease after 1 year, Complement-fixation antibodies, by the 18th day of infection, beginning to decrease after 1 year, Memory T cells, remaining for 50 years. […] Death by smallpox was commonly due to toxemia, following: Hypotension, Coagulopathy, Multiorgan failure, Bacterial infections.
  • #55 Clinical Features of Smallpox – Assessment of Future Scientific Needs for Live Variola Virus – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK230904/
    The mechanisms that allow the localization of variola virus in the skin and the characteristic „centrifugal’ distribution of the rash are not known. […] The lack of a homy, keratinized cell layer permits the lesions on the mucous membranes to ulcerate soon afar their formation, releasing large amounts of highly infectious virus into the saliva. […] Death is usually the result of disseminated intravascular coagulation, hypotension, and cardiovascular collapse; these are exacerbated by clotting defects in the rare hemorrhagic type of smallpox. […] The endothelial cells lining the sinusoids of the liver are often swollen and occasionally proliferating or necrotic. […] The best information on the relative importance of cell-mediated and humoral immune responses to orthopoxvirus infections in humans comes from studies of human subjects in immune-deficient states who are subsequently vaccinated with vaccinia virus. […] The effectiveness of memory T cells in providing protective immunity against orthopoxviruses decreases as the interval between primary and secondary infection increases.
  • #56 Clinical Features of Smallpox – Assessment of Future Scientific Needs for Live Variola Virus – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK230904/
    The mechanisms that allow the localization of variola virus in the skin and the characteristic „centrifugal’ distribution of the rash are not known. […] The lack of a homy, keratinized cell layer permits the lesions on the mucous membranes to ulcerate soon afar their formation, releasing large amounts of highly infectious virus into the saliva. […] Death is usually the result of disseminated intravascular coagulation, hypotension, and cardiovascular collapse; these are exacerbated by clotting defects in the rare hemorrhagic type of smallpox. […] The endothelial cells lining the sinusoids of the liver are often swollen and occasionally proliferating or necrotic. […] The best information on the relative importance of cell-mediated and humoral immune responses to orthopoxvirus infections in humans comes from studies of human subjects in immune-deficient states who are subsequently vaccinated with vaccinia virus. […] The effectiveness of memory T cells in providing protective immunity against orthopoxviruses decreases as the interval between primary and secondary infection increases.
  • #57 Smallpox – Our World in Data
    https://ourworldindata.org/smallpox
    Smallpox is an infectious disease that is caused by the variola virus. It spreads from one person to another, either directly or indirectly. The variola virus infects only humans; other animals are unable to catch smallpox. […] The specific way a smallpox infection would lead to a patient’s death remains unclear. The Oxford Textbook of Medicine notes that people infected may develop symptoms of prostration (total exhaustion), toxemia (toxins in the blood), and hypotension (low blood pressure), which all contribute, but the mechanism by which smallpox causes such symptoms are not clear. […] While smallpox was endemic, there was never a treatment for it. Once a person was infected, it wasn’t possible to treat them; one could only helplessly let the disease run its course and hope they survived.
  • #58 Clinical Features of Smallpox – Assessment of Future Scientific Needs for Live Variola Virus – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK230904/
    The term pathogenesis is used to describe the mechanisms involved in the production of disease, from the spread of infection through the body to the molecular and physiological responses of host cells to a pathogen. […] The pathogenesis of smallpox has been studied in three ways: (1) by using material from human patients; (2) by conducting experiments with variola virus infection of nonhuman primates; and (3) by conducting experiments with model infections in mice, rabbits, and monkeys using related orthopoxviruses. […] Smallpox pathogenesis is a poorly understood series of events in which the virus first disseminates locally, then through the lymphatic system, and finally to the skin without affecting vital organs. […] The primary event that triggers the production of focal lesions in orthopoxvirus infections is the localization of virus particles in the small dermal blood vessels.
