Editing Vibrio cholerae (section)

== Pathogenicity ==
[[File:Toxin2.jpg|thumb|584x584px|Cholera toxin interrupting regulation of adenyl cyclase inside the cell causing efflux of water and sodium into the intestinal lumen]]
''V. cholerae'' [[Pathogen#Pathogenicity|pathogenicity]] genes code for proteins directly or indirectly involved in the virulence of the bacteria. To adapt the host intestinal environment and to avoid being attacked by [[bile acid]]s and [[antimicrobial peptides]], ''V. cholera'' uses its [[Bacterial outer membrane vesicles|outer membrane vesicles]] (OMVs). Upon entry, the bacteria sheds its OMVs, containing all the membrane modifications that make it vulnerable for the host attack.<ref>{{Cite journal|last1=Jugder|first1=Bat-Erdene|last2=Watnick|first2=Paula I.|date=2020-02-12|title=Vibrio cholerae Sheds Its Coat to Make Itself Comfortable in the Gut|journal=Cell Host & Microbe|language=en|volume=27|issue=2|pages=161–163|doi=10.1016/j.chom.2020.01.017|issn=1931-3128|pmid=32053783|doi-access=free}}</ref>

During infection, ''V. cholerae'' secretes [[cholera toxin]] (CT), a [[protein]] that causes profuse, watery [[diarrhea]] (known as "rice-water stool").<ref name="ReferenceA"/><ref name="Cholera"/> This cholera toxin contains 5 B subunits that plays a role in attaching to the intestinal epithelial cells and 1 A subunit that plays a role in toxin activity''.'' Colonization of the small intestine also requires the toxin coregulated [[pilus]] (TCP), a thin, flexible, filamentous appendage on the surface of bacterial cells. Expression of both CT and TCP is mediated by [[Two-component regulatory system|two component systems]] (TCS), which typically consist of a membrane-bound [[histidine kinase]] and an intracellular response element.<ref name=":1">{{Cite journal|last1=Xi|first1=Daoyi|last2=Li|first2=Yujia|last3=Yan|first3=Junxiang|last4=Li|first4=Yuehua|last5=Wang|first5=Xiaochen|last6=Cao|first6=Boyang|title=Small RNA coaR contributes to intestinal colonization in Vibrio cholerae via the two-component system EnvZ/OmpR|journal=Environmental Microbiology|year=2020|volume=22|issue=10|language=en|pages=4231–4243|doi=10.1111/1462-2920.14906|pmid=31868254|issn=1462-2920|doi-access=|bibcode=2020EnvMi..22.4231X }}</ref> TCS enable bacteria to respond to changing environments.<ref name=":1" /> In ''V. cholerae'' several TCS have been identified to be important in colonization, biofilm production and virulence.<ref name=":1" /> Quorum regulatory small RNAs ([[Qrr RNA]]) have been identified as targets of ''V. cholerae'' TCS.<ref name=":1" /><ref name=":2">{{Cite journal| last1=Song|first1=Tianyan|last2=Mika| first2=Franziska|last3=Lindmark|first3=Barbro|last4=Liu|first4=Zhi| last5=Schild|first5=Stefan|last6=Bishop| first6=Anne|last7=Zhu|first7=Jun|last8=Camilli|first8=Andrew|last9=Johansson|first9=Jörgen|last10=Vogel|first10=Jörg|last11=Wai|first11=Sun Nyunt|date=2008|title=A new Vibrio cholerae sRNA modulates colonization and affects release of outer membrane vesicles|journal=Molecular Microbiology|language=en|volume=70|issue=1|pages=100–111|doi=10.1111/j.1365-2958.2008.06392.x|issn=1365-2958|pmc=2628432|pmid=18681937}}</ref><ref>{{Cite journal|last1=Bradley|first1=Evan S.|last2=Bodi|first2=Kip|last3=Ismail|first3=Ayman M.|last4=Camilli|first4=Andrew|date=2011-07-14|title=A Genome-Wide Approach to Discovery of Small RNAs Involved in Regulation of Virulence in Vibrio cholerae|journal=PLOS Pathogens|language=en|volume=7|issue=7|pages=e1002126|doi=10.1371/journal.ppat.1002126|issn=1553-7374|pmc=3136459|pmid=21779167 |doi-access=free }}</ref> Here, the small RNA (sRNA) molecules bind to mRNA to block translation or induce degradation of inhibitors of expression of virulence or colonization genes.<ref name=":1" /><ref name=":2" /> In ''V. cholerae'' the TCS [[EnvZ/OmpR two-component system|EnvZ/OmpR]] alters gene expression via the sRNA ''coaR'' in response to changes in [[Osmotic concentration|osmolarity]] and pH. An important target of ''coaR'' is ''tcpI'', which negatively regulates expression of the major subunit of the TCP encoding gene (''tcpA''). When ''tcpI'' is bound by ''coaR'' it is no longer able to repress expression ''tcpA'', leading to an increased colonization ability.<ref name=":1" /> Expression of ''coaR'' is upregulated by EnvZ/OmpR at a pH of 6,5, which is the normal pH of the intestinal lumen, but is low at higher pH values.<ref name=":1" /> ''V. cholerae''  in the intestinal lumen utilizes the TCP to attach to the intestinal mucosa, not invading the mucosa.<ref name=":1" /> After doing so it secretes cholerae toxin causing its symptoms. This then increases cyclic AMP or cAMP by binding (cholerae toxin) to adenylyl cyclase activating the GS pathway which leads to efflux of water and sodium into the intestinal lumen causing watery stools or rice watery stools.

