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[[Image:Cholera Toxin.png|thumb|right|Cholera Toxin. The delivery region (blue) binds membrane carbohydrates to get into cells. The toxic part (red) is activated inside the cell (PDB code: 1xtc)]]
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[[Image:Cholera Toxin.png|200px|thumb|right|Cholera Toxin. The delivery region (blue) binds membrane carbohydrates to get into cells. The toxic part (red) is activated inside the cell (PDB code: 1xtc)]]
{{Cholera}}
{{Cholera}}
{{CMG}}
{{CMG}}; '''Associate Editors-In-Chief:''' [[Priyamvada Singh|Priyamvada Singh, MBBS]], {{AA}}


==Overview==
==Overview==
Choleria is a severe bacterial gastrointestinal, diarrheal disease. In its most severe forms, cholera is one of the most rapidly fatal illnesses known. A healthy person may become [[hypotension|hypotensive]] within an hour of the onset of symptoms and may die within 2-3 hours if no treatment is provided. More commonly, the disease progresses from the first liquid stool to shock in 4-12 hours, with death following in 18 hours to several days without [[rehydration]] treatment.<ref name=McLeod_2000>{{cite journal |author=McLeod K |title=Our sense of Snow: John Snow in medical geography |journal=Soc Sci Med |volume=50 |issue=7-8 |pages=923-35 |year=2000 |pmid = 10714917}}</ref><ref> WHO Cholera [http://www.who.int/topics/cholera/control/en/index.html]</ref>
Cholera is mainly caused by two pathogenic serotypes of ''V. cholerae'': O1 and O139. ''V. cholerae'' is usually transmitted via the [[fecal-oral route]] to the human host. Following [[ingestion]], the ''V. cholerae'' must overcome the host defense mechanisms such as gastric acidity, intestinal inhibitory factors, and changes in temperature and [[osmolarity]]. After gaining access to [[small intestine]], ''V. cholerae'' uses [[flagella]] to propogate through the mucus layer covering the [[small intestine]] and colonizes the small intestinal cells, using toxin-coregulated pilus (TCP) to form a [[biofilm]]. [[Diarrheal]] illness in the human host is mainly caused by production of [[enterotoxin]].<ref name=Hartwell>Hartwell LH, Hood L, Goldberg ML, Reynolds AE, Silver LM, and Veres RC (2004). ''Genetics: From Genes to Genomes.'' Mc-Graw Hill, Boston: p. 551-552, 572-574 (using the turning off and turning on of [[gene expression]] to make toxin proteins in cholera bacteria as a "comprehensive example" of what is known about the mechanisms by which bacteria change the mix of proteins they manufacture to respond to the changing opportunities for surviving and thriving in different chemical environments).</ref> <ref name="pmid198781">{{cite journal| author=Cassel D, Selinger Z| title=Mechanism of adenylate cyclase activation by cholera toxin: inhibition of GTP hydrolysis at the regulatory site. | journal=Proc Natl Acad Sci U S A | year= 1977 | volume= 74 | issue= 8 | pages= 3307-11 | pmid=198781 | doi= | pmc=431542 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=198781  }} </ref><ref name="pmid9841673">{{cite journal| author=Faruque SM, Albert MJ, Mekalanos JJ| title=Epidemiology, genetics, and ecology of toxigenic Vibrio cholerae. | journal=Microbiol Mol Biol Rev | year= 1998 | volume= 62 | issue= 4 | pages= 1301-14 | pmid=9841673 | doi= | pmc=98947 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9841673  }} </ref><ref name="pmid8389476">{{cite journal| author=Trucksis M, Galen JE, Michalski J, Fasano A, Kaper JB| title=Accessory cholera enterotoxin (Ace), the third toxin of a Vibrio cholerae virulence cassette. | journal=Proc Natl Acad Sci U S A | year= 1993 | volume= 90 | issue= 11 | pages= 5267-71 | pmid=8389476 | doi= | pmc=46697 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8389476  }} </ref><ref name="pmid4329549">{{cite journal| author=Hendrix TR| title=The pathophysiology of cholera. | journal=Bull N Y Acad Med | year= 1971 | volume= 47 | issue= 10 | pages= 1169-80 | pmid=4329549 | doi= | pmc=1749961 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4329549  }} </ref><ref name="pmid14407057">{{cite journal| author=JENKIN CR, ROWLEY D| title=Possible factors in the pathogenesis of cholera. | journal=Br J Exp Pathol | year= 1959 | volume= 40 | issue=  | pages= 474-81 | pmid=14407057 | doi= | pmc=2082309 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14407057  }} </ref><ref name=DiRita_1991>{{cite journal |author=DiRita V, Parsot C, Jander G, Mekalanos J |title=Regulatory cascade controls virulence in Vibrio cholerae |journal=Proc Natl Acad Sci U S A |volume=88 |issue=12 |pages=5403-7 |year=1991 | url=http://www.pnas.org/cgi/reprint/88/12/5403 |id=PMID 2052618}}</ref><ref name="pmid2883655">{{cite journal| author=Taylor RK, Miller VL, Furlong DB, Mekalanos JJ| title=Use of phoA gene fusions to identify a pilus colonization factor coordinately regulated with cholera toxin. | journal=Proc Natl Acad Sci U S A | year= 1987 | volume= 84 | issue= 9 | pages= 2833-7 | pmid=2883655 | doi= | pmc=304754 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2883655  }} </ref><ref name="pmid208069">{{cite journal| author=Cassel D, Pfeuffer T| title=Mechanism of cholera toxin action: covalent modification of the guanyl nucleotide-binding protein of the adenylate cyclase system. | journal=Proc Natl Acad Sci U S A | year= 1978 | volume= 75 | issue= 6 | pages= 2669-73 | pmid=208069 | doi= | pmc=392624 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=208069  }} </ref><ref name="pmid8658163">{{cite journal| author=Waldor MK, Mekalanos JJ| title=Lysogenic conversion by a filamentous phage encoding cholera toxin. | journal=Science | year= 1996 | volume= 272 | issue= 5270 | pages= 1910-4 | pmid=8658163 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8658163  }} </ref>
==Pathophysiology==
Most of the ''V. cholerae'' bacteria in the contaminated water that a potential host drinks do not survive the very acidic conditions of the [[stomach|human stomach]]<ref name=Hartwell>Hartwell LH, Hood L, Goldberg ML, Reynolds AE, Silver LM, and Veres RC (2004). ''Genetics: From Genes to Genomes.'' Mc-Graw Hill, Boston: p. 551-552, 572-574 (using the turning off and turning on of [[gene expression]] to make toxin proteins in cholera bacteria as a "comprehensive example" of what is known about the mechanisms by which bacteria change the mix of proteins they manufacture to respond to the changing opportunities for surviving and thriving in different chemical environments).</ref> But the few bacteria that manage to survive the stomach's acidity conserve their [[nutrient|energy and stored nutrients]] during the perilous passage through the stomach by shutting down much protein production. When the surviving bacteria manage to exit the [[stomach]] and reach the favorable conditions of the [[small intestine]], they need to propel themselves through the thick [[mucous membrane|mucus]] that lines the small intestine to get to the intestinal wall where they can thrive. So they start up production of the hollow cylindrical protein [[flagellin]] to make [[flagella]], the curly whip-like tails that they rotate to propel themselves through the pasty mucus that lines the small intestine.