  • #59 3 Clinical Features of Smallpox | Assessment of Future Scientific Needs for Live Variola Virus | The National Academies Press
    https://nap.nationalacademies.org/read/6445/chapter/7
    The term pathogenesis is used to describe the mechanisms involved in the production of disease, from the spread of infection through the body to the molecular and physiological responses of host cells to a pathogen. […] The pathogenesis of smallpox has been studied in three ways: (1) by using material from human patients; (2) by conducting experiments with variola virus infection of nonhuman primates; and (3) by conducting experiments with model infections in mice, rabbits, and monkeys using related orthopoxviruses. […] Smallpox pathogenesis is a poorly understood series of events in which the virus first disseminates locally, then through the lymphatic system, and finally to the skin without affecting vital organs. […] The primary event that triggers the production of focal lesions in orthopoxvirus infections is the localization of virus particles in the small dermal blood vessels.
  • #60 Monkeys serve as first animal model of smallpox | CIDRAP
    https://www.cidrap.umn.edu/smallpox/monkeys-serve-first-animal-model-smallpox
    Researchers exposed cynomolgus macaques to high doses of variola (smallpox) virus, causing most of them to die of the hemorrhagic form of smallpox within a few days, according to an online report in the Proceedings of the National Academy of Sciences (PNAS). […] „The demonstration that variola virus strains can produce lethal disease in monkeys is a significant advance toward the development of antiviral drugs and improved vaccines, as well as an improved understanding of variola pathogenesis,” says the report by Peter B. Jahrling of the US Army Medical Research Institute of Infectious Diseases (USAMRIID) and colleagues from USAMRIID, the Centers for Disease Control and Prevention, and Stanford University. […] „The i.v. inoculation of high doses of variola virus produced an overwhelming, hemorrhagic disease course, ending in acute deaths, usually within 6 days of inoculation,” the report states.
  • #61 Monkeys serve as first animal model of smallpox | CIDRAP
    https://www.cidrap.umn.edu/smallpox/monkeys-serve-first-animal-model-smallpox
    The use of IV inoculation of the virus eliminated the incubation and prodromal stages of natural smallpox, causing „instantaneous viremia” and resulting in a much shorter clinical course than was typical when smallpox still existed in humans, the authors note. „Yet, the sequence of events in the monkeys is similar to human hemorrhagic smallpox, a form that was almost always fatal.” […] Analysis of tissue from the infected monkeys has already yielded some information about how smallpox changes gene activity in cells attacked by the virus, yielding clues about how it overcomes host defenses, according to a separate report in PNAS. […] „This new research fills in some of the gaps in our understanding of smallpox,” NIAID Director Dr. Anthony Fauci, MD, said in the news release. „Now we are better positioned to speed the development of protective measures.”
  • #62 Monkeys serve as first animal model of smallpox | CIDRAP
    https://www.cidrap.umn.edu/smallpox/monkeys-serve-first-animal-model-smallpox
    The use of IV inoculation of the virus eliminated the incubation and prodromal stages of natural smallpox, causing „instantaneous viremia” and resulting in a much shorter clinical course than was typical when smallpox still existed in humans, the authors note. „Yet, the sequence of events in the monkeys is similar to human hemorrhagic smallpox, a form that was almost always fatal.” […] Analysis of tissue from the infected monkeys has already yielded some information about how smallpox changes gene activity in cells attacked by the virus, yielding clues about how it overcomes host defenses, according to a separate report in PNAS. […] „This new research fills in some of the gaps in our understanding of smallpox,” NIAID Director Dr. Anthony Fauci, MD, said in the news release. „Now we are better positioned to speed the development of protective measures.”
  • #63 Smallpox: Background, Etiology, Epidemiology
    https://emedicine.medscape.com/article/237229-overview
    Smallpox is an acute, contagious disease caused by the variola virus, a member of the genus Orthopoxvirus, in the Poxviridae family. […] Poxviridae are linear, double-stranded deoxyribonucleic acid (DNA) viruses that replicate in the cytoplasm. […] The variola virus is a large, brick-shaped, double-stranded DNA virus that serologically cross-reacts with other members of the poxvirus family, including ectromelia, cowpox, monkeypox, vaccinia, and camelpox. Unlike other DNA viruses, the variola virus multiplies in the cytoplasm of parasitized host cells. […] Because of potential bioterrorism, interest in smallpox pathogenesis has increased. Protein analysis indicates that the variola virus G1R protein binds to cellular nuclear factor kappa-B (NF-kB), thereby inhibiting its function in cell signalling.
