Infekcja shigella, inaczej szigellosis
Patofizjologia i mechanizm

Infekcja wywołana przez bakterie z rodzaju Shigella, zwana szigellozą, jest ostrym zakażeniem jelitowym charakteryzującym się inwazją i namnażaniem się bakterii w komórkach nabłonka jelita grubego, co prowadzi do zapalenia okrężnicy i objawów dysenterii z obecnością krwi i śluzu w stolcu. Patogeneza opiera się na obecności dużego plazmidu wirulencji (~220 kb), kodującego system sekrecji typu III (T3SS) oraz białka efektorowe (IpaA, IpaB, IpaC, IpaD), które umożliwiają bakteriom inwazję, ucieczkę z fagosomu i rozprzestrzenianie się między komórkami. Niektóre szczepy, zwłaszcza S. dysenteriae typ 1, produkują toksynę Shiga o strukturze AB5, która hamuje syntezę białek w komórkach gospodarza i może prowadzić do powikłań pozajelitowych, takich jak zespół hemolityczno-mocznicowy (HUS). Dodatkowo, Shigella wytwarza enterotoksyny ShET-1 i ShET-2, które nasilają objawy kliniczne poprzez indukcję wydzielania płynów i stanu zapalnego. Infekcja przebiega przez inwazję komórek M w jelicie, fagocytozę przez makrofagi z indukcją ich apoptozy i silną odpowiedź zapalną z udziałem IL-1, IL-18 oraz rekrutacją neutrofilów, co prowadzi do uszkodzenia bariery nabłonkowej i rozwoju objawów klinicznych.

  1. Wprowadzenie do patogenezy infekcji Shigella
  2. Molekularne podstawy patogenezy Shigella
    1. Rola plazmidu wirulencji i T3SS
    2. Białka inwazyjne (Ipa) i ich rola
    3. Toksyny i inne czynniki wirulencji
  3. Etapy procesu infekcyjnego Shigella
    1. Wejście do organizmu i przekroczenie bariery nabłonkowej
    2. Interakcja z makrofagami i indukcja apoptozy
    3. Inwazja komórek nabłonkowych i replikacja wewnątrzkomórkowa
    4. Rozprzestrzenianie się międzykomórkowe i ruch oparty na aktynie
  4. Odpowiedź immunologiczna gospodarza i mechanizmy unikania
    1. Indukcja stanu zapalnego i rekrutacja neutrofilów
    2. Modulacja odpowiedzi immunologicznej przez Shigella
    3. Rola inflammasomów w odpowiedzi na infekcję
  5. Patofizjologia i manifestacje kliniczne
    1. Uszkodzenie nabłonka i rozwój dyzenterii
    2. Rola toksyn w manifestacjach klinicznych
    3. Powikłania pozajelitowe
  6. Nowe odkrycia w patogenezie Shigella
    1. Rola mikrobioty jelitowej
    2. Wpływ pH na patogenezę
    3. Adaptacja do oddychania i hipoksja
    4. Rola systemu YfiBNR w wirulencji
    5. Interakcja z peptydem obronnym HD5
  7. Modulacja sumoilacji przez Shigella
  8. Mechanizmy oporności na antybiotyki u Shigella
  9. Nowe strategie zwalczania infekcji Shigella
    1. Nowe cele terapeutyczne
    2. Modele eksperymentalne
    3. Rozwój szczepionek
  10. Podsumowanie mechanizmów patogenezy Shigella
    1. Kolejne rozdziały

Wprowadzenie do patogenezy infekcji Shigella

Infekcja shigella, inaczej szigellosis, jest ostrym zakażeniem jelit wywołanym przez bakterie z rodzaju Shigella, należące do rodziny pałeczek jelitowych Enterobacteriaceae. Patogeneza Shigella obejmuje złożony, wieloetapowy proces, w którym bakterie wykazują zdolność do inwazji i namnażania się w komórkach nabłonka jelita grubego, prowadząc do stanu zapalnego okrężnicy i objawów dysenterii bakteryjnej. Choroba ta charakteryzuje się skąpymi, nieuformowanymi stolcami z domieszką krwi i śluzu.12

Zakażenie bakteriami Shigella stanowi poważny problem zdrowia publicznego na całym świecie, szczególnie w krajach rozwijających się o niskim poziomie higieny i sanitacji. Ze względu na niską dawkę zakaźną (zaledwie 10-200 komórek bakteryjnych), Shigella jest wysoce zakaźnym patogenem, który może wywoływać objawy kliniczne nawet po ekspozycji na bardzo małą liczbę bakterii.34

Infekcja rozpoczyna się od spożycia bakterii (najczęściej drogą fekalno-oralną) i przejścia drobnoustrojów przez kwaśne środowisko żołądka. W przeciwieństwie do innych bakterii, Shigella jest odporna na niskie pH, co umożliwia jej przetrwanie w żołądku. Po dostaniu się do jelita cienkiego bakterie namnażają się, a następnie przechodzą do jelita grubego, gdzie dochodzi do właściwej inwazji nabłonka okrężnicy i rozwoju stanu zapalnego.5

Molekularne podstawy patogenezy Shigella

Wirulencja bakterii Shigella jest uwarunkowana obecnością dużego plazmidu wirulencji o wielkości około 220 kb, który koduje system sekrecji typu III (T3SS) oraz szereg efektorowych białek wirulencji. T3SS pełni kluczową rolę w patogenezie, działa jak „molekularna strzykawka”, która umożliwia translokację około 25 białek efektorowych bezpośrednio z cytoplazmy bakteryjnej do komórki gospodarza.67

System sekrecji typu III (T3SS) oraz powiązane białka efektorowe, jak białka inwazyjne (IpaA, IpaB, IpaC i IpaD), odgrywają kluczową rolę w procesie patogenezy. Białka te umożliwiają manipulowanie komórkami gospodarza, w tym indukcję własnego pochłaniania przez komórki nabłonka, ucieczkę z fagosomu, replikację w cytoplazmie i rozprzestrzenianie się do sąsiednich komórek.89

Geny chromosomalne kontrolują antygeny lipopolisacharydowe (LPS) w ścianach komórkowych bakterii. LPS odgrywa ważną rolę w oporności na nieswoiste mechanizmy obronne gospodarza napotykane podczas inwazji tkanek. Dodatkowo, niektóre szczepy Shigella produkują enterotoksyny i toksynę Shiga, które przyczyniają się do nasilenia objawów chorobowych.1011

Rola plazmidu wirulencji i T3SS

Informacja genetyczna warunkująca wirulencję Shigella jest zakodowana zarówno na chromosomie bakteryjnym, jak i na dużym plazmidzie wirulencji. Plazmid ten jest niezbędnym determinantem wirulencji wszystkich gatunków Shigella i koduje aparat molekularny niezbędny do inwazji tkanek i przeżycia wewnątrzkomórkowego.12

T3SS, stanowiący centralny element tego aparatu, jest podobny do struktury igły i umożliwia bakteriom translokację zestawu około 25 białek z cytoplazmy bakteryjnej bezpośrednio do eukariontycznej komórki gospodarza. Białka te działają jako efektory zakłócające różne procesy w komórce gospodarza, w tym reorganizację cytoszkieletu, co ułatwia internalizację bakterii.1314

Białka efektorowe wprowadzane przez T3SS można podzielić na dwie grupy: pierwsza grupa uczestniczy w początkowym etapie inwazji, a druga grupa jest uwalniana po wniknięciu bakterii do komórki i reguluje dalsze procesy patogenetyczne, takie jak ucieczka z fagosomu, wewnątrzkomórkowy ruch i modulacja odpowiedzi immunologicznej gospodarza.15

Białka inwazyjne (Ipa) i ich rola

Białka inwazyjne Ipa (Invasion plasmid antigens) odgrywają kluczową rolę w procesie inwazji komórek nabłonka. IpaB, IpaC i IpaD tworzą kompleks na końcu „igły” T3SS i są odpowiedzialne za tworzenie porów w błonie komórkowej gospodarza, umożliwiając translokację innych efektorów.16

IpaB może działać jako kanał jonowy w błonie komórki gospodarza, co prowadzi do napływu potasu (K+), który jest rozpoznawany przez NLRC4 (NOD-like receptor C4), co skutkuje aktywacją pyroptozy. Potas odgrywa istotną rolę w stabilności błony komórkowej; zatem brak równowagi między jonami potasu zwiększa ciśnienie osmotyczne i prowadzi do pęknięcia wakuoli. Co ciekawe, zmniejszenie wewnątrzkomórkowego stężenia K+ stymuluje NLRP3 (NOD-, LRR- i białko zawierające domenę piryny 3). Mechanizm ten przyczynia się do inwazji komórek gospodarza i ucieczki z fagosomu.17

IpaC, współdziałając z IpaB, indukuje reorganizację aktyny, co ułatwia wchłonięcie bakterii przez komórkę. Po wejściu do komórki, IpaB i IpaC biorą udział w lizie błony wakuoli fagocytarnej, umożliwiając bakteriom ucieczkę do cytoplazmy, gdzie mogą się namnażać.18

Toksyny i inne czynniki wirulencji

Niektóre szczepy Shigella produkują toksyny, które przyczyniają się do patogenezy zakażenia. Shigella dysenteriae typ 1 produkuje potencjalnie śmiertelną toksynę Shiga, która hamuje syntezę białek w komórkach eukariotycznych i może prowadzić do powikłań pozajelitowych, w tym zespołu hemolityczno-mocznicowego.19

Toksyna Shiga ma strukturę AB5, składającą się z podjednostki A i pięciu podjednostek B. Podjednostki B wiążą się z glikolipidem Gb3 na powierzchni komórek docelowych, podczas gdy podjednostka A zostaje wprowadzona do komórki i hamuje syntezę białek poprzez inaktywację podjednostki 60S rybosomu. To prowadzi do śmierci komórki i uszkodzenia mikronaczyń w jelicie, co objawia się krwawieniem.2021

Zidentyfikowano dwie enterotoksyny powodujące wydzielanie płynów w modelach zwierzęcych: Shigella enterotoxin 1 (ShET-1) i Shigella enterotoxin 2 (ShET-2). ShET-1, znajdowana głównie w S. flexneri, jest kodowana przez chromosomalny gen set. Jest to klasyczna toksyna AB składająca się z kilku podjednostek B, które wiążą się ze specyficznymi cząsteczkami na komórce docelowej, i pojedynczej podjednostki A, która przeprowadza toksyczną reakcję enzymatyczną w komórce.22

ShET-2 jest kodowana przez gen sen znajdujący się na plazmidzie i może być wytwarzana przez wszystkie gatunki Shigella. Poza działaniem enterotoksycznym podobnym do ShET-1, ShET-2 jest także uważana za induktor stanu zapalnego komórek nabłonka poprzez wydzielanie IL-8.23

Etapy procesu infekcyjnego Shigella

Patogeneza infekcji Shigella jest procesem wieloetapowym, obejmującym kilka kluczowych faz, które umożliwiają bakteriom inwazję, namnażanie się i rozprzestrzenianie w organizmie gospodarza.24

Wejście do organizmu i przekroczenie bariery nabłonkowej

Infekcja rozpoczyna się od spożycia bakterii Shigella, najczęściej poprzez skażoną żywność lub wodę. Ze względu na oporność na niskie pH, bakterie są w stanie przetrwać w kwaśnym środowisku żołądka i dotrzeć do jelita cienkiego, gdzie rozpoczynają namnażanie się.25

Pierwszą barierą dla infekcji mikrobiologicznej jest glikoproteinowa mucyna. Shigella ma zdolność do glikozylacji i przebudowy bariery śluzowej na swoją korzyść. Ponieważ Shigella nie może inwazyjnie wnikać przez apikalną powierzchnię nabłonka, jej celem są komórki M w celu penetracji bariery nabłonkowej.26

Komórki M są specyficznymi komórkami w tkance limfoidalnej związanej z błoną śluzową (MALT), które odgrywają znaczącą rolę w transporcie antygenów z światła jelita do komórek prezentujących antygen (APC). Komórki M ze swoimi cienkimi mikrokosmkami i brakiem glikoprotein powierzchniowych są narażone na inwazję Shigella.27

W przeciwieństwie do innych bakterii, Shigella nie wnika do nabłonka od strony apikalnej, ale wykorzystuje komórki M do transportu przez warstwę nabłonka do przestrzeni subnabłonkowej. W przestrzeni tej bakterie są fagocytowane przez rezydujące tam makrofagi.2829

Interakcja z makrofagami i indukcja apoptozy

Po przeniknieciu przez komórki M, bakterie Shigella są wychwytywane przez makrofagi rezydujące w tkance limfatycznej. Jednak zamiast zostać zniszczone w fagolizosmie makrofaga, wirulentne szczepy Shigella lizują fagosomy i inicjują apoptozę makrofagów.30

Śmierć makrofagów jest związana z uwalnianiem prozapalnych cytokin, w tym interleukiny-1 (IL-1) i IL-18. Obie cytokiny są kluczowymi mediatorami ostrej i masywnej odpowiedzi zapalnej wywołanej przez S. flexneri.31

Proces apoptozy makrofagów zależy od kaspazy-1, ale nie od innych kaspaz, takich jak kaspaza-3 (wykonawca śmierci komórkowej) czy kaspaza-11 (aktywator kaspazy-1 w odpowiedzi na stymulację LPS). Białko IpaB wydzielane przez T3SS wiąże się bezpośrednio z kaspazą-1 in vitro. Jednak nie jest jasne, czy IpaB powinien być uważany za bakteryjny PAMP (wzorzec molekularny związany z patogenem), który indukuje tworzenie inflammasomu po infekcji, czy też IpaB bezpośrednio rekrutuje kaspazę-1 do kompleksu inflammasomu.32

Inwazja komórek nabłonkowych i replikacja wewnątrzkomórkowa

Po uwolnieniu się z makrofaga, bakterie Shigella są zdolne do inwazji komórek nabłonkowych od strony podstawno-bocznej, ucieczki z fagosomu i namnażania się w cytoplazmie.33

Po internalizacji Shigella, wokół bakterii tworzy się wakuola. Białko efektorowe IpgD jest transportowane przez T3SS, a ten efektor jest homologiem Salmonella SopB. IpgD ma aktywność fosfatazy fosfoinozytydowej i defosforyluje fosfatydyloinozytol 4,5-bisfosforan (PIP2) do fosfatydyloinozytolu 5-fosforanu (PI5P). PI5P może wzrastać przez stymulację szoku osmotycznego lub podczas infekcji S. flexneri.34

Shigella szybko ucieka z wakuoli fagocytarnej i namnaża się w cytoplazmie komórki gospodarza. Białka IpaB i IpaC odgrywają kluczową rolę w procesie lizy błony wakuoli.35

Rozprzestrzenianie się międzykomórkowe i ruch oparty na aktynie

Jedną z charakterystycznych cech patogenezy Shigella jest jej zdolność do rozprzestrzeniania się z komórki do komórki bez ekspozycji na zewnątrzkomórkowe składniki układu odpornościowego gospodarza. Proces ten zależy od zdolności bakterii do wykorzystania wewnątrzkomórkowej aktyny do przemieszczania się.36

Kluczowym mediatorem efektywnego ruchu poprzez nukleację aktyny na jednym biegunie bakterii jest białko IcsA/VirG. Białko to rekrutuje N-WASP i zwiększa jego powinowactwo do kompleksu Arp2/3, tworząc kompleks IcsA/N-WASP/Arp2/3, który indukuje nukleację aktyny. To prowadzi do tworzenia „ogona kometowego” z aktyny, który popycha bakterie przez cytoplazmę do sąsiednich komórek.3738

Wewnątrzkomórkowy ruch Shigella zależy również od aktywności degradującej tubulinę białka VirA, które otwiera drogę przez sieć mikrotubul dla Shigella. Bakterie wykorzystują filamenty aktynowe do przemieszczania się przez cytoplazmę i tworzenia pseudopodiów, które są następnie pochłaniane przez sąsiednie komórki, umożliwiając rozprzestrzenianie się bez ekspozycji na środowisko zewnątrzkomórkowe.3940

Odpowiedź immunologiczna gospodarza i mechanizmy unikania

Infekcja Shigella wywołuje złożoną odpowiedź immunologiczną gospodarza, jednak bakterie wykształciły różne mechanizmy umożliwiające im unikanie lub modulację tej odpowiedzi.41

Indukcja stanu zapalnego i rekrutacja neutrofilów

Infekcja Shigella prowadzi do indukcji silnej odpowiedzi zapalnej w jelicie grubym. Stan zapalny jest wynikiem aktywacji receptorów rozpoznających wzorce (PRR) przez składniki bakteryjne oraz działania efektorów wprowadzanych przez T3SS.42

Wejście S. flexneri do komórek M prowadzi do rekrutacji polimorfojądrowych neutrofilów (PMN) i zwiększenia rozmiaru komórek M. S. flexneri nie może inwazyjnie wnikać przez apikalną błonę komórki okrężnicy; jednak rekrutacja PMN prowadzi do zniszczenia połączeń nabłonkowych i pomaga Shigella dotrzeć do przestrzeni podstawno-bocznej.43

Lipopolisacharyd (LPS) i metabolity pośrednie aktywują odpowiedź zapalną, a białko TIFA (TRAF-interacting protein with forkhead-associated domain) wchodzące w interakcję z receptorem czynnika martwicy nowotworu (TNF-R) może indukować aktywację TRAF2 i TRAF6, prowadząc do aktywacji inhibitora kinazy czynnika jądrowego-kB (IKK).44

Rekrutacja neutrofilów jest kluczowym elementem odpowiedzi zapalnej na infekcję Shigella. Neutrofile przyciągane do miejsca infekcji przyczyniają się do uszkodzenia tkanki, ale także do eliminacji bakterii. Paradoksalnie, stan zapalny i infiltracja neutrofilów mogą ułatwiać dalszą inwazję bakterii poprzez naruszenie integralności bariery nabłonkowej.45