Once the cholera bacteria reach the [[intestinal wall]], they do not need the flagella propellers to move themselves any more, so they stop producing the protein flagellin, thus again conserving energy and nutrients by changing the mix of proteins that they manufacture, responding to the changed chemical surroundings. And on reaching the intestinal wall, they start producing the toxic proteins that give the infected person a watery [[diarrhea]] which carries the multiplying and thriving new generations of ''V. cholerae'' bacteria out into the drinking water of the next host&mdash;if proper sanitation measures are not in place.
==Pathophysiology==
Cholera is mainly caused by two pathogenic serotypes of ''V. cholerae'': O1 and O139. The pathogenesis underlying acute [[diarrheal]] illness is as follows:<ref name=Hartwell>Hartwell LH, Hood L, Goldberg ML, Reynolds AE, Silver LM, and Veres RC (2004). ''Genetics: From Genes to Genomes.'' Mc-Graw Hill, Boston: p. 551-552, 572-574 (using the turning off and turning on of [[gene expression]] to make toxin proteins in cholera bacteria as a "comprehensive example" of what is known about the mechanisms by which bacteria change the mix of proteins they manufacture to respond to the changing opportunities for surviving and thriving in different chemical environments).</ref><ref name="pmid198781">{{cite journal| author=Cassel D, Selinger Z| title=Mechanism of adenylate cyclase activation by cholera toxin: inhibition of GTP hydrolysis at the regulatory site. | journal=Proc Natl Acad Sci U S A | year= 1977 | volume= 74 | issue= 8 | pages= 3307-11 | pmid=198781 | doi= | pmc=431542 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=198781  }} </ref><ref name="pmid9841673">{{cite journal| author=Faruque SM, Albert MJ, Mekalanos JJ| title=Epidemiology, genetics, and ecology of toxigenic Vibrio cholerae. | journal=Microbiol Mol Biol Rev | year= 1998 | volume= 62 | issue= 4 | pages= 1301-14 | pmid=9841673 | doi= | pmc=98947 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9841673  }} </ref><ref name="pmid8389476">{{cite journal| author=Trucksis M, Galen JE, Michalski J, Fasano A, Kaper JB| title=Accessory cholera enterotoxin (Ace), the third toxin of a Vibrio cholerae virulence cassette. | journal=Proc Natl Acad Sci U S A | year= 1993 | volume= 90 | issue= 11 | pages= 5267-71 | pmid=8389476 | doi= | pmc=46697 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8389476  }} </ref><ref name="pmid4329549">{{cite journal| author=Hendrix TR| title=The pathophysiology of cholera. | journal=Bull N Y Acad Med | year= 1971 | volume= 47 | issue= 10 | pages= 1169-80 | pmid=4329549 | doi= | pmc=1749961 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4329549  }} </ref><ref name="pmid14407057">{{cite journal| author=JENKIN CR, ROWLEY D| title=Possible factors in the pathogenesis of cholera. | journal=Br J Exp Pathol | year= 1959 | volume= 40 | issue=  | pages= 474-81 | pmid=14407057 | doi= | pmc=2082309 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14407057  }} </ref><ref name=DiRita_1991>{{cite journal |author=DiRita V, Parsot C, Jander G, Mekalanos J |title=Regulatory cascade controls virulence in Vibrio cholerae |journal=Proc Natl Acad Sci U S A |volume=88 |issue=12 |pages=5403-7 |year=1991 | url=http://www.pnas.org/cgi/reprint/88/12/5403 |id=PMID 2052618}}</ref><ref name="pmid2883655">{{cite journal| author=Taylor RK, Miller VL, Furlong DB, Mekalanos JJ| title=Use of phoA gene fusions to identify a pilus colonization factor coordinately regulated with cholera toxin. | journal=Proc Natl Acad Sci U S A | year= 1987 | volume= 84 | issue= 9 | pages= 2833-7 | pmid=2883655 | doi= | pmc=304754 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2883655  }} </ref><ref name="pmid208069">{{cite journal| author=Cassel D, Pfeuffer T| title=Mechanism of cholera toxin action: covalent modification of the guanyl nucleotide-binding protein of the adenylate cyclase system. | journal=Proc Natl Acad Sci U S A | year= 1978 | volume= 75 | issue= 6 | pages= 2669-73 | pmid=208069 | doi= | pmc=392624 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=208069  }} </ref><ref name="pmid8658163">{{cite journal| author=Waldor MK, Mekalanos JJ| title=Lysogenic conversion by a filamentous phage encoding cholera toxin. | journal=Science | year= 1996 | volume= 272 | issue= 5270 | pages= 1910-4 | pmid=8658163 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8658163  }} </ref>
===Transmission===
*''V. cholerae'' is usually transmitted via the [[fecal-oral route]] to the human host.
*Following [[ingestion]], the ''V. cholerae'' must overcome host defense mechanisms such as gastric acidity, intestinal inhibitory factors, and changes in temperature and [[osmolarity]].
*Infective dose varies from 102-106.
*The [[incubation period]] varies from a few hours to a few days.