  • #64 Extracts
    https://research.ufl.edu/publications/explore/past/summer2009/extracts/extracts06.html
    University of Florida researchers have learned more about how smallpox conducts its deadly business discoveries that may reveal as much about the human immune system as they do about one of the worlds most feared pathogens. […] In findings published in May in the Proceedings of the National Academy of Sciences, scientists describe how they looked at all of the proteins produced by the smallpox virus in concert with human proteins, and discovered one particular interaction that disables one of the bodys first responders to injury inflammation. […] One of the strategies of the virus is to inhibit inflammation pathways, and this interaction is an inhibitor of human inflammation such that we have never seen before, McFadden said. This helps explain some of the mechanisms that contribute to smallpox pathogenesis.
  • #65 Extracts
    https://research.ufl.edu/publications/explore/past/summer2009/extracts/extracts06.html
    University of Florida researchers have learned more about how smallpox conducts its deadly business discoveries that may reveal as much about the human immune system as they do about one of the worlds most feared pathogens. […] In findings published in May in the Proceedings of the National Academy of Sciences, scientists describe how they looked at all of the proteins produced by the smallpox virus in concert with human proteins, and discovered one particular interaction that disables one of the bodys first responders to injury inflammation. […] One of the strategies of the virus is to inhibit inflammation pathways, and this interaction is an inhibitor of human inflammation such that we have never seen before, McFadden said. This helps explain some of the mechanisms that contribute to smallpox pathogenesis.
  • #66 Extracts
    https://research.ufl.edu/publications/explore/past/summer2009/extracts/extracts06.html
    University of Florida researchers have learned more about how smallpox conducts its deadly business discoveries that may reveal as much about the human immune system as they do about one of the worlds most feared pathogens. […] In findings published in May in the Proceedings of the National Academy of Sciences, scientists describe how they looked at all of the proteins produced by the smallpox virus in concert with human proteins, and discovered one particular interaction that disables one of the bodys first responders to injury inflammation. […] One of the strategies of the virus is to inhibit inflammation pathways, and this interaction is an inhibitor of human inflammation such that we have never seen before, McFadden said. This helps explain some of the mechanisms that contribute to smallpox pathogenesis.
  • #67 Smallpox: Background, Etiology, Epidemiology
    https://emedicine.medscape.com/article/237229-overview
    Smallpox is an acute, contagious disease caused by the variola virus, a member of the genus Orthopoxvirus, in the Poxviridae family. […] Poxviridae are linear, double-stranded deoxyribonucleic acid (DNA) viruses that replicate in the cytoplasm. […] The variola virus is a large, brick-shaped, double-stranded DNA virus that serologically cross-reacts with other members of the poxvirus family, including ectromelia, cowpox, monkeypox, vaccinia, and camelpox. Unlike other DNA viruses, the variola virus multiplies in the cytoplasm of parasitized host cells. […] Because of potential bioterrorism, interest in smallpox pathogenesis has increased. Protein analysis indicates that the variola virus G1R protein binds to cellular nuclear factor kappa-B (NF-kB), thereby inhibiting its function in cell signalling.
  • #68 Smallpox: Background, Etiology, Epidemiology
    https://emedicine.medscape.com/article/237229-overview
    The G1R protein is highly conserved among pathogenic orthopoxviruses and is absent from the less-pathogenic vaccinia strains, thus suggesting that it may serve as a molecular therapeutic target. […] Other studies developed a method of reliably classifying species of variola virus into major and minor species by genotype using novel real-time polymerase chain reaction (PCR) assay probes. […] Implantation of just a few virions of smallpox into the oropharynx or respiratory tracts can cause infection. The virus infects macrophages during the first 72 hours of the incubation phase. The virus migrates and multiplies in the regional lymph nodes, resulting in asymptomatic viremia by the fourth day. The virus multiplies in the spleen, bone marrow, and lymph nodes, resulting in a symptomatic secondary viremia (ie, fever, toxemia) by the eighth day.