Modulacja odpowiedzi immunologicznej przez Shigella

Shigella wykorzystuje szereg mechanizmów do modulowania odpowiedzi immunologicznej gospodarza. Bakterie wydzielają efektory, które aktywnie hamują sygnalizację prozapalną, co może równoważyć nasilenie stanu zapalnego na poziomie korzystnym dla bakterii.46

System T3SS Shigella odgrywa kluczową rolę w wydzielaniu białek OspC1 i OspC3, które hamują szlak sygnałowy interferonu (IFN) i hamują obronę gospodarza przeciwko Shigella. Białka te celują w szlak sygnałowy JAK/STAT, zmniejszając i zapobiegając ekspresji genów stymulowanych interferonem (ISG).47

OspC1 i OspC3 hamują sygnalizację IFN poprzez wiązanie się z kalmoduliną (CaM), która jest wymagana do fosforylacji STAT. Te białka Shigella oddziałują z CaM poprzez ich N-terminalną α-helisę, która naśladuje interakcję z CaMKII. W rezultacie CaM błędnie rozpoznaje białka bakteryjne jako CaMKII, zapobiegając normalnemu funkcjonowaniu szlaku sygnałowego i blokując ekspresję ISG.48

Mechanizmy te pokazują, jak Shigella umiejętnie wykorzystuje i unika potencjalnie szkodliwych odpowiedzi układu odpornościowego, co umożliwia jej przetrwanie i rozprzestrzenianie się w organizmie gospodarza.49

Rola inflammasomów w odpowiedzi na infekcję

W makrofagach, aktywacja NLRC4 (receptora podobnego do NOD C4) i NLRP3 (receptora podobnego do NOD P3) rozpoczyna indukcję pyroptozy i wydzielanie IL-1 i IL-18. Białko igłowe MxiH systemu T3SS jest wykrywane przez białko hamujące apoptozę neuronalną (NAIP), prowadząc do aktywacji inflammasomu NLRC4. Ta aktywacja pośredniczy w uwalnianiu i aktywacji ludzkiego białka hamującego apoptozę neuronalną (hNAIP).50

Po wejściu Shigella do komórki nabłonkowej, wokół bakterii tworzy się falbana błony i prowadzi do rekrutacji NOD1 i składnika sygnalizacji NOD1 downstream, modulatora niezbędnego dla NF-kB (NEMO) do pozycji bakteryjnych. Lokalizacja NOD1 w błonie plazmatycznej zależy od F-aktyny. Inny typ NOD1, NLRs jako czujnik immunologiczny dla składników bakteryjnych, składa się z dwóch części: domeny wiążącej nukleotyd (NBD) i powtórzeń bogatych w leucynę (LRR).51

W jelicie, NOD1 rozpoznaje peptydoglikan bakteryjny i inicjuje produkcję prozapalnych cytokin, w tym IL-8, które przyciągają neutrofile do miejsca infekcji. Aktywacja inflammasomów prowadzi do śmierci komórek i uwalniania cytokin, co przyczynia się do rozwoju stanu zapalnego w odpowiedzi na infekcję Shigella.52

Patofizjologia i manifestacje kliniczne

Zakażenie Shigella wywołuje spektrum objawów klinicznych, od łagodnej biegunki do ciężkiej dyzenterii. Manifestacje te są bezpośrednim wynikiem procesów patogenetycznych zachodzących w jelicie grubym.53

Uszkodzenie nabłonka i rozwój dyzenterii

Bakterie Shigella inwazyjnie wnikają do nabłonka okrężnicy i namnażają się wewnątrzkomórkowo, prowadząc do śmierci komórek i zniszczenia tkanki. Proces ten wywołuje silną odpowiedź zapalną charakteryzującą się infiltracją neutrofilów i makrofagów.54

Radialny rozciąganie lub ekspansja komórek podczas patogenezy bakteryjnej tworzy ogniskowe owrzodzenia śluzówki okrężnicy. Ze względu na owrzodzenia, dodawany jest komponent krwotoczny, a intensywna ostra odpowiedź zapalna jest wywoływana, gdy bakterie docierają do blaszki właściwej (cienkie warstwy tkanki łącznej), zwykle infekcja nie jest rozszerzona poza blaszkę.55

Przewlekłe uszkodzenie nabłonka jelitowego prowadzi do upośledzenia zdolności absorpcyjnych, co skutkuje biegunką wodną oraz wydzielaniem krwi i śluzu do stolca. Kombinacja uszkodzenia tkanki i stanu zapalnego prowadzi do charakterystycznych objawów shigellozy, takich jak biegunka, ból brzucha i gorączka.56

Rola toksyn w manifestacjach klinicznych

Toksyny produkowane przez Shigella przyczyniają się do rozwoju objawów klinicznych zakażenia. Shigella dysenteriae typ 1 produkuje toksynę Shiga, która ma działanie enterotoksyczne, cytotoksyczne i neurotoksyczne.57

Działanie enterotoksyczne: toksyna Shiga przyłącza się do receptorów w jelicie cienkim i blokuje absorpcję elektrolitów, glukozy i aminokwasów ze światła jelita. Prowadzi to do zaburzeń wchłaniania i biegunki wodnej.58

Działanie cytotoksyczne: podjednostka B toksyny Shiga wiąże się z glikolipidem komórki gospodarza w jelicie grubym, a domena A1 jest internalizowana poprzez endocytozę zależną od receptora (zagłębienia powlekane) i powoduje nieodwracalną inaktywację podjednostki rybosomalnej 60S, hamując w ten sposób syntezę białek, powodując śmierć komórek, uszkodzenie mikronaczyń jelita i krwotok.59

Działanie neurotoksyczne: gorączka i skurcze brzucha są uważane za oznaki neurotoksyczności. Toksyna Shiga może również uszkadzać komórki nerwowe, co przyczynia się do objawów neurologicznych obserwowanych w ciężkich przypadkach zakażenia.60

Powikłania pozajelitowe

W rzadkich przypadkach, zakażenie Shigella może prowadzić do powikłań pozajelitowych, szczególnie u pacjentów zakażonych S. dysenteriae typ 1. Toksyna Shiga może uszkodzić komórki śródbłonka kłębuszków nerkowych, prowadząc do niewydolności nerek, znanej jako zespół hemolityczno-mocznicowy (HUS).61

HUS charakteryzuje się triadą objawów: niedokrwistością hemolityczną, małopłytkowością i ostrą niewydolnością nerek. Jest to najpoważniejsze powikłanie zakażenia Shigella i może prowadzić do śmierci, szczególnie u dzieci i osób z obniżoną odpornością.62

Inne powikłania pozajelitowe mogą obejmować reaktywne zapalenie stawów, zapalenie spojówek, zapalenie mięśnia sercowego i zaburzenia neurologiczne. Powikłania te są zazwyczaj wynikiem odpowiedzi immunologicznej na antygeny bakteryjne lub bezpośredniego działania toksyn Shigella.63

Nowe odkrycia w patogenezie Shigella

Badania nad patogenezą zakażeń Shigella nieustannie dostarczają nowych informacji na temat mechanizmów wirulencji tych bakterii oraz interakcji z organizmem gospodarza.64

Rola mikrobioty jelitowej

Ostatnie badania wskazują na istotną rolę mikrobioty jelitowej w modulowaniu podatności na zakażenie Shigella. Komensale jelitowe mogą zapobiegać namnażaniu się patogenów poprzez bezpośrednią konkurencję o przestrzeń i składniki odżywcze, wydzielanie substancji przeciwbakteryjnych lub modulację odpowiedzi immunologicznej.65

S. sonnei, ale nie S. flexneri, posiada aktywny system sekrecji typu VI (T6SS), który zabija współzamieszkujące E. coli w zainfekowanych tkankach. Fenotyp z wadliwym T6SS prowadzi do zmniejszonej przetrwałości w okrężnicy, co wskazuje, że ten aparat jest kluczowy dla S. sonnei do przezwyciężenia oporności kolonizacyjnej ustanowionej przez E. coli.66

Badania z wykorzystaniem innowacyjnego obrazowania fluorescencyjnego 3D i analiz pomagają śledzić podróż S. flexneri in vivo, ujawniając, że patogen celuje w krypty okrężnicy podczas wczesnej fazy infekcji. Te krypty mieszczą jelitowe komórki macierzyste u ich podstawy i mają własną specyficzną dla krypty mikrobiotę rdzeniową (CSCM). Chociaż strefa inwazyjna Shigella rzadko sięga podstawy krypty, aby zakłócić progeniturkę komórek macierzystych, jej interakcja z CSCM i pośrednie konsekwencje dla zdrowia jelit pozostają niezbadane.67

Wpływ pH na patogenezę

Nowe badania sugerują, że różnice pH w różnych odcinkach przewodu pokarmowego mogą wpływać na zdolność Shigella do kolonizacji i inwazji. Eksperymentalna obserwacja wskazuje, że zasadowe warunki, jakie występują w świetle jelita cienkiego, nie sprzyjają patogenezie S. flexneri.68

Proponowany model sugeruje, że gdy S. flexneri przemieszcza się przez dystalną część jelita cienkiego, zasadowe pH środowiska światła jelita zmniejszałoby tworzenie biofilmu, wirulencję i inwazję nabłonka. Gdy dotrze do bardziej kwaśnego światła okrężnicy, bakterie mogą zwiększyć tworzenie biofilmu i ekspresję genów związanych z wirulencją, co ułatwiłoby inwazję nabłonka w tym miejscu.69

Badania te dostarczają nowego mechanistycznego wglądu w patogenezę shigellozy i sugerują, że środowisko pH jelita może być kluczowym czynnikiem determinującym miejsce i stopień infekcji Shigella.70

Adaptacja do oddychania i hipoksja

Badacze odkryli, że bakterie Shigella są nie tylko zdolne do zużywania tlenu w tkance okrężnicy w celu wzrostu i tworzenia ognisk infekcji, ale mogą również dostosować swój sposób oddychania, aby mogły nadal rosnąć po wykorzystaniu tlenu w tych ogniskach.71

Grupa badawcza odkryła również, że ogniska infekcji Shigella miały nietypowo niskie poziomy tlenu (hipoksja). Bakterie Shigella są „fakultatywnymi beztlenowcami”, co oznacza, że choć preferują oddychanie tlenowe (które wykorzystuje O2 jako paliwo), to w przypadku braku tlenu mogą również przełączyć się na oddychanie „beztlenowe”, które nie wymaga O2.72

Badacze wykazali, że oddychanie tlenowe Shigella i ich zdolność do modulowania utlenowania zainfekowanych tkanek umożliwia tworzenie hipoksycznych ognisk infekcji w błonie śluzowej jelita, co stanowi pierwszy etap ich strategii kolonizacji, z ponad 99% populacji bakteryjnej rosnącej w tych obszarach. Gdy w tych ogniskach wyczerpuje się tlen, zdolność adaptacyjna bakterii do środowisk ubogich w O2 daje im kluczową przewagę, która wyjaśnia ich wirulencję i wirulencję innych fakultatywnie beztlenowych enterobakterii.73

Rola systemu YfiBNR w wirulencji

Białko YfiB, obecne w błonie zewnętrznej, działa jako białko sensoryczne w systemie YfiBNR, który jest zaangażowany w regulację poziomów cyklicznego di-GMP wewnątrz komórek bakteryjnych. c-di-GMP jest istotną cząsteczką sygnałową wpływającą na różne procesy komórkowe, takie jak tworzenie biofilmu, cytotoksyczność, ruchliwość, synteza egzopolisacharydów i inne mechanizmy wirulencji, takie jak adhezja i inwazja bakterii.74

Wykazano, że utrata białka YfiB błony zewnętrznej utrudnia funkcję związanego z błoną wewnętrzną YfiN (aktywność DGC), ponieważ peryplazmatyczny YfiR jest zawsze z nim związany, co powoduje zmniejszone stężenie c-di-GMP. Utrata YfiB i wyraźny spadek wewnątrzkomórkowych poziomów c-di-GMP wpływają następnie na inne czynniki wirulencji bakterii, co widać po wolniejszym wytwarzaniu biofilmu; zmniejszonej adhezji i inwazji komórek gospodarza; osłabionej zdolności do tworzenia plakietki; i niższym nagromadzeniem w jelitach C. elegans, co prowadzi do wzrostu długości życia nicieni.7576

Interakcja z peptydem obronnym HD5

Badania wykazały, że HD5, peptyd obronny gospodarza, paradoksalnie zwiększa inwazję Shigella poprzez indukowanie podobnych do filopodiów rozszerzeń (HIFE) za pośrednictwem sygnalizacji P2Y11-Gs-cAMP-PKA. Shigella wykorzystuje HIFE do infekcji, którą można zablokować inhibitorem P2Y11 – NF157, oferując potencjalny cel terapeutyczny.77

HD5 indukuje rozszerzenia filopodialne w komórkach nabłonkowych, które patogen Shigella wykorzystuje do ułatwienia inwazji i infekcji. Odkrycie to otwiera ekscytujące nowe możliwości interwencji terapeutycznej poprzez celowanie w interakcje HD5-P2Y11, aby zapobiec infekcji.78

Badanie to ujawnia nowy mechanizm, poprzez który HD5 zwiększa inwazję Shigella poprzez przebudowę cytoszkieletu zależną od P2Y11, podważając konwencjonalny pogląd na peptydy obronne gospodarza jako ściśle czynniki przeciwbakteryjne.79

Modulacja sumoilacji przez Shigella

Zakłócenie równowagi sumoilacji/desumoilacji jest związane z kilkoma stanami chorobowymi, takimi jak nowotwory i infekcje, jednak mechanizmy regulujące globalną równowagę SUMO pozostają słabo zdefiniowane. Wykazano, że infekcja przez Shigella flexneri, czynnik wywołujący ludzką czerwonkę bakteryjną, wyłącza sumoilację gospodarza podczas infekcji komórek nabłonkowych in vitro i in vivo, a efekt ten jest głównie zapośredniczony przez indukowane przez wapń/kalpainę rozszczepienie enzymu SUMO E1 SAE2, prowadzące w ten sposób do zahamowania sumoilacji.80

Mechanistycznie, wykazano, że efekt ten jest w dużej mierze zapośredniczony przez zależną od kalpain proteolityczną degradację enzymu E1 SAE2. Wykazano, że upośledzona aktywność sumoilacyjna w komórkach gospodarza sprzyja wejściu Shigella i zidentyfikowano RhoGDI, główny negatywny regulator aktywności biologicznych małych GTPaz Rho, jako ważny substrat SUMO wykorzystywany przez komórki gospodarza do ograniczenia inwazji Shigella.81

Odkrycia, że hamowanie napływu wewnątrzkomórkowego wapnia lub aktywności kalpain zapobiegało indukowanej przez Shigella utracie koniugatów SUMO i, odwrotnie, że samo leczenie wapniem i jonomycyną przy braku Shigella wyzwalało hamowanie sumoilacji, wskazują, że zwiększony cytosol wapnia i następująca po nim aktywacja kalpain są odpowiedzialne za degradację SAE2 i upośledzenie sumoilacji.82

Mechanizmy oporności na antybiotyki u Shigella

Oporność na leki u Shigella spp. może wynikać z wielu mechanizmów, takich jak wypompowanie leków przez aktywne pompy efflux, zmniejszenie przepuszczalności komórkowej oraz nadekspresja enzymów modyfikujących i inaktywujących leki lub modyfikacja celu przez mutację.83

Większość antybiotyków stosowanych w leczeniu infekcji Shigella powinna być w stanie przeniknąć przez błonę komórkową, aby osiągnąć wewnątrzkomórkową akumulację i miejsca docelowe. Rzeczywiście, oporność na antybiotyki β-laktamowe jest związana z modyfikacją poryn błony zewnętrznej OmpF (38 kDa) i OmpC (42 kDa) oraz białek cytosoli o masie 26 kDa, OmpR jako regulator transkrypcyjny.84

Aktywne pompy efflux odgrywają znaczącą rolę w fenotypach oporności na antybiotyki bakterii Gram-ujemnych i wypompowywaniu toksycznych związków z ich komórek. System AcrAB-TolC jest trójskładnikowym kompleksem składającym się z TolC (kanał błony zewnętrznej), AcrB (białko transportujące błony wewnętrznej) i peryplazmatycznego AcrA zaangażowanego w montaż i utrzymanie tych dwóch integralnych białek błonowych. Nadekspresja AcrAB-TolC skutkuje ogólnym zmniejszeniem akumulacji chinolonów wewnątrz komórek bakteryjnych, co również skutkuje zmniejszoną wrażliwością na nie.85

Wzrost wielolekooporności (MDR) i pojawienie się beta-laktamaz o rozszerzonym spektrum substratowym (ESBL) u Shigella spp. może być przyczyną niepowodzeń leczenia i związanego z tym ograniczenia opcji terapeutycznych. CDC definiuje bakterie XDR Shigella jako szczepy oporne na wszystkie powszechnie zalecane empiryczne i alternatywne antybiotyki: azytromycynę, ciprofloksacynę, ceftriakson, trimetoprim-sulfametoksazol (TMP-SMX) i ampicylinę.8687

Nowe strategie zwalczania infekcji Shigella

Ze względu na rosnącą oporność Shigella na antybiotyki, istnieje pilna potrzeba opracowania nowych strategii zwalczania tych zakażeń. Badania koncentrują się na trzech głównych kierunkach: nowych celach terapeutycznych, modelach eksperymentalnych i szczepionkach.88

Nowe cele terapeutyczne

Identyfikacja i charakteryzacja nowych czynników wirulencji Shigella może prowadzić do odkrycia nowych celów terapeutycznych. Na przykład, modulacja poziomu c-di-GMP w komórkach bakteryjnych poprzez celowanie w system YfiBNR może osłabić zdolność bakterii do tworzenia biofilmu i inwazji komórek gospodarza.89

Inne potencjalne cele obejmują białka efektorowe T3SS, które są kluczowe dla wirulencji Shigella. Hamowanie sekrecji lub działania tych efektorów mogłoby znacząco osłabić zdolność bakterii do inwazji i przeżycia wewnątrzkomórkowego.90