[[Microbiologist]]s have studied the [[gene expression|genetic mechanisms]] by which the ''V. cholerae'' bacteria turn off the production of some proteins and turn on the production of other proteins as they respond to the series of chemical environments they encounter, passing through the stomach, through the mucous layer of the small intestine, and on to the intestinal wall.<ref name=DiRita_1991>{{cite journal |author=DiRita V, Parsot C, Jander G, Mekalanos J |title=Regulatory cascade controls virulence in Vibrio cholerae |journal=Proc Natl Acad Sci U S A |volume=88 |issue=12 |pages=5403-7 |year=1991 | url=http://www.pnas.org/cgi/reprint/88/12/5403 |id=PMID 2052618}}</ref> Of particular interest have been the genetic mechanisms by which cholera bacteria turn on the protein production of the toxins that interact with host cell mechanisms to pump [[chloride]] ions into the small intestine, creating an ionic pressure which prevents sodium ions from entering the cell. The [[chloride]] and [[sodium]] ions create a salt water environment in the small intestines which through osmosis can pull up to six liters of water per day through the intestinal cells creating the massive amounts of diarrhea. The host can become rapidly [[dehydrated]] if an appropriate mixture of dilute salt water and sugar is not taken to replace the blood's water and salts lost in the [[diarrhea]].
===Colonization===
*After gaining access to [[small intestine]], ''V. cholerae'' uses [[flagella]] to propagate through the mucus layer covering [[small intestine]] and colonizes the small intestinal cells using toxin-coregulated pilus (TCP) forming a [[biofilm]].