  • #69 2 Overview of Smallpox and Its Surveillance and Control | Live Variola Virus: Considerations for Continuing Research | The National Academies Press
    https://nap.nationalacademies.org/read/12616/chapter/4
    In response to the detection of variola, three options exist for controlling any resulting outbreak of disease: isolation and quarantine, vaccination, and administration of antiviral drugs. […] Progress has also been made in the development of drugs for treatment and postexposure prophylaxis of smallpox. […] Despite the research that has been accomplished since 1999, capability gaps for smallpox control remain.
  • #70 2 Overview of Smallpox and Its Surveillance and Control | Live Variola Virus: Considerations for Continuing Research | The National Academies Press
    https://nap.nationalacademies.org/read/12616/chapter/4
    In response to the detection of variola, three options exist for controlling any resulting outbreak of disease: isolation and quarantine, vaccination, and administration of antiviral drugs. […] Progress has also been made in the development of drugs for treatment and postexposure prophylaxis of smallpox. […] Despite the research that has been accomplished since 1999, capability gaps for smallpox control remain.
  • #71 Smallpox – Infectious Diseases – Merck Manual Professional Edition
    https://www.merckmanuals.com/professional/infectious-diseases/pox-viruses/smallpox
    Smallpox is transmitted from person to person by inhalation of respiratory droplets or, less efficiently, by direct contact. […] The virus invades the oropharyngeal or respiratory mucosa and multiplies in regional lymph nodes, causing subsequent viremia. It eventually localizes in small blood vessels of the dermis and the oropharyngeal mucosa. Other organs are seldom clinically involved, except for occasionally the central nervous system, with encephalitis. Secondary bacterial infection of the skin, lungs, and bones may develop. […] The antiviral drug tecovirimat was approved by the US Food and Drug Administration (FDA) in 2018 and, in June 2021, the FDA approved brincidofovir (CMX 001) for treatment of smallpox. Both approvals were based on experimental studies and, although their effectiveness against smallpox in humans is unknown, in laboratory tests, both stopped the growth of the virus that causes smallpox and were effective in treating animals that had diseases similar to smallpox. Additionally, cidofovir, which is not FDA-approved for treatment of smallpox, could be used during an outbreak under an appropriate regulatory mechanism. […] Treatment of smallpox is generally supportive, with antibiotics for secondary bacterial infections.
  • #72 Smallpox lesion characterization in placebo-treated and tecovirimat-treated macaques using traditional and novel methods | PLOS Pathogens
    https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1012007
    Smallpox was the most rampant infectious disease killer of the 20th century, yet much remains unknown about the pathogenesis of the variola virus. […] Using archived tissues from a study conducted at the Centers for Disease Control and Prevention, we endeavored to describe lesions in placebo-treated macaques to further characterize the model and describe lesion mitigation in tecovirimat-treated macaques. […] The mechanism of action of this antiviral is inhibition of the VP37 protein preventing proper formation of enveloped virions. […] Much of what we know about smallpox is based on data gathered prior to the eradication of smallpox and the last reported natural human case in 1977. […] This study applies some of these new methods to archived FFPE tissues, collected as part of a previous study and stored at USAMRIID, to describe the pathology of placebo-treated versus tecovirimat-treated animals.
  • #73 Smallpox lesion characterization in placebo-treated and tecovirimat-treated macaques using traditional and novel methods | PLOS Pathogens
    https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1012007
    Due to the paucity of published pathology data on NHP models of smallpox disease, we endeavored to better characterize the gross lesions and histopathologic findings for this disease model to include a characterization of lesions between placebo-treated and tecovirimat-treated groups. […] In the placebo-treated group, the 3 macaques that succumbed prior to the end of the study had histologic lesions and positive immunohistochemical findings consistent with VARV infection. […] To further validate the VARV infection, we developed an RNA in situ hybridization (ISH) assay to detect VARV-specific transcript B19R, which is deleted in mpox virus (MPXV). […] The remaining three placebo-treated animals all had gross and histologic lesions consistent with a resolving poxviral infection. […] Overall, tecovirimat ameliorated the typical gross and histologic lesions associated with VARV induced disease in macaques when animals were treated as late as day 4 post-infection. […] The ability to treat as early as possible, in this case prior to lesion development, can have an impact on disease course and residual pathology.