Szczegółowe poznanie szlaków metabolicznych niezbędnych dla przeżycia Shigella w różnych mikroniszach jelita może również dostarczyć nowych celów dla interwencji terapeutycznych.91

Modele eksperymentalne

Rozwój nowych modeli eksperymentalnych ma kluczowe znaczenie dla lepszego zrozumienia patogenezy Shigella i testowania potencjalnych interwencji terapeutycznych. Użycie enteroidów pochodzących z ludzkich jelitowych komórek macierzystych jako modelu infekcji S. flexneri może umożliwić testowanie aktualnych paradygmatów inwazji, wewnątrzkomórkowej replikacji i rozprzestrzeniania się S. flexneri.92

Jednym z aspektów infekcji Shigella, który jest słabo zrozumiany, jest podstawa jej tropizmu do nabłonka okrężnicy; modele te mogą być wykorzystane do określenia, czy istnieje specyficzność tkankowa dla inwazji S. flexneri.93

Chip Intestine-Chip odtwarza siły mechaniczne działające na inwazję patogenu i stwierdzono, że perystaltyka jest krytyczna dla określonych etapów procesu infekcji. Najbardziej zaskakujące było zaobserwowanie, że Shigella może bezpośrednio infekować enterocyty od strony nabłonkowej (ze światła jelita) zgodnie z oczekiwaniami in vivo z taką skutecznością i powtarzalnością.9495

Rozwój szczepionek

Dowody, że kliniczna infekcja Shigella, zarówno po naturalnej infekcji, jak i wywołanej eksperymentalnie, zapewnia ochronę serologiczną homologiczną, są zachętą do opracowania skutecznej szczepionki. Infekcja Shigella wywołuje szerokie spektrum odpowiedzi immunologicznych na antygeny Shigella, w tym przeciwciała przeciwko polisacharydom antygenu O, antygenonom inwazyjnym plazmidu i innym białkom, a także odporność komórkową.96

Odpowiedzi ochronne są w dużej mierze uważane za ukierunkowane na swoisty dla serotypu antygen O. Rola innych odpowiedzi immunologicznych na infekcję Shigella w zakresie ochrony pozostaje nieokreślona. Eksperymentalne modele shigellozy u ochotników i naczelnych innych niż ludzie ujawniły szczegóły procesu patogennego infekcji Shigella i dostarczyły kluczowego narzędzia do oceny kandydatów na szczepionki.97

W modelu zapalenia rogówki i spojówki u świnek morskich, dwuskładnikowa szczepionka śluzówkowa składająca się z atenuowanych szczepów S. flexneri 2a i S. flexneri 3a zapewniała znaczącą ochronę krzyżową przed wyzwaniem wieloma innymi podserotypami S. flexneri.98

Podsumowanie mechanizmów patogenezy Shigella

Patogeneza infekcji Shigella jest złożonym, wieloetapowym procesem, który obejmuje inwazję nabłonka okrężnicy, namnażanie wewnątrzkomórkowe i rozprzestrzenianie się do sąsiednich komórek. Bakterie wykorzystują szereg wyrafinowanych strategii molekularnych, aby manipulować komórkami gospodarza i unikać jego mechanizmów obronnych.99

T3SS i związane z nim białka efektorowe stanowią główny mechanizm wirulencji, umożliwiający bakteriom inwazję komórek nabłonka, ucieczkę z fagosomu i manipulację odpowiedzią immunologiczną gospodarza. Dodatkowo, toksyny produkowane przez niektóre szczepy Shigella, szczególnie toksyna Shiga wytwarzana przez S. dysenteriae typ 1, przyczyniają się do ciężkości objawów klinicznych i mogą prowadzić do poważnych powikłań pozajelitowych.100

Nowe odkrycia dotyczące adaptacji Shigella do różnych warunków środowiskowych, interakcji z mikrobiotą jelitową i modyfikacji odpowiedzi immunologicznej gospodarza poszerzają nasze zrozumienie patogenezy shigellozy i mogą prowadzić do opracowania nowych strategii terapeutycznych. Szczególnie istotne są badania nad mechanizmami oporności na antybiotyki, które stanowią rosnące wyzwanie w leczeniu zakażeń Shigella.101

Zrozumienie złożonych mechanizmów patogenezy Shigella ma kluczowe znaczenie dla opracowania skutecznych strategii zapobiegania i leczenia zakażeń tymi bakteriami, które nadal stanowią poważny problem zdrowia publicznego na całym świecie.102

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  1. 09.04.2026
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Materiały źródłowe

