Editing Shigella (section)

== Pathogenesis ==
''Shigella'' infection is typically by [[Fecal–oral route|ingestion]]. Depending on the host's health, fewer than 100 bacterial cells may cause an infection.<ref>{{cite book |last=Levinson |first=Warren E |title=Review of Medical Microbiology and Immunology |year=2006 |publisher=McGraw-Hill Medical Publishing Division |isbn=978-0-07-146031-6 |edition=9th |page=30}}</ref> ''Shigella'' species generally invade the [[epithelium|epithelial]] lining of the [[Large intestine|colon]], causing severe inflammation and death of the cells lining the colon. This inflammation produces the hallmark diarrhea — even [[dysentery]] — of ''Shigella'' infection.<ref name=Baron/> Toxins produced by some strains contribute to disease during infection. [[Shigella flexneri|''S. flexneri'']] strains produce ShET1 and ShET2, which may contribute to diarrhea.<ref name=Baron/> ''S. dysenteriae'' strains produce <!--the [[enterotoxin]]-->  the hemolytic [[Shiga toxin]], similar to the [[verotoxin]] produced by [[enterohemorrhagic Escherichia coli|enterohemorrhagic ''E. coli'']]. Both Shiga toxin and verotoxin are associated with causing potentially fatal [[hemolytic-uremic syndrome]].<ref name=Baron/>

Because they do not interact with the apical surface of epithelial cells — preferring the basolateral side ''— Shigella'' species invade the host through the [[M-cells]] interspersed in the epithelia of the [[small intestine]].<ref name="Mounier">{{cite journal | title=Shigella flexneri Enters Human Colonic Caco-2 Epithelial Cells through the Basolateral Pole | author=Mounier, Joëlle | journal=Infection and Immunity |date=January 1992 | volume=60 | issue=1 | pages=237–248 | pmc=257528 | first2=T | last3=Hellio | first3=R | last4=Lesourd | first4=M | last5=Sansonetti | first5=PJ | pmid=1729185| last2=Vasselon | doi=10.1128/IAI.60.1.237-248.1992 }}</ref> ''Shigella'' uses a [[Type III secretion system|type-III secretion system]] that acts as a biological syringe to translocate toxic effector proteins to the target human cell. The effector proteins can alter the metabolism of the target cell — leading, for example, to the [[lysis]] of [[Vacuole|vacuolar]] membranes or reorganization of actin polymerization to facilitate intracellular motility of ''Shigella'' bacteria inside the host cell. For instance, the IcsA effector protein (an autotransporter, not a type-III secretion-system effector) triggers actin reorganization by [[Wiskott–Aldrich syndrome protein|N-WASP]] recruitment of [[Arp2/3 complex]]es,  promoting cell-to-cell spread.<ref>{{Cite journal|last1=Snapper|first1=Scott B.|last2=Takeshima|first2=Fuminao|last3=Antón|first3=Inés|last4=Liu|first4=Ching-Hui|last5=Thomas|first5=Sheila M.|last6=Nguyen|first6=Deanna|last7=Dudley|first7=Darryll|last8=Fraser|first8=Hunter|last9=Purich|first9=Daniel|s2cid=23962367|date=October 2001|title=N-WASP deficiency reveals distinct pathways for cell surface projections and microbial actin-based motility|journal=Nature Cell Biology|language=En|volume=3|issue=10|pages=897–904|doi=10.1038/ncb1001-897|pmid=11584271|issn=1476-4679}}</ref>
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 α-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.

While bacterial inhibition of the IFN signaling pathway remains largely unexplored, it is a well-studied mechanism in viruses. However, research by Alponde et al. (2022) identified homologous proteins and provided strong evidence that inhibiting IFN signaling is a conserved bacterial strategy.|Alponde, R., Ceccarelli, D. F., Wu, X., Dhe-Paganon, S., & Park, E. (2022).| Bacterial calmodulin inhibitors block host innate immune signaling.| Cell, |185(12),| 2090-2103.|https://doi.org/10.1016/j.cell.2022.04.025</ref>

After infection, ''Shigella'' cells multiply [[Pathogenic bacteria#Intracellular|intracellularly]] and spread to neighboring epithelial cells, resulting in tissue destruction and the characteristic [[pathology]] of shigellosis.<ref>{{cite web |url=http://textbookofbacteriology.net/Shigella_2.html |first=Kenneth |last=Todar |title=''Shigella'' and Shigellosis |work=Todar's Online Textbook of Bacteriology}}{{self-published source|date=September 2015}}</ref>{{self-published inline|date=September 2015}}<ref>{{cite journal |first1=Toshihiko |last1=Suzuki |first2=Chihiro |last2=Sasakawa |title=Molecular basis of the intracellular spreading of ''Shigella'' |journal=Infection and Immunity |volume=69 |issue=10 |pages=5959–66 |year=2001 |pmid=11553531 |pmc=98722 |doi=10.1128/IAI.69.10.5959-5966.2001 }}</ref> The most common symptoms are [[diarrhea]], [[fever]], [[nausea]], [[vomiting]], [[stomach cramp]]s, and [[flatulence]]. Infection is also commonly known to cause large and painful bowel movements. The stool may contain blood, mucus, or pus. Hence, ''Shigella'' cells may cause dysentery. In rare cases, young children may have [[Epileptic seizure|seizures]]. Symptoms can take as long as a week to appear, but most often begin two to four days after ingestion. Symptoms usually last for several days, but can last for weeks. ''Shigella'' is implicated as one of the pathogenic causes of [[reactive arthritis]] worldwide.<ref>{{cite journal |last1=Hill Gaston |first1=J |title=Arthritis associated with enteric infection |journal=Best Practice & Research Clinical Rheumatology |volume=17 |issue=2 |pages=219–39 |year=2003 |pmid=12787523 |doi=10.1016/S1521-6942(02)00104-3 }}</ref>