  • #74 Smallpox – Infectious Diseases – Merck Manual Professional Edition
    https://www.merckmanuals.com/professional/infectious-diseases/pox-viruses/smallpox
    Smallpox is transmitted from person to person by inhalation of respiratory droplets or, less efficiently, by direct contact. […] The virus invades the oropharyngeal or respiratory mucosa and multiplies in regional lymph nodes, causing subsequent viremia. It eventually localizes in small blood vessels of the dermis and the oropharyngeal mucosa. Other organs are seldom clinically involved, except for occasionally the central nervous system, with encephalitis. Secondary bacterial infection of the skin, lungs, and bones may develop. […] The antiviral drug tecovirimat was approved by the US Food and Drug Administration (FDA) in 2018 and, in June 2021, the FDA approved brincidofovir (CMX 001) for treatment of smallpox. Both approvals were based on experimental studies and, although their effectiveness against smallpox in humans is unknown, in laboratory tests, both stopped the growth of the virus that causes smallpox and were effective in treating animals that had diseases similar to smallpox. Additionally, cidofovir, which is not FDA-approved for treatment of smallpox, could be used during an outbreak under an appropriate regulatory mechanism. […] Treatment of smallpox is generally supportive, with antibiotics for secondary bacterial infections.
  • #75 About Smallpox | Smallpox | CDC
    https://www.cdc.gov/smallpox/about/index.html
    Smallpox was an infectious disease caused by the variola virus. […] Variola virus, a virus from Orthopoxviridae family that causes smallpox, highly contagious disease eradicated by vaccination. […] Before smallpox was eradicated, it was a serious infectious disease caused by the variola virus. It was contagious meaning, it spread from one person to another. […] While some antiviral drugs may help treat smallpox disease, there is no treatment for smallpox that has been tested in people who are sick with the disease and proven effective. […] Although smallpox has been eradicated, it is possible that variola virus could be used in a biological attack.
  • #76 About Smallpox | Smallpox | CDC
    https://www.cdc.gov/smallpox/about/index.html
    Smallpox was an infectious disease caused by the variola virus. […] Variola virus, a virus from Orthopoxviridae family that causes smallpox, highly contagious disease eradicated by vaccination. […] Before smallpox was eradicated, it was a serious infectious disease caused by the variola virus. It was contagious meaning, it spread from one person to another. […] While some antiviral drugs may help treat smallpox disease, there is no treatment for smallpox that has been tested in people who are sick with the disease and proven effective. […] Although smallpox has been eradicated, it is possible that variola virus could be used in a biological attack.
  • #77 Biosecurity and Biodefense Resource – Federation of American Scientists
    https://biosecurity.fas.org/resource/factsheets/smallpox.htm
    Smallpox is caused by the double-stranded DNA orthopoxviruses Variola major and Variola minor. […] Delivery: The smallpox virus can infect humans through inhalation, ingestion, or injection. A smallpox attack would likely rely on victims inhaling Variola via an aerosol or through an infectious individual deliberately infected with the virus. […] Mechanism: After inhalation and being trapped in mucus lining the lungs, the virus is unsuccessfully „eaten” by macrophages. Taken to the lymph nodes, the virus manufactures more viruses while inside the macrophage. Entering the bloodstream 3-4 days after initial infection, Variola spreads throughout the body and incubates in the bone marrow, spleen, and other organs. The virus enters the bloodstream 5-6 days later triggering the first symptoms and targeting blood vessels near the skin. The tongue, inside the mouth, and skin develop flat, red lesions that rise into blisters before becoming pus-filled pimples. […] Smallpox is fatal in 30% of infections. In 2% to 6% of smallpox infections, lesions are classified as hemorrhagic, characterized by bleeding sores, or flat; where the lesions are soft and flat. The mortality rates for those types of infections are over 95%.