  • #1 Shigella – Medical Microbiology – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK8038/
    Infection is initiated by ingestion of shigellae (usually via fecal-oral contamination). An early symptom, diarrhea (possibly elicited by enterotoxins and/or cytotoxin), may occur as the organisms pass through the small intestine. The hallmarks of shigellosis are bacterial invasion of the colonic epithelium and inflammatory colitis. These are interdependent processes amplified by local release of cytokines and by the infiltration of inflammatory elements. Colitis in the rectosigmoid mucosa, with concomitant malabsorption, results in the characteristic sign of bacillary dysentery: scanty, unformed stools tinged with blood and mucus. […] The pathogenic mechanism of shigellosis is complex, involving a possible enterotoxic and/or cytotoxic diarrheal prodrome, cytokine-mediated inflammation of the colon, and necrosis of the colonic epithelium. The underlying physiological insult that initiates this inflammatory cascade is the invasion of Shigella into the colonic epithelium and the lamina propria. The resulting colitis and ulceration of the mucosa result in bloody, mucoid stools, and/or febrile diarrhea.
  • #2 Molecular Pathogenesis of Shigella spp.: Controlling Host Cell Signaling, Invasion, and Death by Type III Secretion
    https://pmc.ncbi.nlm.nih.gov/articles/PMC2223840/
    Once released from the dying macrophage, S. flexneri is able to invade EC from the basolateral side, escapes from the phagosome, and replicates in the cytoplasm. Cytoplasmic S. flexneri moves by directed polymerization of actin, which allows the bacteria to spread to adjacent EC, avoiding exposure to extracellular components of the host immune defense. […] The severe tissue destruction caused by Shigella spp. results in an impaired adsorption of water, nutrients, and solutes, which might cause the watery diarrhea as well as the blood and mucus in stools characteristic of shigellosis. […] Even though massive inflammation promotes the initial infection by S. flexneri, recent reports provide evidence that bacteria secrete effectors that actively downregulate proinflammatory signals, perhaps to balance the severity of the inflammation on a level beneficial for the bacteria. It is becoming increasingly clear that S. flexneri skillfully exploits and evades the potentially harmful responses of the immune system.
  • #3 Shigella Infection: Practice Essentials, Pathophysiology, Etiology
    https://emedicine.medscape.com/article/968773-overview
    Shigella infection is a major public health problem in developing countries where sanitation is poor. […] Shigellosis is spread by means of fecal-oral transmission. Other modes of transmission include ingestion of contaminated food or water (untreated wading pools, interactive water fountain), contact with a contaminated inanimate object, and certain mode of sexual contact. Vectors like the housefly can spread the disease by physically transporting infected feces. […] The infectivity dose (ID) is extremely low. As few as 10 S dysenteriae bacilli can cause clinical disease, whereas 100-200 bacilli are needed for S sonnei or S flexneri infection. The reasons for this low-dose response are not completely clear. One possible explanation is that virulent Shigellae can withstand the low pH of gastric juice. Most isolates of Shigella survive acidic treatment at pH 2.5 for at least 2 hours.
  • #4 Shigellosis – Wikipedia
    https://en.wikipedia.org/wiki/Shigellosis
    Shigellosis is caused by a bacterial infection with Shigella, a bacterium that is genetically similar to and was once classified as E. coli. […] Upon ingestion, the bacteria pass through the gastrointestinal tract until they reach the small intestine. There they begin to multiply until they reach the large intestine. In the large intestine, the bacteria cause cell injury and the beginning stages of Shigellosis via two main mechanisms: direct invasion of epithelial cells in the large intestine and production of enterotoxin 1 and enterotoxin 2. […] Unlike other bacteria, Shigella is not destroyed by the gastric acid in the stomach. As a result, it takes only 10 to 200 cells to cause an infection. This infectious dose is several orders of magnitude smaller than that of other species of bacteria (e.g., cholera, caused by the bacterium Vibrio cholerae, has an infectious dose between 108 and 1011 cells).
  • #5 Shigella – Medical Microbiology – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK8038/
    Infection is initiated by ingestion of shigellae (usually via fecal-oral contamination). An early symptom, diarrhea (possibly elicited by enterotoxins and/or cytotoxin), may occur as the organisms pass through the small intestine. The hallmarks of shigellosis are bacterial invasion of the colonic epithelium and inflammatory colitis. These are interdependent processes amplified by local release of cytokines and by the infiltration of inflammatory elements. Colitis in the rectosigmoid mucosa, with concomitant malabsorption, results in the characteristic sign of bacillary dysentery: scanty, unformed stools tinged with blood and mucus. […] The pathogenic mechanism of shigellosis is complex, involving a possible enterotoxic and/or cytotoxic diarrheal prodrome, cytokine-mediated inflammation of the colon, and necrosis of the colonic epithelium. The underlying physiological insult that initiates this inflammatory cascade is the invasion of Shigella into the colonic epithelium and the lamina propria. The resulting colitis and ulceration of the mucosa result in bloody, mucoid stools, and/or febrile diarrhea.
  • #6 Molecular Pathogenesis of Shigella spp.: Controlling Host Cell Signaling, Invasion, and Death by Type III Secretion
    https://pmc.ncbi.nlm.nih.gov/articles/PMC2223840/
    The genetic information constituting the phenotypes of Shigella spp. is encoded on the bacterial chromosome and on a large virulence plasmid. The virulence plasmid is an essential virulence determinant of all Shigella spp. and encodes the molecular machinery necessary for tissue invasion and the intracellular lifestyle. The central element of this machinery is a T3SS. The T3SS enables the bacteria to translocate a set of approximately 25 proteins from the bacterial cytoplasm directly into the eukaryotic host cell, where these effector proteins interfere with various host cell processes. […] The essential part of the molecular machinery required for bacterial invasion and intracellular survival is encoded on the large S. flexneri virulence plasmid. […] The first group consists of proteins secreted by the S. flexneri T3SS that act as effectors manipulating host cell processes in favor of the bacteria.
  • #7 Molecular Mechanisms of Shigella Pathogenesis; Recent Advances
    https://www.mdpi.com/1422-0067/24/3/2448
    Shigella species are the main cause of bacillary diarrhoea or shigellosis in humans. […] Shigella species uses attachment, invasion, intracellular motility, toxin secretion and host cell interruption mechanisms, causing mild diarrhoea, haemorrhagic colitis and haemolytic uremic syndrome diseases in humans through the expression of effector delivery systems, protein effectors, toxins, host cell immune system evasion and iron uptake genes. […] The virulence and pathogenesis of Shigella strains require T3SS, the most important pathogenicity mechanism of Shigella species. […] Shigella employs these seven steps, and releases different effector proteins to damage, invade and suppress the immune system of the host gastrointestinal epithelial cells, contributing, eventually, to mild diarrhoeal symptoms in the patient.
  • #8 Molecular mechanisms of Shigella effector proteins: a common pathogen among diarrheic pediatric population | Molecular and Cellular Pediatrics | Full Text
    https://molcellped.springeropen.com/articles/10.1186/s40348-022-00145-z
    Different gastrointestinal pathogens cause diarrhea which is a very common problem in children aged under 5 years. Among bacterial pathogens, Shigella is one of the main causes of diarrhea among children, and it accounts for approximately 11% of all deaths among children aged under 5 years. Shigella uses unique effector proteins to modulate intracellular pathways. Shigella cannot invade epithelial cells on the apical site; therefore, it needs to pass epithelium through other cells rather than the epithelial cell. After passing epithelium, macrophage swallows Shigella, and the latter should prepare itself to exhibit at least two types of responses: (I) escaping phagocyte and (II) mediating invasion of and injury to the recurrent PMN. The presence of PMN and invitation to a greater degree resulted in gut membrane injuries and greater bacterial penetration. Infiltration of Shigella to the basolateral space mediates (A) cell attachment, (B) cell entry, (C) evasion of autophagy recognition, (D) vacuole formation and vacuole rapture, (E) intracellular life, (F) Shiga toxin, and (G) immune response. In this review, an attempt is made to explain the role of each factor in Shigella infection.
  • #9 Molecular mechanisms of Shigella effector proteins: a common pathogen among diarrheic pediatric population | Molecular and Cellular Pediatrics | Full Text
    https://molcellped.springeropen.com/articles/10.1186/s40348-022-00145-z
    Regarding Shigella pathogenesis, after internalization inside the intestine lumen, bacteria should be infiltrated to the subcellular position. Shigella needs an M cell to cross the epithelial layer; an M cell is a particular epithelial cell that carries sampling antigen and transports it across the epithelial cell to the M cell pocket. In the M cell pocket, bacteria are delivered to the resident macrophage and T cell to propagate immune responses. Following the internalization of Shigella into the macrophage, it massively duplicates, resulting in macrophage dying and bacterial release. After release from macrophage, Shigella appears on a basolateral surface, and after binding with the epithelial cell, it inserts effector proteins via type-three secretion system (T3SS). […] In Shigella, T3SSs mediate internalization into the epithelial cell after engulfment with the vacuole. Then, a unique effector protein degrades double-layer vacuole, which in turn helps bacteria escape into the cytoplasm. After reaching the cytosol, Shigella uses an actin filament to make movements. Free movement affects the cytoplasmic membrane and makes a pseudopod; afterward, this pseudopod is swallowed by an adjacent cell. Shigella spp. effector proteins with their mechanisms, targets, and outcomes are shown in Table 1. Overall, the infiltration of Shigella to the basolateral space mediates seven steps including (A) cell attachment, (B) cell entry, (C) evasion of autophagy recognition, (D) vacuole formation and vacuole rapture, (E) intracellular life, (F) Shiga toxin, and (G) immune response. In general, Shigella utilizes these seven steps and effector proteins to invade hosts, damage tissue sites, and thwart the immune system from responding.
  • #10 Shigella Infection: Practice Essentials, Pathophysiology, Etiology
    https://emedicine.medscape.com/article/968773-overview
    The characteristic virulence trait is encoded on a large (220 kb) plasmid responsible for synthesis of polypeptides that cause cytotoxicity. Shigellae that lose the virulence plasmid are no longer pathogenic. […] Siderophores, a group of plasmid-coded genes, control the acquisition of iron from host cells from its protein-bound state. […] Regulatory genes control expression of virulence genes. Shiga toxin (Stx) is not essential for virulence of S dysenteriae type 1 but contributes to the severity of dysentery. […] The A1 fraction acts like N-glycosidase; it removes single adenine residue from 28S rRNA of ribosome and inhibits protein synthesis. […] Stxs may play a role in the progression of mucosal lesions after colonic cells are invaded, or they may induce vascular damage in the colonic mucosa.
  • #11 Shigella Infection: Practice Essentials, Pathophysiology, Etiology
    https://emedicine.medscape.com/article/968773-overview
    Chromosomal genes control lipopolysaccharide (LPS) antigens in cell walls. LPS plays an important role in resistance to nonspecific host defense encountered during tissue invasion. […] Shigella bacteria invade the intestinal epithelium through M cells and proceed to spread from cell to cell, causing death and sloughing of contiguously invaded epithelial cells and inducing a potent inflammatory response resulting in the characteristic dysentery syndrome. In addition to this series of pathogenic events, only S dysenteriae type 1 has the ability to elaborate the potent Shiga toxin that inhibits protein synthesis in eukaryotic cells and that may lead to extraintestinal complications, including hemolytic-uremic syndrome and death.
  • #12 Molecular Pathogenesis of Shigella spp.: Controlling Host Cell Signaling, Invasion, and Death by Type III Secretion
    https://pmc.ncbi.nlm.nih.gov/articles/PMC2223840/
    The genetic information constituting the phenotypes of Shigella spp. is encoded on the bacterial chromosome and on a large virulence plasmid. The virulence plasmid is an essential virulence determinant of all Shigella spp. and encodes the molecular machinery necessary for tissue invasion and the intracellular lifestyle. The central element of this machinery is a T3SS. The T3SS enables the bacteria to translocate a set of approximately 25 proteins from the bacterial cytoplasm directly into the eukaryotic host cell, where these effector proteins interfere with various host cell processes. […] The essential part of the molecular machinery required for bacterial invasion and intracellular survival is encoded on the large S. flexneri virulence plasmid. […] The first group consists of proteins secreted by the S. flexneri T3SS that act as effectors manipulating host cell processes in favor of the bacteria.
  • #13 Molecular Pathogenesis of Shigella spp.: Controlling Host Cell Signaling, Invasion, and Death by Type III Secretion
    https://pmc.ncbi.nlm.nih.gov/articles/PMC2223840/
    The genetic information constituting the phenotypes of Shigella spp. is encoded on the bacterial chromosome and on a large virulence plasmid. The virulence plasmid is an essential virulence determinant of all Shigella spp. and encodes the molecular machinery necessary for tissue invasion and the intracellular lifestyle. The central element of this machinery is a T3SS. The T3SS enables the bacteria to translocate a set of approximately 25 proteins from the bacterial cytoplasm directly into the eukaryotic host cell, where these effector proteins interfere with various host cell processes. […] The essential part of the molecular machinery required for bacterial invasion and intracellular survival is encoded on the large S. flexneri virulence plasmid. […] The first group consists of proteins secreted by the S. flexneri T3SS that act as effectors manipulating host cell processes in favor of the bacteria.
  • #14 Shigella spp.: Infectious substances pathogen safety data sheet – Canada.ca
    https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/shigella.html
    A large virulence plasmid is essential for the pathogenesis of Shigella spp. as it facilitates invasion and spread into macrophages and enterocytes. Several other plasmids and pathogenicity islands (PAIs) have been acquired over the evolution of Shigella spp. that allow for effective invasion of host cells and protection against host immune responses. The plasmid pINV encodes a type III secretion system and several virulence factors, thus, it facilitates the intracellular lifestyle of Shigella spp. […] Shigella spp. also secrete virulence factors that induce inflammation and effectors that down-regulate the host immune response. Several plasmids, such as spA and pKSR100, confer antimicrobial resistance. The largest PAI also gives resistance to antimicrobials, as well as enables iron sequestration and modification of the O antigen through the production of an enterotoxin. The impact of bacteriophages on the evolution and virulence of Shigella spp. is substantial as they are commonly associated with PAIs. Insertion sequence elements are abundant within Shigella spp. leading to genome rearrangements, in addition to gain and/or loss of gene function. There are pathogenic differences between the Shigella spp. S. dysenteriae is considered the most virulent and can produce a potent cytotoxin known as Shigatoxin.
  • #15 Molecular Pathogenesis of Shigella spp.: Controlling Host Cell Signaling, Invasion, and Death by Type III Secretion
    https://pmc.ncbi.nlm.nih.gov/articles/PMC2223840/
    The genetic information constituting the phenotypes of Shigella spp. is encoded on the bacterial chromosome and on a large virulence plasmid. The virulence plasmid is an essential virulence determinant of all Shigella spp. and encodes the molecular machinery necessary for tissue invasion and the intracellular lifestyle. The central element of this machinery is a T3SS. The T3SS enables the bacteria to translocate a set of approximately 25 proteins from the bacterial cytoplasm directly into the eukaryotic host cell, where these effector proteins interfere with various host cell processes. […] The essential part of the molecular machinery required for bacterial invasion and intracellular survival is encoded on the large S. flexneri virulence plasmid. […] The first group consists of proteins secreted by the S. flexneri T3SS that act as effectors manipulating host cell processes in favor of the bacteria.
  • #16 Molecular mechanisms of Shigella effector proteins: a common pathogen among diarrheic pediatric population | Molecular and Cellular Pediatrics | Full Text
    https://molcellped.springeropen.com/articles/10.1186/s40348-022-00145-z
    Invasion of apical epithelial cells is limited, which is proportional to the basolateral surface. Moreover, the addition of M cells to the apical surface mediates increased invasion by S. flexneri. LPS and intermediate metabolite activate the inflammatory response, and tumor necrosis factor receptor (TNF-R)-associated factor (TRAF) protein interacting with the forkhead-associated domain (TIFA) may induce the activation of TRAF2 and TRAF6, leading to activation of the inhibitor of the nuclear factor-kB kinase (IKK). […] In Shigella, T3SS is encoded via a large plasmid and has been used to translocate the effector protein to the eukaryotic cell. The attachment component of T3SS consists of IpaB, IpaC, and IpaD members. The first two members are involved in the formation of pores in the eukaryotic cell, and the latter facilitates the assembly of the first two members. Following the activation of T3SS, IpaB, IpaC, and IpaD are released, and they bind with the 51 integrin, thus mediating actin rearrangement.
  • #17 Molecular mechanisms of Shigella effector proteins: a common pathogen among diarrheic pediatric population | Molecular and Cellular Pediatrics | Full Text
    https://molcellped.springeropen.com/articles/10.1186/s40348-022-00145-z
    IpaB can act as an ion channel in the host cell membrane that leads to the influx of potassium (K+), which is recognized via NLR family CARD domain-containing protein 4 (NLRC4) resulting in the activation of pyroptosis. Potassium plays an essential role in membrane stability; thus, the imbalance between potassium ions intensifies osmotic pressure and vacuole rapture. Interestingly, the reduction of intracellular K+ concentration stimulates NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3). This molecule causes host cell invasion and phagosome escaping. […] After the internalization of Shigella, vacuole forms around the bacteria. IpgD effector protein is translocated via the T3SS, and this effector is a homolog to the Salmonella SopB. IpgD has a phosphoinositide phosphatase activity and dephosphorylates phosphatidylinositol 4,5-biphosphates (PIP2) into phosphatidylinositol 5-phosphate (PI5P). PI5P can be increased through the stimulation of osmotic shock or during S. flexneri infection.
  • #18 Enteropathogenic Escherichia coli, Samonella, Shigella and Yersinia: cellular aspects of host-bacteria interactions in enteric diseases | Gut Pathogens | Full Text
    https://gutpathogens.biomedcentral.com/articles/10.1186/1757-4749-2-8
    In Shigella, the bacterial proteins responsible for adhesion are the same as those that initiate the process of invasion. Following adherence, Shigella initiate activation of T3SS and secretion of effector proteins into the host cell. […] The protein IpaB binds to the receptor for hyaluronic acid, CD44, while IpaB complexed with IpaC binds to the fibronectin receptor, 51 integrin. […] After having formed a pore in the membrane of M or epithelial cells, the IpaB/C complex triggers the initial events in actin polymerization. […] Once internalized by M cells of the FAE, Shigella, unlike Salmonella, disrupts the vacuole membrane in a process dependent on the IpaB and IpaC invasins and escapes into the host cell cytoplasm, where it proliferates. […] The polymerization of actin depends on the action of IcsA (intracellular spread A)/VirG, an outer membrane protein that has a polar distribution on the bacterial surface.
  • #19 Shigella Infection: Practice Essentials, Pathophysiology, Etiology
    https://emedicine.medscape.com/article/968773-overview
    Chromosomal genes control lipopolysaccharide (LPS) antigens in cell walls. LPS plays an important role in resistance to nonspecific host defense encountered during tissue invasion. […] Shigella bacteria invade the intestinal epithelium through M cells and proceed to spread from cell to cell, causing death and sloughing of contiguously invaded epithelial cells and inducing a potent inflammatory response resulting in the characteristic dysentery syndrome. In addition to this series of pathogenic events, only S dysenteriae type 1 has the ability to elaborate the potent Shiga toxin that inhibits protein synthesis in eukaryotic cells and that may lead to extraintestinal complications, including hemolytic-uremic syndrome and death.
  • #20 shigella webpage
    https://www2.gvsu.edu/chm463/toxins/shigella.htm