By inserting separately, successive sections of ''V. cholerae'' DNA into the DNA of other bacteria such as ''[[E. coli]]'' that would not naturally produce the protein toxins, researchers have investigated the mechanisms by which ''V. cholerae'' responds to the changing chemical environments of the stomach, mucous layers, and intestinal wall. Researchers have discovered that there is a complex [[cascade]] of regulatory proteins that control expression of ''V. cholerae'' virulence determinants. In responding to the chemical environment at the intestinal wall, the ''V. cholerae'' bacteria produce the TcpP/TcpH proteins which, together with the ToxR/ToxS proteins, activate the expression of the ToxT regulatory protein. ToxT then directly activates expression of virulence genes that produce the toxins that cause diarrhea in the infected person and that permit the bacteria to colonize the intestine.<ref name=DiRita_1991 /> Current research aims at discovering "the signal that makes the cholera bacteria stop swimming and start to colonize (that is, adhere to the cells of) the small intestine."<ref name=Hartwell>p. 574</ref>
===Enterotoxin===
*[[Diarrheal]] illness in human host is mainly caused by production of [[enterotoxin]].
*The production of [[enterotoxin]] protein in the small intestinal cells is the main mechanism responsible for causing acute [[diarrheal]] illness.
*It has 5B subunits and 2A subunits.
**B subunits bind the [[enterocytes]] via GM1 [[ganglioside]] receptors and cause internalization of A subunits in the cells via [[endocytosis]].
**A subunits then bind and activate the [[adenylate cyclase]] enzyme in the enterocytes, increasing the levels of [[cAMP]].
*Increased levels of [[enterotoxin]] cause activation of the [[cystic fibrosis transmembrane conductance regulator]] (CFTR), causing increased secretion of water, [[sodium]], and [[chloride]] from [[enterocytes]], which causes watery [[diarrhea]].
 