  • #78 Rapid National Response to Smallpox Attack in the United States – Michigan Journal of Public Affairs
    https://mjpa.umich.edu/2025/03/18/rapid-national-response-to-smallpox-attack-in-the-united-states/
    Smallpox, caused by variola virus, had a mortality rate of 30%, and 65-80% of survivors developed scars. […] Smallpox could therefore quickly spread throughout the population, where each case of smallpox may result in an additional 3.5 to 6 cases. […] There have been three concerning cases of poxvirus gene editing in the 21st century. In 2001, Jackson et al. created a modified mousepox virus that could infect and kill vaccinated mice. Since mousepox is a model for smallpox research, this study provides evidence that variola could potentially be similarly manipulated to circumvent smallpox vaccination. […] These studies demonstrate the potential to create new, deadlier smallpox variants using widely available genetic engineering techniques. […] In an emergency featuring a 30% mortality rate, the lack of an overarching vision could be catastrophic.
  • #79 Clinical Features of Smallpox – Assessment of Future Scientific Needs for Live Variola Virus – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK230904/
    The term pathogenesis is used to describe the mechanisms involved in the production of disease, from the spread of infection through the body to the molecular and physiological responses of host cells to a pathogen. […] The pathogenesis of smallpox has been studied in three ways: (1) by using material from human patients; (2) by conducting experiments with variola virus infection of nonhuman primates; and (3) by conducting experiments with model infections in mice, rabbits, and monkeys using related orthopoxviruses. […] Smallpox pathogenesis is a poorly understood series of events in which the virus first disseminates locally, then through the lymphatic system, and finally to the skin without affecting vital organs. […] The primary event that triggers the production of focal lesions in orthopoxvirus infections is the localization of virus particles in the small dermal blood vessels.
  • #80 3 Clinical Features of Smallpox | Assessment of Future Scientific Needs for Live Variola Virus | The National Academies Press
    https://nap.nationalacademies.org/read/6445/chapter/7
    The term pathogenesis is used to describe the mechanisms involved in the production of disease, from the spread of infection through the body to the molecular and physiological responses of host cells to a pathogen. […] The pathogenesis of smallpox has been studied in three ways: (1) by using material from human patients; (2) by conducting experiments with variola virus infection of nonhuman primates; and (3) by conducting experiments with model infections in mice, rabbits, and monkeys using related orthopoxviruses. […] Smallpox pathogenesis is a poorly understood series of events in which the virus first disseminates locally, then through the lymphatic system, and finally to the skin without affecting vital organs. […] The primary event that triggers the production of focal lesions in orthopoxvirus infections is the localization of virus particles in the small dermal blood vessels.
  • #81 Clinical Features of Smallpox – Assessment of Future Scientific Needs for Live Variola Virus – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK230904/
    The mechanisms that allow the localization of variola virus in the skin and the characteristic „centrifugal’ distribution of the rash are not known. […] The lack of a homy, keratinized cell layer permits the lesions on the mucous membranes to ulcerate soon afar their formation, releasing large amounts of highly infectious virus into the saliva. […] Death is usually the result of disseminated intravascular coagulation, hypotension, and cardiovascular collapse; these are exacerbated by clotting defects in the rare hemorrhagic type of smallpox. […] The endothelial cells lining the sinusoids of the liver are often swollen and occasionally proliferating or necrotic. […] The best information on the relative importance of cell-mediated and humoral immune responses to orthopoxvirus infections in humans comes from studies of human subjects in immune-deficient states who are subsequently vaccinated with vaccinia virus. […] The effectiveness of memory T cells in providing protective immunity against orthopoxviruses decreases as the interval between primary and secondary infection increases.
  • #82 Immunopathogenesis of Orthopoxviridae: insights into immunology from smallpox to monkeypox (mpox)
    https://www.explorationpub.com/Journals/ei/Article/1003119
    Since 2019, notable global viral outbreaks have occurred necessitating further research and healthcare system investigations. […] This review aims to present facts about MPXV-specific pathogenesis, epidemiology, and immunology alongside historical perspectives. […] Infection with MPXV makes it difficult to differentiate from other diseases or skin conditions. Antiviral therapeutic drugs were typically prescribed for smallpox and mpox disease; however, the molecular and immunological mechanisms with cellular changes remain of interest. […] MPXV infects a host through intradermal, oropharynx, and nasopharyngeal routes. […] In brief, Poxviridae use cell permeation, adsorption, membrane fusion, and lysis, which are four key stages to propagate while interacting with cellular proteins. […] MPXV genome is composed of approximately 190 open reading frames (ORFs).

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