    Shigella dysenteriae cause a Bacillary dysentery disease. The bacteria release the Shiga exotoxin that inhibits protein synthesis by lysing 28S rRNA. […] Shigella invade the villus cells of the large intestine by penetrating the colonic mucosa, but do not invade the blood, or perforate the intestine beyond the epithelium into the lamina propria. Shigella enter the intestinal mucosa by attaching to, and invading lymphoid cells in Peyer’s patches. These specialized lymphoid cells are called „M cells,” and normally transport foreign antigens from the intestine to underlying macrophages. The bacteria are internalized by the epithelial cells via a process similar to phagocytosis. This usually occurs with an endosome, but these bacteria have the ability to lyse the phagocytic vacuoles of macrophage cells and replicate in their cytoplasm. The bacteria are then spread into adjacent epithelial cells by propulsive movements of actin. This way, the bacteria avoid antibody-mediated humoral immunity. Shigella produce Ipa proteins in order to help escape from the endosome, but also produce them early on in order to initiate a cascade of cellular signalization that internalizes the bacteria with endosomes. While present in the mucosa, Shigella typically cause an inflammatory response that results in extensive tissue damage. They release a heat-stabile lipopolysaccharide endotoxin that can cause fever. The LPS of Gram-negative bacteria contains cell wall antigens (O antigens) that can elicit a variety of inflammatory responses in an animal. This endotoxin is part of the outer membrane of the Shigella cell, and has a low degree of specificity and a low degree of potency. It has an MW of 10kDa, and does not show enzymatic activity. Shigella also use apoptosis in order to intentionally activate the host’s inflammatory response. Subsequent infiltration and diapedisis by leukocytes disrupts the tight-junction of the bowel epithelium, thus allowing a massive invasion by bacteria still in the colon, resulting in a massive invasion and degradation of the intestinal mucosa.
  • #21 shigella webpage
    https://www2.gvsu.edu/chm463/toxins/shigella.htm
    Additionally, a heat-labile exotoxin is released by Shigella dysenteriae that damages the mucosa and villi. This toxin, Shiga toxin, has enterotoxic, cytotoxic, and neurotoxic effects. The protein has a MW of 50-1000kDa, diffuses extracellularly, is highly potent and has a high degree of specificity. It causes local areas of erosion that give rise to bleeding and heavy mucous secretion. The toxin also leads to nerve cell damage. Shiga toxin is composed of A (enzymatic) and B (binding) subunits in a ratio of 1:5. One component binds to the host cell surface, while the other passes into the cell membrane or cytoplasm before acting. The B subunit binds host cell glycolipids, while the A1 domain causes inactivation of the 60S ribosomal subunit, leading to cell death from inhibition of protein synthesis. Part of an A subunit has N-glycosidase activity on a single adenosine residue, lysing the bond between the base and ribose. This two-domain (A-5B) structure is similar to the Shiga-like toxin of enterohemorrhagic E. Coli (EHEC), but coded by a lysogenic bacteria.
  • #22
    https://link.springer.com/article/10.1007/s40475-014-0019-6
    In the colonic mucosa, Shigella is transcytosed across M cells into the underlying gut-associated lymphoid tissues. They later enter macrophages and induce apoptosis, leading to release of the bacteria on the basal side of the epithelium. Upon receipt of a secretion signal, Shigella invades epithelial cells from the basolateral side and spreads to adjacent cells. Proinflammatory signaling by host cells further activates the immune response, which initially exacerbates infection and tissue destruction. Ultimately, the infection is resolved when PMN phagocytose and kill the invading Shigella. […] In addition to these virulence factors, Shigella also may produce one or more of several toxins. Two enterotoxins that cause fluid secretion in animal models have been identified: Shigella enterotoxin 1 (ShET-1) and Shigella enterotoxin 2 (ShET-2). ShET1, predominantly found in S. flexneri, is encoded by the chromosomal gene set. It is a classical AB toxin comprised of several B subunits that bind to specific molecules on the target cell and a single A subunit that carries out the toxic enzymatic reaction within the cell. ShET-2 is encoded by a plasmid-borne gene sen and may be expressed by all Shigella species. Aside from an enterotoxic activity similar to that of ShET-1, ShET-2 is also believed to induce inflammation of epithelial cells via IL-8 secretion.
  • #23
    https://link.springer.com/article/10.1007/s40475-014-0019-6
    In the colonic mucosa, Shigella is transcytosed across M cells into the underlying gut-associated lymphoid tissues. They later enter macrophages and induce apoptosis, leading to release of the bacteria on the basal side of the epithelium. Upon receipt of a secretion signal, Shigella invades epithelial cells from the basolateral side and spreads to adjacent cells. Proinflammatory signaling by host cells further activates the immune response, which initially exacerbates infection and tissue destruction. Ultimately, the infection is resolved when PMN phagocytose and kill the invading Shigella. […] In addition to these virulence factors, Shigella also may produce one or more of several toxins. Two enterotoxins that cause fluid secretion in animal models have been identified: Shigella enterotoxin 1 (ShET-1) and Shigella enterotoxin 2 (ShET-2). ShET1, predominantly found in S. flexneri, is encoded by the chromosomal gene set. It is a classical AB toxin comprised of several B subunits that bind to specific molecules on the target cell and a single A subunit that carries out the toxic enzymatic reaction within the cell. ShET-2 is encoded by a plasmid-borne gene sen and may be expressed by all Shigella species. Aside from an enterotoxic activity similar to that of ShET-1, ShET-2 is also believed to induce inflammation of epithelial cells via IL-8 secretion.
  • #24 Molecular mechanisms of Shigella effector proteins: a common pathogen among diarrheic pediatric population | Molecular and Cellular Pediatrics | Full Text
    https://molcellped.springeropen.com/articles/10.1186/s40348-022-00145-z
    Regarding Shigella pathogenesis, after internalization inside the intestine lumen, bacteria should be infiltrated to the subcellular position. Shigella needs an M cell to cross the epithelial layer; an M cell is a particular epithelial cell that carries sampling antigen and transports it across the epithelial cell to the M cell pocket. In the M cell pocket, bacteria are delivered to the resident macrophage and T cell to propagate immune responses. Following the internalization of Shigella into the macrophage, it massively duplicates, resulting in macrophage dying and bacterial release. After release from macrophage, Shigella appears on a basolateral surface, and after binding with the epithelial cell, it inserts effector proteins via type-three secretion system (T3SS). […] In Shigella, T3SSs mediate internalization into the epithelial cell after engulfment with the vacuole. Then, a unique effector protein degrades double-layer vacuole, which in turn helps bacteria escape into the cytoplasm. After reaching the cytosol, Shigella uses an actin filament to make movements. Free movement affects the cytoplasmic membrane and makes a pseudopod; afterward, this pseudopod is swallowed by an adjacent cell. Shigella spp. effector proteins with their mechanisms, targets, and outcomes are shown in Table 1. Overall, the infiltration of Shigella to the basolateral space mediates seven steps including (A) cell attachment, (B) cell entry, (C) evasion of autophagy recognition, (D) vacuole formation and vacuole rapture, (E) intracellular life, (F) Shiga toxin, and (G) immune response. In general, Shigella utilizes these seven steps and effector proteins to invade hosts, damage tissue sites, and thwart the immune system from responding.
  • #25 Shigella Infection: Practice Essentials, Pathophysiology, Etiology
    https://emedicine.medscape.com/article/968773-overview
    Shigella infection is a major public health problem in developing countries where sanitation is poor. […] Shigellosis is spread by means of fecal-oral transmission. Other modes of transmission include ingestion of contaminated food or water (untreated wading pools, interactive water fountain), contact with a contaminated inanimate object, and certain mode of sexual contact. Vectors like the housefly can spread the disease by physically transporting infected feces. […] The infectivity dose (ID) is extremely low. As few as 10 S dysenteriae bacilli can cause clinical disease, whereas 100-200 bacilli are needed for S sonnei or S flexneri infection. The reasons for this low-dose response are not completely clear. One possible explanation is that virulent Shigellae can withstand the low pH of gastric juice. Most isolates of Shigella survive acidic treatment at pH 2.5 for at least 2 hours.
  • #26 Molecular mechanisms of Shigella effector proteins: a common pathogen among diarrheic pediatric population | Molecular and Cellular Pediatrics | Full Text
    https://molcellped.springeropen.com/articles/10.1186/s40348-022-00145-z
    The first barrier to microbial infection is mucin glycoprotein. Shigella can glycosylate and remodel the mucus barrier to its benefit. Given that Shigella cannot invade the apical epithelial surface, the target M cells penetrate the epithelial barrier. M cells are particular cells in mucosal-associated lymphoid tissue (MALT) that play a significant role in the transport of antigen from lumen to antigen-presenting cells (APC). M cells with their thin microvilli along with the absence of surface glycoprotein are exposed to the Shigella invasion. The entrance of S. flexneri to the M cells leads to the recurrence of polymorphonuclear neutrophils (PMN) and increase in the size of M cell. S. flexneri cannot invade the apical membrane of the colonic cell; however, the recurrence of PMN leads to the destruction of epithelial conjunction and helps Shigella reach the basolateral space.
  • #27 Molecular mechanisms of Shigella effector proteins: a common pathogen among diarrheic pediatric population | Molecular and Cellular Pediatrics | Full Text
    https://molcellped.springeropen.com/articles/10.1186/s40348-022-00145-z
    The first barrier to microbial infection is mucin glycoprotein. Shigella can glycosylate and remodel the mucus barrier to its benefit. Given that Shigella cannot invade the apical epithelial surface, the target M cells penetrate the epithelial barrier. M cells are particular cells in mucosal-associated lymphoid tissue (MALT) that play a significant role in the transport of antigen from lumen to antigen-presenting cells (APC). M cells with their thin microvilli along with the absence of surface glycoprotein are exposed to the Shigella invasion. The entrance of S. flexneri to the M cells leads to the recurrence of polymorphonuclear neutrophils (PMN) and increase in the size of M cell. S. flexneri cannot invade the apical membrane of the colonic cell; however, the recurrence of PMN leads to the destruction of epithelial conjunction and helps Shigella reach the basolateral space.
  • #28 Molecular Pathogenesis of Shigella spp.: Controlling Host Cell Signaling, Invasion, and Death by Type III Secretion
    https://pmc.ncbi.nlm.nih.gov/articles/PMC2223840/
    Most of the current knowledge on mechanisms underlying Shigella pathogenesis is derived from studies of S. flexneri. Infection with the invasive pathogen S. flexneri is a multistep process. To gain access to the intestinal mucosa, S. flexneri crosses the intestinal epithelium, which evolved as a physical and functional barrier to protect the body against the invasion of commensal and pathogenic bacteria. In the initial phase of infection, S. flexneri apparently does not invade the epithelial barrier from the apical side but instead triggers its uptake into microfold cells (M cells) and is transcytosed across the epithelial layer. […] After transcytosis, S. flexneri is released into an intraepithelial pocket, where the bacteria encounter resident macrophages that engulf and degrade incoming material. S. flexneri ensures its survival in macrophages by rapidly inducing apoptosis. Macrophage cell death is accompanied by the release of the proinflammatory cytokines interleukin-1 (IL-1) and IL-18. Both cytokines are critical mediators of the acute and massive inflammatory response elicited by S. flexneri.
  • #29 Shigella – Medical Microbiology – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK8038/
    The pathogenic mechanism that underlies these pathological manifestations is diagrammed in Figure 22-3. This cartoon incorporates experimental observations from tissue cultures and from animal models of shigellosis such as rabbit ligated ileal loops injected with virulent organisms. In the latter model, Shigella infection is initiated at the membranous (M) cells that are associated with macroscopic lymphoid follicles (Peyer’s patches). Biopsy studies in rhesus monkeys suggest that shigellae also infect microscopic lymphoid follicles of the primate colon. During the early stages of infection, bacteria are transcytosed through the M cells into the subepithelial space. In the subepithelial space, the organisms are phagocytosed by resident macrophages. However, virulent shigellae are not killed and digested in the macrophage phagolysome. The bacteria lyse the phagosome and initiate apoptosis (programmed cell death). During this process, the infected macrophage releases the inflammatory cytokine IL-1, which elicits infiltration of PMN.
  • #30 Molecular Pathogenesis of Shigella spp.: Controlling Host Cell Signaling, Invasion, and Death by Type III Secretion
    https://pmc.ncbi.nlm.nih.gov/articles/PMC2223840/
    Most of the current knowledge on mechanisms underlying Shigella pathogenesis is derived from studies of S. flexneri. Infection with the invasive pathogen S. flexneri is a multistep process. To gain access to the intestinal mucosa, S. flexneri crosses the intestinal epithelium, which evolved as a physical and functional barrier to protect the body against the invasion of commensal and pathogenic bacteria. In the initial phase of infection, S. flexneri apparently does not invade the epithelial barrier from the apical side but instead triggers its uptake into microfold cells (M cells) and is transcytosed across the epithelial layer. […] After transcytosis, S. flexneri is released into an intraepithelial pocket, where the bacteria encounter resident macrophages that engulf and degrade incoming material. S. flexneri ensures its survival in macrophages by rapidly inducing apoptosis. Macrophage cell death is accompanied by the release of the proinflammatory cytokines interleukin-1 (IL-1) and IL-18. Both cytokines are critical mediators of the acute and massive inflammatory response elicited by S. flexneri.
  • #31 Molecular Pathogenesis of Shigella spp.: Controlling Host Cell Signaling, Invasion, and Death by Type III Secretion
    https://pmc.ncbi.nlm.nih.gov/articles/PMC2223840/
    Most of the current knowledge on mechanisms underlying Shigella pathogenesis is derived from studies of S. flexneri. Infection with the invasive pathogen S. flexneri is a multistep process. To gain access to the intestinal mucosa, S. flexneri crosses the intestinal epithelium, which evolved as a physical and functional barrier to protect the body against the invasion of commensal and pathogenic bacteria. In the initial phase of infection, S. flexneri apparently does not invade the epithelial barrier from the apical side but instead triggers its uptake into microfold cells (M cells) and is transcytosed across the epithelial layer. […] After transcytosis, S. flexneri is released into an intraepithelial pocket, where the bacteria encounter resident macrophages that engulf and degrade incoming material. S. flexneri ensures its survival in macrophages by rapidly inducing apoptosis. Macrophage cell death is accompanied by the release of the proinflammatory cytokines interleukin-1 (IL-1) and IL-18. Both cytokines are critical mediators of the acute and massive inflammatory response elicited by S. flexneri.
  • #32 Molecular Pathogenesis of Shigella spp.: Controlling Host Cell Signaling, Invasion, and Death by Type III Secretion
    https://pmc.ncbi.nlm.nih.gov/articles/PMC2223840/
    The dissemination of S. flexneri in the epithelial layer crucially depends on the ability to move by directed actin polymerization. The essential mediators of efficient movement by actin nucleation at one pole of the bacterium are IcsA/VirG, SopA/IscP, VirA, and PhoN2 (apyrase). […] The intracellular lifestyle protects Shigella spp. from immune system effector cells present in the subepithelial layer. S. flexneri secretes at least two different type III effectors, which promote the survival of the invaded host cells. […] The onset of S. flexneri-induced macrophage death depends on caspase-1 but not other caspases, such as caspase-3, an executioner of cell death, or caspase-11, an activator of caspase-1 in response to LPS challenge. […] The Mxi-Spa-secreted S. flexneri translocator/effector protein IpaB binds caspase-1 directly in vitro. However, it is not clear whether IpaB has to be considered a bacterial PAMP, which induces inflammasome formation upon infection, or if IpaB directly recruits caspase-1 into the inflammasome complex.
  • #33 Molecular Pathogenesis of Shigella spp.: Controlling Host Cell Signaling, Invasion, and Death by Type III Secretion
    https://pmc.ncbi.nlm.nih.gov/articles/PMC2223840/
    Most of the current knowledge on mechanisms underlying Shigella pathogenesis is derived from studies of S. flexneri. Infection with the invasive pathogen S. flexneri is a multistep process. To gain access to the intestinal mucosa, S. flexneri crosses the intestinal epithelium, which evolved as a physical and functional barrier to protect the body against the invasion of commensal and pathogenic bacteria. In the initial phase of infection, S. flexneri apparently does not invade the epithelial barrier from the apical side but instead triggers its uptake into microfold cells (M cells) and is transcytosed across the epithelial layer. […] After transcytosis, S. flexneri is released into an intraepithelial pocket, where the bacteria encounter resident macrophages that engulf and degrade incoming material. S. flexneri ensures its survival in macrophages by rapidly inducing apoptosis. Macrophage cell death is accompanied by the release of the proinflammatory cytokines interleukin-1 (IL-1) and IL-18. Both cytokines are critical mediators of the acute and massive inflammatory response elicited by S. flexneri.
  • #34 Molecular mechanisms of Shigella effector proteins: a common pathogen among diarrheic pediatric population | Molecular and Cellular Pediatrics | Full Text
    https://molcellped.springeropen.com/articles/10.1186/s40348-022-00145-z
    IpaB can act as an ion channel in the host cell membrane that leads to the influx of potassium (K+), which is recognized via NLR family CARD domain-containing protein 4 (NLRC4) resulting in the activation of pyroptosis. Potassium plays an essential role in membrane stability; thus, the imbalance between potassium ions intensifies osmotic pressure and vacuole rapture. Interestingly, the reduction of intracellular K+ concentration stimulates NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3). This molecule causes host cell invasion and phagosome escaping. […] After the internalization of Shigella, vacuole forms around the bacteria. IpgD effector protein is translocated via the T3SS, and this effector is a homolog to the Salmonella SopB. IpgD has a phosphoinositide phosphatase activity and dephosphorylates phosphatidylinositol 4,5-biphosphates (PIP2) into phosphatidylinositol 5-phosphate (PI5P). PI5P can be increased through the stimulation of osmotic shock or during S. flexneri infection.
  • #35 Enteropathogenic Escherichia coli, Samonella, Shigella and Yersinia: cellular aspects of host-bacteria interactions in enteric diseases | Gut Pathogens | Full Text
    https://gutpathogens.biomedcentral.com/articles/10.1186/1757-4749-2-8
    In Shigella, the bacterial proteins responsible for adhesion are the same as those that initiate the process of invasion. Following adherence, Shigella initiate activation of T3SS and secretion of effector proteins into the host cell. […] The protein IpaB binds to the receptor for hyaluronic acid, CD44, while IpaB complexed with IpaC binds to the fibronectin receptor, 51 integrin. […] After having formed a pore in the membrane of M or epithelial cells, the IpaB/C complex triggers the initial events in actin polymerization. […] Once internalized by M cells of the FAE, Shigella, unlike Salmonella, disrupts the vacuole membrane in a process dependent on the IpaB and IpaC invasins and escapes into the host cell cytoplasm, where it proliferates. […] The polymerization of actin depends on the action of IcsA (intracellular spread A)/VirG, an outer membrane protein that has a polar distribution on the bacterial surface.
  • #36 Molecular Pathogenesis of Shigella spp.: Controlling Host Cell Signaling, Invasion, and Death by Type III Secretion
    https://pmc.ncbi.nlm.nih.gov/articles/PMC2223840/
    Once released from the dying macrophage, S. flexneri is able to invade EC from the basolateral side, escapes from the phagosome, and replicates in the cytoplasm. Cytoplasmic S. flexneri moves by directed polymerization of actin, which allows the bacteria to spread to adjacent EC, avoiding exposure to extracellular components of the host immune defense. […] The severe tissue destruction caused by Shigella spp. results in an impaired adsorption of water, nutrients, and solutes, which might cause the watery diarrhea as well as the blood and mucus in stools characteristic of shigellosis. […] Even though massive inflammation promotes the initial infection by S. flexneri, recent reports provide evidence that bacteria secrete effectors that actively downregulate proinflammatory signals, perhaps to balance the severity of the inflammation on a level beneficial for the bacteria. It is becoming increasingly clear that S. flexneri skillfully exploits and evades the potentially harmful responses of the immune system.
  • #37 Enteropathogenic Escherichia coli, Samonella, Shigella and Yersinia: cellular aspects of host-bacteria interactions in enteric diseases | Gut Pathogens | Full Text
    https://gutpathogens.biomedcentral.com/articles/10.1186/1757-4749-2-8
    In Shigella, the bacterial proteins responsible for adhesion are the same as those that initiate the process of invasion. Following adherence, Shigella initiate activation of T3SS and secretion of effector proteins into the host cell. […] The protein IpaB binds to the receptor for hyaluronic acid, CD44, while IpaB complexed with IpaC binds to the fibronectin receptor, 51 integrin. […] After having formed a pore in the membrane of M or epithelial cells, the IpaB/C complex triggers the initial events in actin polymerization. […] Once internalized by M cells of the FAE, Shigella, unlike Salmonella, disrupts the vacuole membrane in a process dependent on the IpaB and IpaC invasins and escapes into the host cell cytoplasm, where it proliferates. […] The polymerization of actin depends on the action of IcsA (intracellular spread A)/VirG, an outer membrane protein that has a polar distribution on the bacterial surface.
  • #38 Enteropathogenic Escherichia coli, Samonella, Shigella and Yersinia: cellular aspects of host-bacteria interactions in enteric diseases | Gut Pathogens | Full Text
    https://gutpathogens.biomedcentral.com/articles/10.1186/1757-4749-2-8
    IcsA/VirG recruits host cell cytoskeletal proteins; it interacts with N-WASP and increases its affinity for Arp2/3, forming the complex IcsA/N-WASP/Arp2/3 that induces actin nucleation. […] Shigella intracellular movement also depends on the tubulin-degrading activity of VirA, which opens the way through the microtubule network for Shigella. […] The effector IpgD is a phosphatase with homology to SopB/SigD of Salmonella; it generates PtdIns(5)P from PtdIns(4,5)P2 at the site of entry, and PtdIns(5)P in turn activates the PI-3 kinase/Akt pathway, thus contributing to cell survival. […] These events are summarized in Fig. 2a.