''V. cholerae'' can cause syndromes ranging from asymptomatic to cholera gravis.<ref name="jones1984">{{cite journal|last1=Howard-Jones|first1=N|year=1984|title=Robert Koch and the cholera vibrio: a centenary|journal=BMJ|volume=288|issue=6414|pages=379–81|doi=10.1136/bmj.288.6414.379|pmc=1444283|pmid=6419937}}</ref> In [[Endemic (epidemiology)|endemic]] areas, 75% of cases are asymptomatic, 20% are mild to moderate, and 2–5% are severe forms such as cholera gravis.<ref name="jones1984" /> Symptoms include abrupt onset of watery [[diarrhea]] (a grey and cloudy liquid), occasional [[vomiting]], and abdominal cramps.<ref name="cdc.gov" /><ref name="jones1984" /> [[Dehydration]] ensues, with symptoms and signs such as thirst, dry mucous membranes, decreased skin turgor, sunken eyes, [[hypotension]], weak or absent [[radial pulse]], [[tachycardia]], [[tachypnea]], hoarse voice, [[oliguria]], cramps, [[kidney failure]], [[seizure]]s, [[somnolence]], coma, and death.<ref name="cdc.gov" /> Death due to dehydration can occur in a few hours to days in untreated children. The disease is also particularly dangerous for pregnant women and their fetuses during late pregnancy, as it may cause premature labor and fetal death.<ref name="jones1984" /><ref name="davis2003">{{cite journal|last1=Davis|first1=B|title=Filamentous phages linked to virulence of Vibrio cholerae|journal=Current Opinion in Microbiology|date=February 2003|volume=6|issue=1|pages=35–42|doi=10.1016/S1369-5274(02)00005-X|pmid=12615217|last2=Waldor|first2=M. K.}}</ref><ref name="boyd2002">{{cite journal|last=Boyd|first=EF|author2=Waldor, MK |title=Evolutionary and functional analyses of variants of the toxin-coregulated pilus protein TcpA from toxigenic Vibrio cholerae non-O1/non-O139 serogroup isolates.|journal=Microbiology|date=Jun 2002|volume=148|issue=Pt 6|pages=1655–66|pmid=12055286|doi=10.1099/00221287-148-6-1655|doi-access=free}}</ref> A study done by the Centers for Disease Control (CDC) in Haiti found that in pregnant women who contracted the disease, 16% of 900 women had fetal death. Risk factors for these deaths include: third trimester, younger maternal age, severe dehydration, and vomiting<ref>{{cite journal | author = Schillberg E., Ariti C., Bryson L., Delva-Senat R., Price D., GrandPierre , Lenglet A. | year = 2016 | title = Factors Related to Fetal Death in Pregnant Women with Cholera, Haiti, 2011–2014 | journal = Emerging Infectious Diseases | volume = 22 | issue = 1| pages = 124–127 | doi = 10.3201/eid2201.151078 | pmid = 26692252 | pmc = 4696702 | doi-access = free }}</ref> Dehydration poses the biggest health risk to pregnant women in countries that there are high rates of cholera.  In cases of cholera gravis involving severe dehydration, up to 60% of patients can die; however, less than 1% of cases treated with [[Management of dehydration|rehydration therapy]] are fatal. The disease typically lasts 4–6 days.<ref name="jones1984" /><ref name="miller2002">{{cite journal|last=Miller|first=Melissa B.|author2=Skorupski, Karen |author3=Lenz, Derrick H. |author4=Taylor, Ronald K. |author5= Bassler, Bonnie L. |title=Parallel Quorum Sensing Systems Converge to Regulate Virulence in Vibrio cholerae|journal=Cell|date=August 2002|volume=110|issue=3|pages=303–314|doi=10.1016/S0092-8674(02)00829-2|pmid=12176318|s2cid=696469|doi-access=free}}</ref> Worldwide, [[diarrhoeal disease]], caused by cholera and many other pathogens, is the second-leading cause of death for children under the age of 5 and at least 120,000 deaths are estimated to be caused by cholera each year.<ref name="nielsen2006">{{cite journal|last=Nielsen|first=Alex Toftgaard|author2=Dolganov, Nadia A. |author3=Otto, Glen |author4=Miller, Michael C. |author5=Wu, Cheng Yen |author6= Schoolnik, Gary K. |title=RpoS Controls the Vibrio cholerae Mucosal Escape Response|journal=PLOS Pathogens|year=2006|volume=2|issue=10|pages=e109|doi=10.1371/journal.ppat.0020109|pmid=17054394 |pmc=1617127 |doi-access=free }}</ref><ref name="faruque1998">{{cite journal|last=Faruque|first=SM|author2=Albert, MJ |author3=Mekalanos, JJ |title=Epidemiology, genetics, and ecology of toxigenic Vibrio cholerae.|journal=Microbiology and Molecular Biology Reviews|date=Dec 1998|volume=62|issue=4|pages=1301–14|doi=10.1128/MMBR.62.4.1301-1314.1998|pmid=9841673|pmc=98947}}</ref> In 2002, the WHO deemed that the case fatality ratio for cholera was about 3.95%.<ref name="jones1984" />