  • #39 Enteropathogenic Escherichia coli, Samonella, Shigella and Yersinia: cellular aspects of host-bacteria interactions in enteric diseases | Gut Pathogens | Full Text
    https://gutpathogens.biomedcentral.com/articles/10.1186/1757-4749-2-8
    IcsA/VirG recruits host cell cytoskeletal proteins; it interacts with N-WASP and increases its affinity for Arp2/3, forming the complex IcsA/N-WASP/Arp2/3 that induces actin nucleation. […] Shigella intracellular movement also depends on the tubulin-degrading activity of VirA, which opens the way through the microtubule network for Shigella. […] The effector IpgD is a phosphatase with homology to SopB/SigD of Salmonella; it generates PtdIns(5)P from PtdIns(4,5)P2 at the site of entry, and PtdIns(5)P in turn activates the PI-3 kinase/Akt pathway, thus contributing to cell survival. […] These events are summarized in Fig. 2a.
  • #40 Molecular mechanisms of Shigella effector proteins: a common pathogen among diarrheic pediatric population | Molecular and Cellular Pediatrics | Full Text
    https://molcellped.springeropen.com/articles/10.1186/s40348-022-00145-z
    Regarding Shigella pathogenesis, after internalization inside the intestine lumen, bacteria should be infiltrated to the subcellular position. Shigella needs an M cell to cross the epithelial layer; an M cell is a particular epithelial cell that carries sampling antigen and transports it across the epithelial cell to the M cell pocket. In the M cell pocket, bacteria are delivered to the resident macrophage and T cell to propagate immune responses. Following the internalization of Shigella into the macrophage, it massively duplicates, resulting in macrophage dying and bacterial release. After release from macrophage, Shigella appears on a basolateral surface, and after binding with the epithelial cell, it inserts effector proteins via type-three secretion system (T3SS). […] In Shigella, T3SSs mediate internalization into the epithelial cell after engulfment with the vacuole. Then, a unique effector protein degrades double-layer vacuole, which in turn helps bacteria escape into the cytoplasm. After reaching the cytosol, Shigella uses an actin filament to make movements. Free movement affects the cytoplasmic membrane and makes a pseudopod; afterward, this pseudopod is swallowed by an adjacent cell. Shigella spp. effector proteins with their mechanisms, targets, and outcomes are shown in Table 1. Overall, the infiltration of Shigella to the basolateral space mediates seven steps including (A) cell attachment, (B) cell entry, (C) evasion of autophagy recognition, (D) vacuole formation and vacuole rapture, (E) intracellular life, (F) Shiga toxin, and (G) immune response. In general, Shigella utilizes these seven steps and effector proteins to invade hosts, damage tissue sites, and thwart the immune system from responding.
  • #41 Molecular Pathogenesis of Shigella spp.: Controlling Host Cell Signaling, Invasion, and Death by Type III Secretion
    https://pmc.ncbi.nlm.nih.gov/articles/PMC2223840/
    Once released from the dying macrophage, S. flexneri is able to invade EC from the basolateral side, escapes from the phagosome, and replicates in the cytoplasm. Cytoplasmic S. flexneri moves by directed polymerization of actin, which allows the bacteria to spread to adjacent EC, avoiding exposure to extracellular components of the host immune defense. […] The severe tissue destruction caused by Shigella spp. results in an impaired adsorption of water, nutrients, and solutes, which might cause the watery diarrhea as well as the blood and mucus in stools characteristic of shigellosis. […] Even though massive inflammation promotes the initial infection by S. flexneri, recent reports provide evidence that bacteria secrete effectors that actively downregulate proinflammatory signals, perhaps to balance the severity of the inflammation on a level beneficial for the bacteria. It is becoming increasingly clear that S. flexneri skillfully exploits and evades the potentially harmful responses of the immune system.
  • #42 Shigella – Medical Microbiology – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK8038/
    The pathogenic mechanism that underlies these pathological manifestations is diagrammed in Figure 22-3. This cartoon incorporates experimental observations from tissue cultures and from animal models of shigellosis such as rabbit ligated ileal loops injected with virulent organisms. In the latter model, Shigella infection is initiated at the membranous (M) cells that are associated with macroscopic lymphoid follicles (Peyer’s patches). Biopsy studies in rhesus monkeys suggest that shigellae also infect microscopic lymphoid follicles of the primate colon. During the early stages of infection, bacteria are transcytosed through the M cells into the subepithelial space. In the subepithelial space, the organisms are phagocytosed by resident macrophages. However, virulent shigellae are not killed and digested in the macrophage phagolysome. The bacteria lyse the phagosome and initiate apoptosis (programmed cell death). During this process, the infected macrophage releases the inflammatory cytokine IL-1, which elicits infiltration of PMN.
  • #43 Molecular mechanisms of Shigella effector proteins: a common pathogen among diarrheic pediatric population | Molecular and Cellular Pediatrics | Full Text
    https://molcellped.springeropen.com/articles/10.1186/s40348-022-00145-z
    The first barrier to microbial infection is mucin glycoprotein. Shigella can glycosylate and remodel the mucus barrier to its benefit. Given that Shigella cannot invade the apical epithelial surface, the target M cells penetrate the epithelial barrier. M cells are particular cells in mucosal-associated lymphoid tissue (MALT) that play a significant role in the transport of antigen from lumen to antigen-presenting cells (APC). M cells with their thin microvilli along with the absence of surface glycoprotein are exposed to the Shigella invasion. The entrance of S. flexneri to the M cells leads to the recurrence of polymorphonuclear neutrophils (PMN) and increase in the size of M cell. S. flexneri cannot invade the apical membrane of the colonic cell; however, the recurrence of PMN leads to the destruction of epithelial conjunction and helps Shigella reach the basolateral space.
  • #44 Molecular mechanisms of Shigella effector proteins: a common pathogen among diarrheic pediatric population | Molecular and Cellular Pediatrics | Full Text
    https://molcellped.springeropen.com/articles/10.1186/s40348-022-00145-z
    Invasion of apical epithelial cells is limited, which is proportional to the basolateral surface. Moreover, the addition of M cells to the apical surface mediates increased invasion by S. flexneri. LPS and intermediate metabolite activate the inflammatory response, and tumor necrosis factor receptor (TNF-R)-associated factor (TRAF) protein interacting with the forkhead-associated domain (TIFA) may induce the activation of TRAF2 and TRAF6, leading to activation of the inhibitor of the nuclear factor-kB kinase (IKK). […] In Shigella, T3SS is encoded via a large plasmid and has been used to translocate the effector protein to the eukaryotic cell. The attachment component of T3SS consists of IpaB, IpaC, and IpaD members. The first two members are involved in the formation of pores in the eukaryotic cell, and the latter facilitates the assembly of the first two members. Following the activation of T3SS, IpaB, IpaC, and IpaD are released, and they bind with the 51 integrin, thus mediating actin rearrangement.
  • #45 Shigella – Medical Microbiology – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK8038/
    The pathogenic mechanism that underlies these pathological manifestations is diagrammed in Figure 22-3. This cartoon incorporates experimental observations from tissue cultures and from animal models of shigellosis such as rabbit ligated ileal loops injected with virulent organisms. In the latter model, Shigella infection is initiated at the membranous (M) cells that are associated with macroscopic lymphoid follicles (Peyer’s patches). Biopsy studies in rhesus monkeys suggest that shigellae also infect microscopic lymphoid follicles of the primate colon. During the early stages of infection, bacteria are transcytosed through the M cells into the subepithelial space. In the subepithelial space, the organisms are phagocytosed by resident macrophages. However, virulent shigellae are not killed and digested in the macrophage phagolysome. The bacteria lyse the phagosome and initiate apoptosis (programmed cell death). During this process, the infected macrophage releases the inflammatory cytokine IL-1, which elicits infiltration of PMN.
  • #46 Molecular Pathogenesis of Shigella spp.: Controlling Host Cell Signaling, Invasion, and Death by Type III Secretion
    https://pmc.ncbi.nlm.nih.gov/articles/PMC2223840/
    Once released from the dying macrophage, S. flexneri is able to invade EC from the basolateral side, escapes from the phagosome, and replicates in the cytoplasm. Cytoplasmic S. flexneri moves by directed polymerization of actin, which allows the bacteria to spread to adjacent EC, avoiding exposure to extracellular components of the host immune defense. […] The severe tissue destruction caused by Shigella spp. results in an impaired adsorption of water, nutrients, and solutes, which might cause the watery diarrhea as well as the blood and mucus in stools characteristic of shigellosis. […] Even though massive inflammation promotes the initial infection by S. flexneri, recent reports provide evidence that bacteria secrete effectors that actively downregulate proinflammatory signals, perhaps to balance the severity of the inflammation on a level beneficial for the bacteria. It is becoming increasingly clear that S. flexneri skillfully exploits and evades the potentially harmful responses of the immune system.
  • #47 Shigella – Wikipedia
    https://en.wikipedia.org/wiki/Shigella
    The Type III Secretion System (T3SS) plays a crucial role when Shigella secretes its OspC1 and OspC3 proteins to suppress the interferon (IFN) signaling pathway and inhibit the host defense against Shigella. These proteins have been found to target the JAK/STAT signaling pathway, reducing and preventing interferon-stimulated gene (ISG) expression. […] OspC1 and OspC3 inhibit IFN signaling by binding to calmodulin (CaM), which is required for the phosphorylation of STAT. These Shigella proteins interact with CaM through their N-terminal -helix, which mimics the interaction with CaMKII. As a result, CaM mistakenly recognizes the bacterial proteins as CaMKII, preventing the normal function of the signaling pathway and blocking ISG expression. […] After infection, Shigella cells multiply intracellularly and spread to neighboring epithelial cells, resulting in tissue destruction and the characteristic pathology of shigellosis.
  • #48 Shigella – Wikipedia
    https://en.wikipedia.org/wiki/Shigella
    The Type III Secretion System (T3SS) plays a crucial role when Shigella secretes its OspC1 and OspC3 proteins to suppress the interferon (IFN) signaling pathway and inhibit the host defense against Shigella. These proteins have been found to target the JAK/STAT signaling pathway, reducing and preventing interferon-stimulated gene (ISG) expression. […] OspC1 and OspC3 inhibit IFN signaling by binding to calmodulin (CaM), which is required for the phosphorylation of STAT. These Shigella proteins interact with CaM through their N-terminal -helix, which mimics the interaction with CaMKII. As a result, CaM mistakenly recognizes the bacterial proteins as CaMKII, preventing the normal function of the signaling pathway and blocking ISG expression. […] After infection, Shigella cells multiply intracellularly and spread to neighboring epithelial cells, resulting in tissue destruction and the characteristic pathology of shigellosis.
  • #49 Molecular Pathogenesis of Shigella spp.: Controlling Host Cell Signaling, Invasion, and Death by Type III Secretion
    https://pmc.ncbi.nlm.nih.gov/articles/PMC2223840/
    Once released from the dying macrophage, S. flexneri is able to invade EC from the basolateral side, escapes from the phagosome, and replicates in the cytoplasm. Cytoplasmic S. flexneri moves by directed polymerization of actin, which allows the bacteria to spread to adjacent EC, avoiding exposure to extracellular components of the host immune defense. […] The severe tissue destruction caused by Shigella spp. results in an impaired adsorption of water, nutrients, and solutes, which might cause the watery diarrhea as well as the blood and mucus in stools characteristic of shigellosis. […] Even though massive inflammation promotes the initial infection by S. flexneri, recent reports provide evidence that bacteria secrete effectors that actively downregulate proinflammatory signals, perhaps to balance the severity of the inflammation on a level beneficial for the bacteria. It is becoming increasingly clear that S. flexneri skillfully exploits and evades the potentially harmful responses of the immune system.
  • #50 Molecular mechanisms of Shigella effector proteins: a common pathogen among diarrheic pediatric population | Molecular and Cellular Pediatrics | Full Text
    https://molcellped.springeropen.com/articles/10.1186/s40348-022-00145-z
    After the entrance of Shigella to the epithelial cell, membrane ruffle forms around the bacteria and leads to the recurrence of NOD1 and the component of NOD1 downstream signaling NF-B essential modulator (NEMO) to the bacterial positions. Localization of NOD1 in the plasma membrane depends on F-actin. Another type of NOD1, NLRs as an immune sensor for bacterial components, consist of two parts: nucleotide-binding domain (NBD) and leucine-rich repeat (LRR). […] In macrophages, the activation of NLRC4 (nod-like receptor C4) and NLRP3 (nod-like receptor P3) commenced, thus inducing pyroptosis and secretion of IL-1 and IL-18. MxiH needle protein of T3SS is detected by neuronal apoptosis inhibitory protein (NAIP), leading to the activation of NLRC4 inflammasome. This activation mediates the release and activation of human neuronal apoptosis inhibitory protein (hNAIP).
  • #51 Molecular mechanisms of Shigella effector proteins: a common pathogen among diarrheic pediatric population | Molecular and Cellular Pediatrics | Full Text
    https://molcellped.springeropen.com/articles/10.1186/s40348-022-00145-z
    After the entrance of Shigella to the epithelial cell, membrane ruffle forms around the bacteria and leads to the recurrence of NOD1 and the component of NOD1 downstream signaling NF-B essential modulator (NEMO) to the bacterial positions. Localization of NOD1 in the plasma membrane depends on F-actin. Another type of NOD1, NLRs as an immune sensor for bacterial components, consist of two parts: nucleotide-binding domain (NBD) and leucine-rich repeat (LRR). […] In macrophages, the activation of NLRC4 (nod-like receptor C4) and NLRP3 (nod-like receptor P3) commenced, thus inducing pyroptosis and secretion of IL-1 and IL-18. MxiH needle protein of T3SS is detected by neuronal apoptosis inhibitory protein (NAIP), leading to the activation of NLRC4 inflammasome. This activation mediates the release and activation of human neuronal apoptosis inhibitory protein (hNAIP).
  • #52 Molecular mechanisms of Shigella effector proteins: a common pathogen among diarrheic pediatric population | Molecular and Cellular Pediatrics | Full Text
    https://molcellped.springeropen.com/articles/10.1186/s40348-022-00145-z
    After the entrance of Shigella to the epithelial cell, membrane ruffle forms around the bacteria and leads to the recurrence of NOD1 and the component of NOD1 downstream signaling NF-B essential modulator (NEMO) to the bacterial positions. Localization of NOD1 in the plasma membrane depends on F-actin. Another type of NOD1, NLRs as an immune sensor for bacterial components, consist of two parts: nucleotide-binding domain (NBD) and leucine-rich repeat (LRR). […] In macrophages, the activation of NLRC4 (nod-like receptor C4) and NLRP3 (nod-like receptor P3) commenced, thus inducing pyroptosis and secretion of IL-1 and IL-18. MxiH needle protein of T3SS is detected by neuronal apoptosis inhibitory protein (NAIP), leading to the activation of NLRC4 inflammasome. This activation mediates the release and activation of human neuronal apoptosis inhibitory protein (hNAIP).
  • #53 Shigella – Medical Microbiology – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK8038/
    Infection is initiated by ingestion of shigellae (usually via fecal-oral contamination). An early symptom, diarrhea (possibly elicited by enterotoxins and/or cytotoxin), may occur as the organisms pass through the small intestine. The hallmarks of shigellosis are bacterial invasion of the colonic epithelium and inflammatory colitis. These are interdependent processes amplified by local release of cytokines and by the infiltration of inflammatory elements. Colitis in the rectosigmoid mucosa, with concomitant malabsorption, results in the characteristic sign of bacillary dysentery: scanty, unformed stools tinged with blood and mucus. […] The pathogenic mechanism of shigellosis is complex, involving a possible enterotoxic and/or cytotoxic diarrheal prodrome, cytokine-mediated inflammation of the colon, and necrosis of the colonic epithelium. The underlying physiological insult that initiates this inflammatory cascade is the invasion of Shigella into the colonic epithelium and the lamina propria. The resulting colitis and ulceration of the mucosa result in bloody, mucoid stools, and/or febrile diarrhea.
  • #54 Shigella Infection: Practice Essentials, Pathophysiology, Etiology
    https://emedicine.medscape.com/article/968773-overview
    Chromosomal genes control lipopolysaccharide (LPS) antigens in cell walls. LPS plays an important role in resistance to nonspecific host defense encountered during tissue invasion. […] Shigella bacteria invade the intestinal epithelium through M cells and proceed to spread from cell to cell, causing death and sloughing of contiguously invaded epithelial cells and inducing a potent inflammatory response resulting in the characteristic dysentery syndrome. In addition to this series of pathogenic events, only S dysenteriae type 1 has the ability to elaborate the potent Shiga toxin that inhibits protein synthesis in eukaryotic cells and that may lead to extraintestinal complications, including hemolytic-uremic syndrome and death.
  • #55 Shigella-Epidemiology, Pathogenesis, and Treatment – Microbiology Notes
    https://microbiologynotes.org/shigella-epidemiology-pathogenesis-and-treatment/
    The radial stretching or expansion of the cell during the pathogenesis of the bacteria forms focal mucosal ulcers of the colon. […] Because of the ulcers, the hemorrhagic component is added and an intense acute inflammatory response is evoked when bacteria reach the lamina propria (thin layers of the connective tissue), usually, infection is not extended beyond the lamina. […] In this case, diarrhea caused by the process is majorly inflammatory, consists of a small volume of stool consist of RBCs, WBCs, and bacteria. […] Dysentery strains of Shigella produce exotoxins like Shiga toxin, which has one A subunit and five B subunits. […] The B subunits bind with glycolipid (Gb3) present in the host cell and promote the transfers of the A subunit into the cell. […] The A subunit functions to cleave the 28S rRNA in the 60S ribosomal subunit, which prevents the binding of the aminoacyl in RNA transfer and disrupts the synthesis of the proteins. […] The combined action of toxin subunits damages the epithelial cells of the intestines, in the rare case of some patients, Shiga toxin can damage the glomerular endothelial cells, which causes renal failure.
  • #56 Shigella – Medical Microbiology – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK8038/
    Infection is initiated by ingestion of shigellae (usually via fecal-oral contamination). An early symptom, diarrhea (possibly elicited by enterotoxins and/or cytotoxin), may occur as the organisms pass through the small intestine. The hallmarks of shigellosis are bacterial invasion of the colonic epithelium and inflammatory colitis. These are interdependent processes amplified by local release of cytokines and by the infiltration of inflammatory elements. Colitis in the rectosigmoid mucosa, with concomitant malabsorption, results in the characteristic sign of bacillary dysentery: scanty, unformed stools tinged with blood and mucus. […] The pathogenic mechanism of shigellosis is complex, involving a possible enterotoxic and/or cytotoxic diarrheal prodrome, cytokine-mediated inflammation of the colon, and necrosis of the colonic epithelium. The underlying physiological insult that initiates this inflammatory cascade is the invasion of Shigella into the colonic epithelium and the lamina propria. The resulting colitis and ulceration of the mucosa result in bloody, mucoid stools, and/or febrile diarrhea.
  • #57 BSCI 424 Pathogenic Microbiology — Shigella
    https://science.umd.edu/classroom/bsci424/pathogendescriptions/Shigella.htm
    Exotoxin (Shiga toxin) is neurotoxic, cytotoxic, and enterotoxic, encoded by chromosomal genes, with two domain (A-5B) structure similar to the Shiga-like toxin of enterohemorrhagic E. coli (EHEC). […] Enterotoxic effect: Shiga toxin adheres to small intestine receptors and blocks absorption (uptake) of electrolytes, glucose, and amino acids from the intestinal lumen. […] Cytotoxic effect: B subunit of Shiga toxin binds host cell glycolipid in large intestine, A1 domain internalized via receptor-mediated endocytosis (coated pits) and causes irreversible inactivation of the 60S ribosomal subunit, thereby inhibiting protein synthesis, causing cell death, microvasculature damage to the intestine, and hemorrhage. […] Neurotoxic effect: Fever, abdominal cramping are considered signs of neurotoxicity.
  • #58 BSCI 424 Pathogenic Microbiology — Shigella
    https://science.umd.edu/classroom/bsci424/pathogendescriptions/Shigella.htm
    Exotoxin (Shiga toxin) is neurotoxic, cytotoxic, and enterotoxic, encoded by chromosomal genes, with two domain (A-5B) structure similar to the Shiga-like toxin of enterohemorrhagic E. coli (EHEC). […] Enterotoxic effect: Shiga toxin adheres to small intestine receptors and blocks absorption (uptake) of electrolytes, glucose, and amino acids from the intestinal lumen. […] Cytotoxic effect: B subunit of Shiga toxin binds host cell glycolipid in large intestine, A1 domain internalized via receptor-mediated endocytosis (coated pits) and causes irreversible inactivation of the 60S ribosomal subunit, thereby inhibiting protein synthesis, causing cell death, microvasculature damage to the intestine, and hemorrhage. […] Neurotoxic effect: Fever, abdominal cramping are considered signs of neurotoxicity.
  • #59 BSCI 424 Pathogenic Microbiology — Shigella
    https://science.umd.edu/classroom/bsci424/pathogendescriptions/Shigella.htm
    Exotoxin (Shiga toxin) is neurotoxic, cytotoxic, and enterotoxic, encoded by chromosomal genes, with two domain (A-5B) structure similar to the Shiga-like toxin of enterohemorrhagic E. coli (EHEC). […] Enterotoxic effect: Shiga toxin adheres to small intestine receptors and blocks absorption (uptake) of electrolytes, glucose, and amino acids from the intestinal lumen. […] Cytotoxic effect: B subunit of Shiga toxin binds host cell glycolipid in large intestine, A1 domain internalized via receptor-mediated endocytosis (coated pits) and causes irreversible inactivation of the 60S ribosomal subunit, thereby inhibiting protein synthesis, causing cell death, microvasculature damage to the intestine, and hemorrhage. […] Neurotoxic effect: Fever, abdominal cramping are considered signs of neurotoxicity.
  • #60 BSCI 424 Pathogenic Microbiology — Shigella
    https://science.umd.edu/classroom/bsci424/pathogendescriptions/Shigella.htm
    Exotoxin (Shiga toxin) is neurotoxic, cytotoxic, and enterotoxic, encoded by chromosomal genes, with two domain (A-5B) structure similar to the Shiga-like toxin of enterohemorrhagic E. coli (EHEC). […] Enterotoxic effect: Shiga toxin adheres to small intestine receptors and blocks absorption (uptake) of electrolytes, glucose, and amino acids from the intestinal lumen. […] Cytotoxic effect: B subunit of Shiga toxin binds host cell glycolipid in large intestine, A1 domain internalized via receptor-mediated endocytosis (coated pits) and causes irreversible inactivation of the 60S ribosomal subunit, thereby inhibiting protein synthesis, causing cell death, microvasculature damage to the intestine, and hemorrhage. […] Neurotoxic effect: Fever, abdominal cramping are considered signs of neurotoxicity.
  • #61 Shigella-Epidemiology, Pathogenesis, and Treatment – Microbiology Notes
    https://microbiologynotes.org/shigella-epidemiology-pathogenesis-and-treatment/
    The radial stretching or expansion of the cell during the pathogenesis of the bacteria forms focal mucosal ulcers of the colon. […] Because of the ulcers, the hemorrhagic component is added and an intense acute inflammatory response is evoked when bacteria reach the lamina propria (thin layers of the connective tissue), usually, infection is not extended beyond the lamina. […] In this case, diarrhea caused by the process is majorly inflammatory, consists of a small volume of stool consist of RBCs, WBCs, and bacteria. […] Dysentery strains of Shigella produce exotoxins like Shiga toxin, which has one A subunit and five B subunits. […] The B subunits bind with glycolipid (Gb3) present in the host cell and promote the transfers of the A subunit into the cell. […] The A subunit functions to cleave the 28S rRNA in the 60S ribosomal subunit, which prevents the binding of the aminoacyl in RNA transfer and disrupts the synthesis of the proteins. […] The combined action of toxin subunits damages the epithelial cells of the intestines, in the rare case of some patients, Shiga toxin can damage the glomerular endothelial cells, which causes renal failure.
  • #62
    https://link.springer.com/article/10.1007/s40475-014-0019-6
    Shiga toxin 1(Stx 1), the most widely known Shigella toxin, is produced by SD1. Responsible for the most severe manifestations of shigellosis, Stx1 has an AB5 subunit structure. The five B subunits bind Shiga toxin to the glycolipid Gb3 receptor present on target cells such as intestinal villi, glomerular endothelial cells, mesangial cells, podocytes, and renal tubular cells. The A subunit is a cytotoxic protein that acts on the 28S rRNA component of eukaryotic ribosomes, leading to protein synthesis inhibition and destruction of endothelial cells. It is also believed to increase the expression of chemokines and cytokines, which in turn leads to chemoattraction and activation of neutrophils, and ultimately, to the binding of inflammatory cells to the endothelium.
  • #63 For health professionals: Shigellosis (Shigella) – Canada.ca
    https://www.canada.ca/en/public-health/services/diseases/shigella/health-professionals.html
    Shigellosis is an acute infectious diarrheal disease caused by a group of bacteria called Shigella. Shigella bacteria are extremely acid-tolerant. After ingestion, the bacteria progress from the stomach to the small intestine, where they multiply. Large numbers of bacteria then advance to the colon and enter the colonic epithelium. […] S. dysenteriae is considered the most virulent. It can produce a potent cytotoxin known as Shigatoxin. […] Shigella bacteria spread through the direct or indirect fecal-oral route. The illness is highly infectious and can also be spread from person to person. […] Shigellosis is an acute infection with onset of symptoms. In particular, it causes watery diarrhea usually occurring within 24 to 48 hours of ingestion of the etiologic agent. […] Infection may be mild or asymptomatic. Illness can range from mild watery diarrhea to severe inflammatory bacillary dysentery or shigellosis.
  • #64 Shigella pathogenesis: molecular and computational insights
    http://www.aimspress.com/article/10.3934/molsci.2020007
    Shigellosis, characterized by inflammation and ulceration of the large intestine, is caused by infection with Shigella species. […] WHO has identified Shigella as a potential target pathogen against which new drugs need to be formulated and in silico approach has the potential to identify drug targets. Molecular modeling of Shigella invasion proteins using computational tools may divulge novel therapeutic targets that can be used for future pharmacological intervention. Detailed annotation of previously unknown Hypothetical Proteins using an in-silico pipeline can identify crucial proteins in pathogenesis cascade, which can be explored further as effective drug targets, which may eventually enable us to combat the menace of shigellosis.
  • #65
    https://journals.lww.com/co-infectiousdiseases/fulltext/2018/10000/recent_insights_into_shigella__a_major_contributor.11.aspx
    Until recently, the focus of Shigella pathogenesis research has been on its interaction with the human host, and this overlooks the roles of the heterogenous colonic landscape and its coinhabiting microbial communities. Use of innovative 3D fluorescent imaging and analyses help track S. flexneri journey in vivo, revealing that the pathogen targets colonic crypts during the early phase of infection. These crypts house the intestinal stem cells at their base and harbour their own crypt-specific core microbiota (CSCM). Though Shigella’s invasive zone rarely reaches the crypt base to disrupt stem cells progeniture, its interaction with the CSCM and indirect consequences on gut health remain unexplored. Successful invasion requires Shigella to overcome two gut-specific barriers: the microbiota and the mucus layer. Colonic commensals could prevent pathogen proliferation by either direct competition for space and nutrient, secretion of antimicrobials, or modulation of immune response. Additionally, S. sonnei, but not S. flexneri, harbours an active type VI secretion system (T6SS), which kills co-inhabiting E. coli at infecting tissues. A defective T6SS phenotype leads to reduced persistence in the colon, indicating that this apparatus is crucial for S. sonnei to overcome E. coli-established colonization resistance.
  • #66
    https://journals.lww.com/co-infectiousdiseases/fulltext/2018/10000/recent_insights_into_shigella__a_major_contributor.11.aspx
    Until recently, the focus of Shigella pathogenesis research has been on its interaction with the human host, and this overlooks the roles of the heterogenous colonic landscape and its coinhabiting microbial communities. Use of innovative 3D fluorescent imaging and analyses help track S. flexneri journey in vivo, revealing that the pathogen targets colonic crypts during the early phase of infection. These crypts house the intestinal stem cells at their base and harbour their own crypt-specific core microbiota (CSCM). Though Shigella’s invasive zone rarely reaches the crypt base to disrupt stem cells progeniture, its interaction with the CSCM and indirect consequences on gut health remain unexplored. Successful invasion requires Shigella to overcome two gut-specific barriers: the microbiota and the mucus layer. Colonic commensals could prevent pathogen proliferation by either direct competition for space and nutrient, secretion of antimicrobials, or modulation of immune response. Additionally, S. sonnei, but not S. flexneri, harbours an active type VI secretion system (T6SS), which kills co-inhabiting E. coli at infecting tissues. A defective T6SS phenotype leads to reduced persistence in the colon, indicating that this apparatus is crucial for S. sonnei to overcome E. coli-established colonization resistance.
  • #67
    https://journals.lww.com/co-infectiousdiseases/fulltext/2018/10000/recent_insights_into_shigella__a_major_contributor.11.aspx
    Until recently, the focus of Shigella pathogenesis research has been on its interaction with the human host, and this overlooks the roles of the heterogenous colonic landscape and its coinhabiting microbial communities. Use of innovative 3D fluorescent imaging and analyses help track S. flexneri journey in vivo, revealing that the pathogen targets colonic crypts during the early phase of infection. These crypts house the intestinal stem cells at their base and harbour their own crypt-specific core microbiota (CSCM). Though Shigella’s invasive zone rarely reaches the crypt base to disrupt stem cells progeniture, its interaction with the CSCM and indirect consequences on gut health remain unexplored. Successful invasion requires Shigella to overcome two gut-specific barriers: the microbiota and the mucus layer. Colonic commensals could prevent pathogen proliferation by either direct competition for space and nutrient, secretion of antimicrobials, or modulation of immune response. Additionally, S. sonnei, but not S. flexneri, harbours an active type VI secretion system (T6SS), which kills co-inhabiting E. coli at infecting tissues. A defective T6SS phenotype leads to reduced persistence in the colon, indicating that this apparatus is crucial for S. sonnei to overcome E. coli-established colonization resistance.
  • #68 Biofilm Formation and Virulence of Shigella flexneri is Modulated by pH of Gastrointestinal Tract | bioRxiv
    https://www.biorxiv.org/content/10.1101/2020.10.16.336651v1.full-text
    Taken together, these experiments support a model whereby Shigella infection is favored in the colon because of the local pH differences in these organs. […] In this study, we utilized previously established biofilm formation methods to test whether deoxycholate-induced biofilms of Shigella flexneri could form under various pH conditions. […] Collectively, these studies demonstrate that basic conditions, as found in the lumen of the small intestine, are not favorable for S. flexneri pathogenesis and provide new mechanistic insight into shigellosis pathogenesis. […] We propose that as S. flexneri transits through the distal small intestine, the basic pH of the luminal environment would act to reduce biofilm formation, virulence, and epithelial invasion. As it reaches the more acidic colonic lumen, the bacteria could increase biofilm formation and virulence-related gene expression which would facilitate epithelial invasion at this site.
  • #69 Biofilm Formation and Virulence of Shigella flexneri is Modulated by pH of Gastrointestinal Tract | bioRxiv
    https://www.biorxiv.org/content/10.1101/2020.10.16.336651v1.full-text
    Taken together, these experiments support a model whereby Shigella infection is favored in the colon because of the local pH differences in these organs. […] In this study, we utilized previously established biofilm formation methods to test whether deoxycholate-induced biofilms of Shigella flexneri could form under various pH conditions. […] Collectively, these studies demonstrate that basic conditions, as found in the lumen of the small intestine, are not favorable for S. flexneri pathogenesis and provide new mechanistic insight into shigellosis pathogenesis. […] We propose that as S. flexneri transits through the distal small intestine, the basic pH of the luminal environment would act to reduce biofilm formation, virulence, and epithelial invasion. As it reaches the more acidic colonic lumen, the bacteria could increase biofilm formation and virulence-related gene expression which would facilitate epithelial invasion at this site.
  • #70 Biofilm Formation and Virulence of Shigella flexneri is Modulated by pH of Gastrointestinal Tract | bioRxiv
    https://www.biorxiv.org/content/10.1101/2020.10.16.336651v1.full-text
    Taken together, these experiments support a model whereby Shigella infection is favored in the colon because of the local pH differences in these organs. […] In this study, we utilized previously established biofilm formation methods to test whether deoxycholate-induced biofilms of Shigella flexneri could form under various pH conditions. […] Collectively, these studies demonstrate that basic conditions, as found in the lumen of the small intestine, are not favorable for S. flexneri pathogenesis and provide new mechanistic insight into shigellosis pathogenesis. […] We propose that as S. flexneri transits through the distal small intestine, the basic pH of the luminal environment would act to reduce biofilm formation, virulence, and epithelial invasion. As it reaches the more acidic colonic lumen, the bacteria could increase biofilm formation and virulence-related gene expression which would facilitate epithelial invasion at this site.
  • #71 Dysentery: Shigella, bacteria with adaptation to respiration – News from the Institut Pasteur
    https://www.pasteur.fr/en/press-area/press-documents/dysentery-shigella-bacteria-adaptation-respiration?language=fr
    Bacillary dysentery caused by the intestinal bacteria Shigella is a major health problem in tropical regions and developing countries. […] Researchers from Inserm and the Institut Pasteur have studied the mechanisms of Shigella virulence. They found that these bacteria are not only able to consume the oxygen in colonic tissue in order to grow and create foci of infection, but can also adapt their mode of respiration so that they can continue to grow once the oxygen in these foci has been used up. […] Shigella bacteria invade the cells of the intestinal wall and then the colonic mucosa, causing major inflammation combined with severe tissue damage. […] The research group also found that foci of Shigella infection had abnormally low levels of oxygen (hypoxia). […] Shigella bacteria are „facultative anaerobes,” which means that while they favor aerobic respiration (which uses O2 as fuel), if oxygen is lacking they can also switch to „anaerobic” respiration, which does not require O2.
  • #72 Dysentery: Shigella, bacteria with adaptation to respiration – News from the Institut Pasteur
    https://www.pasteur.fr/en/press-area/press-documents/dysentery-shigella-bacteria-adaptation-respiration?language=fr
    Bacillary dysentery caused by the intestinal bacteria Shigella is a major health problem in tropical regions and developing countries. […] Researchers from Inserm and the Institut Pasteur have studied the mechanisms of Shigella virulence. They found that these bacteria are not only able to consume the oxygen in colonic tissue in order to grow and create foci of infection, but can also adapt their mode of respiration so that they can continue to grow once the oxygen in these foci has been used up. […] Shigella bacteria invade the cells of the intestinal wall and then the colonic mucosa, causing major inflammation combined with severe tissue damage. […] The research group also found that foci of Shigella infection had abnormally low levels of oxygen (hypoxia). […] Shigella bacteria are „facultative anaerobes,” which means that while they favor aerobic respiration (which uses O2 as fuel), if oxygen is lacking they can also switch to „anaerobic” respiration, which does not require O2.
  • #73 Dysentery: Shigella, bacteria with adaptation to respiration – News from the Institut Pasteur
    https://www.pasteur.fr/en/press-area/press-documents/dysentery-shigella-bacteria-adaptation-respiration?language=fr
    The researchers have thus shown that aerobic respiration of Shigella and their capacity to modulate the oxygenation of infected tissues enables the formation of hypoxic foci of infection within the intestinal mucosa, which constitutes the first stage in their colonization strategy, with over 99% of the bacterial population growing in these areas. […] When these foci are depleted of oxygen, the adaptability of the bacteria to O2-poor environments gives them a crucial advantage that explains their virulence and that of other facultative anaerobic enterobacteria.
  • #74 YfiB: An Outer Membrane Protein Involved in the Virulence of Shigella flexneri | bioRxiv
    https://www.biorxiv.org/content/10.1101/2021.09.20.461158.full
    The intracellular pathogen Shigella flexneri, which is the causative agent of bacillary dysentery, significantly influences the worldwide implication of diarrheal infections, consequentially causing about 1.1 million deaths each year. […] The present study aims to illustrate the role of yfiB gene in Shigella virulence, which is a part of the periplasmic YfiBNR tripartite signaling system. This system is involved in the regulation of cyclic-di-GMP levels inside the bacterial cells, which is a vital messenger molecule impacting varied cellular processes such as biofilm formation, cytotoxicity, motility, synthesis of exopolysaccharide, and other virulence mechanisms like adhesion and invasion of the bacteria. […] Through a combination of genetic, biochemical, and virulence assays, we show how knocking out the yfiB gene can disrupt the entire YfiBNR system and affect biofilm formation, bacterial invasion, host-surface attachment, and the overall virulence of Shigella.
  • #75 YfiB: An Outer Membrane Protein Involved in the Virulence of Shigella flexneri | bioRxiv
    https://www.biorxiv.org/content/10.1101/2021.09.20.461158.full
    This leads to the stimulation of YfiN’s DGC activity, c-di-GMP production, resulting in enhanced biofilm and various other virulence factors. […] To do this, we generated a yfiB gene knockout, using double homologous recombination and studied its effect on Shigella’s survival and pathogenesis, using various in-vivo and in-vitro virulence assays. […] This is the first known report to validate YfiB regulation of YfiN’s DGC activity and thereby regulating c-di-GMP levels appropriately is indispensable for S. flexneri to cause an effective infection in the host. […] In this work, we remarkably show that altering intracellular c-di-GMP levels can severely affect the pathogenesis of Shigella flexneri. […] This study suggests that the loss of outer-membrane YfiB protein, hinders the function of the inner membrane-bound YfiN (DGC activity), as the periplasmic YfiR is always bound to it, which causes a decreased concentration of c-di-GMP.
  • #76 YfiB: An Outer Membrane Protein Involved in the Virulence of Shigella flexneri | bioRxiv
    https://www.biorxiv.org/content/10.1101/2021.09.20.461158.full
    Loss of YfiB and the apparent decrease in intracellular c-di-GMP levels, subsequently affect other downstream virulence factors of the bacteria, as seen by a slower biofilm production; decreased adhesion, and invasion of host cells; weakened ability to form plaques; and lower accumulation in guts of C. elegans, which leads to a surge in the life span of the worms. […] This shows how YfiB and the YfiBNR system have a significant impact on the intestinal accumulation of S. flexneri in the guts of C. elegans worms.
  • #77 Unveiling the Intricate Mechanism of HD5-Mediated Shigella Invasion: A Scientific Odyssey | Research Communities by Springer Nature
    https://communities.springernature.com/posts/unveiling-the-intricate-mechanism-of-hd5-mediated-shigella-invasion-a-scientific-odyssey
    Our study reveals that HD5, a host defense peptide, paradoxically enhances Shigella invasion by inducing filopodia-like extensions (HIFE) via P2Y11-Gs-cAMP-PKA signaling. […] Shigella exploits HIFE for infection, which can be blocked by the P2Y11 inhibitor NF157, offering a potential therapeutic target. […] HD5 induces filopodial extensions in epithelial cells that the pathogen Shigella exploits to facilitate invasion and infection. […] This discovery opens exciting new avenues for therapeutic intervention by targeting HD5-P2Y11 interactions to prevent infection. […] Our study reveals a novel mechanism by which HD5 enhances Shigella invasion through P2Y11-mediated cytoskeletal remodeling, challenging the conventional view of host defense peptides as strictly antimicrobial agents.
  • #78 Unveiling the Intricate Mechanism of HD5-Mediated Shigella Invasion: A Scientific Odyssey | Research Communities by Springer Nature
    https://communities.springernature.com/posts/unveiling-the-intricate-mechanism-of-hd5-mediated-shigella-invasion-a-scientific-odyssey
    Our study reveals that HD5, a host defense peptide, paradoxically enhances Shigella invasion by inducing filopodia-like extensions (HIFE) via P2Y11-Gs-cAMP-PKA signaling. […] Shigella exploits HIFE for infection, which can be blocked by the P2Y11 inhibitor NF157, offering a potential therapeutic target. […] HD5 induces filopodial extensions in epithelial cells that the pathogen Shigella exploits to facilitate invasion and infection. […] This discovery opens exciting new avenues for therapeutic intervention by targeting HD5-P2Y11 interactions to prevent infection. […] Our study reveals a novel mechanism by which HD5 enhances Shigella invasion through P2Y11-mediated cytoskeletal remodeling, challenging the conventional view of host defense peptides as strictly antimicrobial agents.
  • #79 Unveiling the Intricate Mechanism of HD5-Mediated Shigella Invasion: A Scientific Odyssey | Research Communities by Springer Nature
    https://communities.springernature.com/posts/unveiling-the-intricate-mechanism-of-hd5-mediated-shigella-invasion-a-scientific-odyssey
    Our study reveals that HD5, a host defense peptide, paradoxically enhances Shigella invasion by inducing filopodia-like extensions (HIFE) via P2Y11-Gs-cAMP-PKA signaling. […] Shigella exploits HIFE for infection, which can be blocked by the P2Y11 inhibitor NF157, offering a potential therapeutic target. […] HD5 induces filopodial extensions in epithelial cells that the pathogen Shigella exploits to facilitate invasion and infection. […] This discovery opens exciting new avenues for therapeutic intervention by targeting HD5-P2Y11 interactions to prevent infection. […] Our study reveals a novel mechanism by which HD5 enhances Shigella invasion through P2Y11-mediated cytoskeletal remodeling, challenging the conventional view of host defense peptides as strictly antimicrobial agents.
  • #80 Shigella entry unveils a calcium/calpain-dependent mechanism for inhibiting sumoylation | eLife
    https://elifesciences.org/articles/27444
    Disruption of the sumoylation/desumoylation equilibrium is associated with several disease states such as cancer and infections, however the mechanisms regulating the global SUMO balance remain poorly defined. […] Here, we show that infection by Shigella flexneri, the causative agent of human bacillary dysentery, switches off host sumoylation during epithelial cell infection in vitro and in vivo and that this effect is mainly mediated by a calcium/calpain-induced cleavage of the SUMO E1 enzyme SAE2, thus leading to sumoylation inhibition. […] Mechanistically, we demonstrate that this effect is, in large part, mediated by a calpain-dependent proteolytic degradation of the E1 SAE2 enzyme. […] We show that impaired sumoylation activity in host cells favors Shigella entry and identified RhoGDI, a master negative regulator of the biological activities of small Rho GTPases, as an important SUMO substrate used by host cells to limit Shigella invasion.
  • #81 Shigella entry unveils a calcium/calpain-dependent mechanism for inhibiting sumoylation | eLife
    https://elifesciences.org/articles/27444
    Disruption of the sumoylation/desumoylation equilibrium is associated with several disease states such as cancer and infections, however the mechanisms regulating the global SUMO balance remain poorly defined. […] Here, we show that infection by Shigella flexneri, the causative agent of human bacillary dysentery, switches off host sumoylation during epithelial cell infection in vitro and in vivo and that this effect is mainly mediated by a calcium/calpain-induced cleavage of the SUMO E1 enzyme SAE2, thus leading to sumoylation inhibition. […] Mechanistically, we demonstrate that this effect is, in large part, mediated by a calpain-dependent proteolytic degradation of the E1 SAE2 enzyme. […] We show that impaired sumoylation activity in host cells favors Shigella entry and identified RhoGDI, a master negative regulator of the biological activities of small Rho GTPases, as an important SUMO substrate used by host cells to limit Shigella invasion.
  • #82 Shigella entry unveils a calcium/calpain-dependent mechanism for inhibiting sumoylation | eLife
    https://elifesciences.org/articles/27444
    This work provides mechanistic insight into how sumoylation, by counteracting cytoskeletal rearrangement, impairs bacterial infection. […] Our findings that inhibiting either intracellular calcium influx or calpain activity prevented Shigella-induced loss of SUMO-conjugates and, conversely, that the sole treatment with calcium and ionomycin in the absence of Shigella triggered sumoylation inhibition indicate that increased cytosolic calcium and subsequent calpain activation are responsible for SAE2 degradation and impairment of sumoylation. […] Thus, in addition to identifying sumoylation of RhoGDI as an important event counteracting cytoskeletal remodeling and bacterial entry, our work reveals the ability of calcium signals to control global sumoylation levels.
  • #83 Shigella: Antibiotic-Resistance Mechanisms And New Horizons For Treatm | IDR
    https://www.dovepress.com/shigella-antibiotic-resistance-mechanisms-and-new-horizons-for-treatme-peer-reviewed-fulltext-article-IDR
    Shigella spp. are a common cause of diarrheal disease and have remained an important pathogen responsible for increased rates of morbidity and mortality caused by dysentery each year around the globe. […] Drug resistance in Shigella spp. can result from many mechanisms, such as extrusion of drugs by active efflux pumps, decrease in cellular permeability, and overexpression of drug-modifying and -inactivating enzymes or target modification by mutation. […] The current study was done to review various antibiotic-resistance mechanisms of Shigella spp., with a particular focus on epidemiology and new mechanisms of resistance and their acquisition, and also to discuss treatment and prevention measures for diseases caused by these organisms. […] Natural resistance to antimicrobial drugs by various mechanisms preventing the drug from being absorbed is capable of transforming the drug, its biotransformation into the cell, or reducing affinity with the drugs target.
  • #84 Shigella: Antibiotic-Resistance Mechanisms And New Horizons For Treatm | IDR
    https://www.dovepress.com/shigella-antibiotic-resistance-mechanisms-and-new-horizons-for-treatme-peer-reviewed-fulltext-article-IDR
    Most antibiotics used in treatment of Shigella infection should be able to penetrate the cell membrane to reach intracellular accumulation and target sites. […] Indeed, resistance toward -lactam antibiotics is associated with modification of the outer-membrane porins OmpF (38 kDa) and OmpC (42 kDa) and cytosolic proteins of 26 kDa, OmpR as a transcriptional regulator. […] Active efflux pumps play a significant role in antibiotic-resistance phenotypes of Gram-negative bacteria and expelling toxic compounds from their cells. […] The AcrABTolC system is a tripartite complex comprising TolC (outer-membrane channel), AcrB (inner-membrane transporter protein), and periplasmic AcrA involved in assembly and maintenance of these two integral membrane proteins. […] Indeed, overexpression of AcrABTolC results in overall decreased accumulation of quinolones inside bacterial cells, also resulting in reduced susceptibility to them.
  • #85 Shigella: Antibiotic-Resistance Mechanisms And New Horizons For Treatm | IDR
    https://www.dovepress.com/shigella-antibiotic-resistance-mechanisms-and-new-horizons-for-treatme-peer-reviewed-fulltext-article-IDR
    Most antibiotics used in treatment of Shigella infection should be able to penetrate the cell membrane to reach intracellular accumulation and target sites. […] Indeed, resistance toward -lactam antibiotics is associated with modification of the outer-membrane porins OmpF (38 kDa) and OmpC (42 kDa) and cytosolic proteins of 26 kDa, OmpR as a transcriptional regulator. […] Active efflux pumps play a significant role in antibiotic-resistance phenotypes of Gram-negative bacteria and expelling toxic compounds from their cells. […] The AcrABTolC system is a tripartite complex comprising TolC (outer-membrane channel), AcrB (inner-membrane transporter protein), and periplasmic AcrA involved in assembly and maintenance of these two integral membrane proteins. […] Indeed, overexpression of AcrABTolC results in overall decreased accumulation of quinolones inside bacterial cells, also resulting in reduced susceptibility to them.
  • #86 Health Alert Network (HAN) – 00486 | Increase in Extensively Drug-Resistant Shigellosis in the United States
    https://www.cdc.gov/han/2023/han00486.html
    Shigella bacteria are transmitted by the fecal-oral route, directly through person-to-person contact including sexual contact, and indirectly through contaminated food, water, and other routes. Shigella bacteria are easily transmitted because of the low infectious dose (as few as 10100 organisms), and outbreaks tend to occur among people in close-contact settings. […] CDC defines XDR Shigella bacteria as strains that are resistant to all commonly recommended empiric and alternative antibiotics azithromycin, ciprofloxacin, ceftriaxone, trimethoprim-sulfamethoxazole (TMP-SMX), and ampicillin. Currently, there are no data from clinical studies of treatment of XDR Shigella to inform recommendations for the optimal antimicrobial treatment of these infections. As such, CDC does not have recommendations for optimal antimicrobial treatment of XDR Shigella infections. […] XDR Shigella isolates in the United States typically do not carry resistance mechanisms for fosfomycin or carbapenems.
  • #87 Shigella: Antibiotic-Resistance Mechanisms And New Horizons For Treatm | IDR
    https://www.dovepress.com/shigella-antibiotic-resistance-mechanisms-and-new-horizons-for-treatme-peer-reviewed-fulltext-article-IDR
    The increase in MDR and emergence of ESBL in Shigella spp. may be the cause of treatment failures and accordingly limitation in therapeutic options. […] In this review, antibiotic-resistance mechanisms and therapeutic strategies have been summarized regarding Shigella infection. […] The multifarious nature of antibiotic-resistance mechanisms contributes in an increase in the number of MDR strains and causes conventional antibiotic therapeutics to be highly inefficient against shigellosis. […] Development of innovative therapeutic and alternative strategies is also required for prevention and treatment of Shigella infections.
  • #88 Shigella: Antibiotic-Resistance Mechanisms And New Horizons For Treatm | IDR
    https://www.dovepress.com/shigella-antibiotic-resistance-mechanisms-and-new-horizons-for-treatme-peer-reviewed-fulltext-article-IDR
    The increase in MDR and emergence of ESBL in Shigella spp. may be the cause of treatment failures and accordingly limitation in therapeutic options. […] In this review, antibiotic-resistance mechanisms and therapeutic strategies have been summarized regarding Shigella infection. […] The multifarious nature of antibiotic-resistance mechanisms contributes in an increase in the number of MDR strains and causes conventional antibiotic therapeutics to be highly inefficient against shigellosis. […] Development of innovative therapeutic and alternative strategies is also required for prevention and treatment of Shigella infections.
  • #89 YfiB: An Outer Membrane Protein Involved in the Virulence of Shigella flexneri | bioRxiv
    https://www.biorxiv.org/content/10.1101/2021.09.20.461158.full
    The intracellular pathogen Shigella flexneri, which is the causative agent of bacillary dysentery, significantly influences the worldwide implication of diarrheal infections, consequentially causing about 1.1 million deaths each year. […] The present study aims to illustrate the role of yfiB gene in Shigella virulence, which is a part of the periplasmic YfiBNR tripartite signaling system. This system is involved in the regulation of cyclic-di-GMP levels inside the bacterial cells, which is a vital messenger molecule impacting varied cellular processes such as biofilm formation, cytotoxicity, motility, synthesis of exopolysaccharide, and other virulence mechanisms like adhesion and invasion of the bacteria. […] Through a combination of genetic, biochemical, and virulence assays, we show how knocking out the yfiB gene can disrupt the entire YfiBNR system and affect biofilm formation, bacterial invasion, host-surface attachment, and the overall virulence of Shigella.
  • #90 Shigella: Antibiotic-Resistance Mechanisms And New Horizons For Treatm | IDR
    https://www.dovepress.com/shigella-antibiotic-resistance-mechanisms-and-new-horizons-for-treatme-peer-reviewed-fulltext-article-IDR
    The increase in MDR and emergence of ESBL in Shigella spp. may be the cause of treatment failures and accordingly limitation in therapeutic options. […] In this review, antibiotic-resistance mechanisms and therapeutic strategies have been summarized regarding Shigella infection. […] The multifarious nature of antibiotic-resistance mechanisms contributes in an increase in the number of MDR strains and causes conventional antibiotic therapeutics to be highly inefficient against shigellosis. […] Development of innovative therapeutic and alternative strategies is also required for prevention and treatment of Shigella infections.
  • #91 Dysentery: Shigella, bacteria with adaptation to respiration – News from the Institut Pasteur
    https://www.pasteur.fr/en/press-area/press-documents/dysentery-shigella-bacteria-adaptation-respiration?language=fr
    The researchers have thus shown that aerobic respiration of Shigella and their capacity to modulate the oxygenation of infected tissues enables the formation of hypoxic foci of infection within the intestinal mucosa, which constitutes the first stage in their colonization strategy, with over 99% of the bacterial population growing in these areas. […] When these foci are depleted of oxygen, the adaptability of the bacteria to O2-poor environments gives them a crucial advantage that explains their virulence and that of other facultative anaerobic enterobacteria.
  • #92 A Colonoid Model For Shigella Flexneri Pathogenesis | National Agricultural Library
    https://www.nal.usda.gov/research-tools/food-safety-research-projects/colonoid-model-shigella-flexneri-pathogenesis
    The enteric, intracellular human pathogen Shigella causes hundreds of millions of cases of the diarrheal disease shigellosis per year worldwide, which results in as many as one million deaths. […] While much is known regarding the mechanism of pathogenesis, there are still gaps in our knowledge. […] A potential solution to this problem is the development of enteroids derived from human intestinal stem cells as a model for Shigella flexneri infection. […] We will use enteroids to test the current paradigms of S. flexneri invasion, intracellular replication, and spread, in order to determine how S. flexneri responds to its normal host environment. […] In the first Aim, we will establish the basic parameters for colonoid infection by S. flexneri and test the hypothesis that M-cells are required in the invasion process in human intestine.
  • #93 A Colonoid Model For Shigella Flexneri Pathogenesis | National Agricultural Library
    https://www.nal.usda.gov/research-tools/food-safety-research-projects/colonoid-model-shigella-flexneri-pathogenesis
    One aspect of Shigella infection that is poorly understood is the basis for its tropism for colonic epithelium; in Aim 3 we will use human intestinal enteroids derived from duodenal, jejunal, ileal and colonic tissue to determine whether there is tissue specificity for S. flexneri invasion. […] Completion of this project will not only allow us to examine basic assumptions about Shigella pathogenesis but will also result in the development of a model system for future studies of the interaction between Shigella and the human epithelium.
  • #94 Modeling Bacterial Infection with Organ-Chips | Emulate Blog
    https://emulatebio.com/shigella-infection-model-organ-chips/
    Shigella are bacteria that cause Shigellosis, a gastrointestinal disease inducing severe stomach cramps, fever, and diarrhea. The onset of symptoms can begin from 1-2 days of contact and results from the rapid invasion of the pathogen within intestinal epithelial cells, leading to the destruction of healthy human colon tissue. […] In order to address whether Shigella flexneri could infect the human colon epithelium in the chip, a wild-type strain expressing GFP (Shigella-WT-GFP) in the intestinal lumen of the Intestine-Chip was introduced. […] Shigella invasion was observed when only a few hundred bacteria were introduced into the intestinal lumen. The observation that only minimal loads were required for infection is consistent with data from the clinic. Given this correlation between in vivo and chip data, the approach in the chip allowed us to dissect the fundamentals mediating Shigella invasion at the tissue scale. In particular, identification that Shigella directly infect enterocytes from the epithelial channel, shifting the current paradigm about the early stage of invasion.
  • #95 Modeling Bacterial Infection with Organ-Chips | Emulate Blog
    https://emulatebio.com/shigella-infection-model-organ-chips/
    The design of the Intestine-Chip recreates the mechanical forces on the pathogen invasion and found that peristalsis is critical for specific stages of the infection process. […] Most surprising was the observation that Shigella could directly infect enterocytes from the epithelial side (from the intestinal lumen) as expected in vivo with such efficiency and reproducibility.
  • #96 Clinical trials of Shigella vaccines: two steps forward and one step back on a long, hard road | Nature Reviews Microbiology
    https://www.nature.com/articles/nrmicro1662
    Evidence that clinical infection with Shigella, either following natural infection or volunteer challenge, confers serotype-specific homologous protection provides incentive for the development of an effective vaccine. […] Shigella infection elicits a wide spectrum of immune responses to Shigella antigens, including antibodies to O-antigen polysaccharides, invasion plasmid antigens and other proteins, as well as cell-mediated immunity. Protective responses are largely thought to be targeted to the serotype-specific O-antigen. The role of the other immune responses to Shigella infection in protection remains undetermined. […] Experimental models of shigellosis in volunteers and non-human primates have revealed details of the pathogenic process of Shigella infection and have provided a crucial tool for the evaluation of vaccine candidates.
  • #97 Clinical trials of Shigella vaccines: two steps forward and one step back on a long, hard road | Nature Reviews Microbiology
    https://www.nature.com/articles/nrmicro1662
    Evidence that clinical infection with Shigella, either following natural infection or volunteer challenge, confers serotype-specific homologous protection provides incentive for the development of an effective vaccine. […] Shigella infection elicits a wide spectrum of immune responses to Shigella antigens, including antibodies to O-antigen polysaccharides, invasion plasmid antigens and other proteins, as well as cell-mediated immunity. Protective responses are largely thought to be targeted to the serotype-specific O-antigen. The role of the other immune responses to Shigella infection in protection remains undetermined. […] Experimental models of shigellosis in volunteers and non-human primates have revealed details of the pathogenic process of Shigella infection and have provided a crucial tool for the evaluation of vaccine candidates.
  • #98 Clinical trials of Shigella vaccines: two steps forward and one step back on a long, hard road | Nature Reviews Microbiology
    https://www.nature.com/articles/nrmicro1662
    Demonstrated that NHPs experiencing Shigella diarrhoea for some hours before the onset of dysentery had net jejunal secretion, implying the action of an enterotoxin. […] Identification and characterization of ShET1. […] This randomized, double-blind clinical trial confirmed that ShET1 and ShET2 cause diarrhoea. […] In the guinea pig keratoconjunctivitis model, a bivalent mucosal vaccine consisting of attenuated S. flexneri 2a and S. flexneri 3a strains conferred significant cross-protection against challenge with multiple other S. flexneri subserotypes. […] The lipopolysaccharide of Shigella bacteria as a virulence factor. […] Optimization of virulence functions through glucosylation of Shigella LPS.
  • #99 Molecular Pathogenesis of Shigella spp.: Controlling Host Cell Signaling, Invasion, and Death by Type III Secretion
    https://pmc.ncbi.nlm.nih.gov/articles/PMC2223840/
    Shigella spp. are gram-negative pathogenic bacteria that evolved from harmless enterobacterial relatives and may cause devastating diarrhea upon ingestion. Research performed over the last 25 years revealed that a type III secretion system (T3SS) encoded on a large plasmid is a key virulence factor of Shigella flexneri. The T3SS determines the interactions of S. flexneri with intestinal cells by consecutively translocating two sets of effector proteins into the target cells. Thus, S. flexneri controls invasion into EC, intra- and intercellular spread, macrophage cell death, as well as host inflammatory responses. Some of the translocated effector proteins show novel biochemical activities by which they intercept host cell signal transduction pathways. An understanding of the molecular mechanisms underlying Shigella pathogenesis will foster the development of a safe and efficient vaccine, which, in parallel with improved hygiene, should curb infections by this widespread pathogen.
  • #100 Shigella Infection: Practice Essentials, Pathophysiology, Etiology
    https://emedicine.medscape.com/article/968773-overview
    Chromosomal genes control lipopolysaccharide (LPS) antigens in cell walls. LPS plays an important role in resistance to nonspecific host defense encountered during tissue invasion. […] Shigella bacteria invade the intestinal epithelium through M cells and proceed to spread from cell to cell, causing death and sloughing of contiguously invaded epithelial cells and inducing a potent inflammatory response resulting in the characteristic dysentery syndrome. In addition to this series of pathogenic events, only S dysenteriae type 1 has the ability to elaborate the potent Shiga toxin that inhibits protein synthesis in eukaryotic cells and that may lead to extraintestinal complications, including hemolytic-uremic syndrome and death.
  • #101 Shigella: Antibiotic-Resistance Mechanisms And New Horizons For Treatm | IDR
    https://www.dovepress.com/shigella-antibiotic-resistance-mechanisms-and-new-horizons-for-treatme-peer-reviewed-fulltext-article-IDR
    The increase in MDR and emergence of ESBL in Shigella spp. may be the cause of treatment failures and accordingly limitation in therapeutic options. […] In this review, antibiotic-resistance mechanisms and therapeutic strategies have been summarized regarding Shigella infection. […] The multifarious nature of antibiotic-resistance mechanisms contributes in an increase in the number of MDR strains and causes conventional antibiotic therapeutics to be highly inefficient against shigellosis. […] Development of innovative therapeutic and alternative strategies is also required for prevention and treatment of Shigella infections.
  • #102 Molecular Pathogenesis of Shigella spp.: Controlling Host Cell Signaling, Invasion, and Death by Type III Secretion
    https://pmc.ncbi.nlm.nih.gov/articles/PMC2223840/
    Shigella spp. are gram-negative pathogenic bacteria that evolved from harmless enterobacterial relatives and may cause devastating diarrhea upon ingestion. Research performed over the last 25 years revealed that a type III secretion system (T3SS) encoded on a large plasmid is a key virulence factor of Shigella flexneri. The T3SS determines the interactions of S. flexneri with intestinal cells by consecutively translocating two sets of effector proteins into the target cells. Thus, S. flexneri controls invasion into EC, intra- and intercellular spread, macrophage cell death, as well as host inflammatory responses. Some of the translocated effector proteins show novel biochemical activities by which they intercept host cell signal transduction pathways. An understanding of the molecular mechanisms underlying Shigella pathogenesis will foster the development of a safe and efficient vaccine, which, in parallel with improved hygiene, should curb infections by this widespread pathogen.

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zapalenie mięśnia sercowego plazmid wirulencji bakterie shigella komórki M kaspaza-1 system sekrecji typu III system sekrecji typu VI małopłytkowość wielolekooporność apoptoza makrofagów niedokrwistość hemolityczna infekcja Shigella tkanka limfoidalna związana z błoną śluzową zapalenie spojówek droga fekalno-oralna toksyna shiga interleukina-1 szigelloza enterotoksyna dyzenteria bakteryjna reaktywne zapalenie stawów białka efektorowe zespół hemolityczno-mocznicowy zapalenie okrężnicy