===Virulence factors===
The different [[virulence factors]] involved in the pathogenesis of ''[[V. cholerae]]'' involve activation of [[transcription factors]] such as ToxR, TcpP, and ToxT. Different toxins expressed by these [[transcription factors]] include:
*Zona occludens toxin (zot, causes invasion by decreasing intestinal tissue resistance)
*Accessory cholera toxin (ace, increases fluid secretion)
*Toxin-coregulated pilus (tcpA, essential colonization factor and receptor for the CTXf phage)
*NAG-specific heat-labile toxin (st)
*Outer membrane porin proteins (ompU and ompT)


== References ==
== References ==
{{Reflist|2}}
{{Reflist|2}}
== External links ==
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[[Category:Foodborne illnesses]]
[[Category:Bacterial diseases]]
[[Category:Water-borne diseases]]
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[[Category:Biological weapons]]
[[Category:Neglected diseases]]
[[Category:Overview complete]]


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Latest revision as of 20:55, 29 July 2020

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editors-In-Chief: Priyamvada Singh, MBBS, Aysha Anwar, M.B.B.S[2]

Overview

Cholera is mainly caused by two pathogenic serotypes of V. cholerae: O1 and O139. V. cholerae is usually transmitted via the fecal-oral route to the human host. Following ingestion, the V. cholerae must overcome the host defense mechanisms such as gastric acidity, intestinal inhibitory factors, and changes in temperature and osmolarity. After gaining access to small intestine, V. cholerae uses flagella to propogate through the mucus layer covering the small intestine and colonizes the small intestinal cells, using toxin-coregulated pilus (TCP) to form a biofilm. Diarrheal illness in the human host is mainly caused by production of enterotoxin.[1] [2][3][4][5][6][7][8][9][10]

Pathophysiology

Cholera is mainly caused by two pathogenic serotypes of V. cholerae: O1 and O139. The pathogenesis underlying acute diarrheal illness is as follows:[1][2][3][4][5][6][7][8][9][10]

Transmission

  • V. cholerae is usually transmitted via the fecal-oral route to the human host.
  • Following ingestion, the V. cholerae must overcome host defense mechanisms such as gastric acidity, intestinal inhibitory factors, and changes in temperature and osmolarity.
  • Infective dose varies from 102-106.
  • The incubation period varies from a few hours to a few days.

Colonization

Enterotoxin

Virulence factors

The different virulence factors involved in the pathogenesis of V. cholerae involve activation of transcription factors such as ToxR, TcpP, and ToxT. Different toxins expressed by these transcription factors include:

  • Zona occludens toxin (zot, causes invasion by decreasing intestinal tissue resistance)
  • Accessory cholera toxin (ace, increases fluid secretion)
  • Toxin-coregulated pilus (tcpA, essential colonization factor and receptor for the CTXf phage)
  • NAG-specific heat-labile toxin (st)
  • Outer membrane porin proteins (ompU and ompT)

References

  1. ↑ 1.0 1.1 Hartwell LH, Hood L, Goldberg ML, Reynolds AE, Silver LM, and Veres RC (2004). Genetics: From Genes to Genomes. Mc-Graw Hill, Boston: p. 551-552, 572-574 (using the turning off and turning on of gene expression to make toxin proteins in cholera bacteria as a "comprehensive example" of what is known about the mechanisms by which bacteria change the mix of proteins they manufacture to respond to the changing opportunities for surviving and thriving in different chemical environments).
  2. ↑ 2.0 2.1 Cassel D, Selinger Z (1977). "Mechanism of adenylate cyclase activation by cholera toxin: inhibition of GTP hydrolysis at the regulatory site". Proc Natl Acad Sci U S A. 74 (8): 3307–11. PMC 431542. PMID 198781.
  3. ↑ 3.0 3.1 Faruque SM, Albert MJ, Mekalanos JJ (1998). "Epidemiology, genetics, and ecology of toxigenic Vibrio cholerae". Microbiol Mol Biol Rev. 62 (4): 1301–14. PMC 98947. PMID 9841673.
  4. ↑ 4.0 4.1 Trucksis M, Galen JE, Michalski J, Fasano A, Kaper JB (1993). "Accessory cholera enterotoxin (Ace), the third toxin of a Vibrio cholerae virulence cassette". Proc Natl Acad Sci U S A. 90 (11): 5267–71. PMC 46697. PMID 8389476.
  5. ↑ 5.0 5.1 Hendrix TR (1971). "The pathophysiology of cholera". Bull N Y Acad Med. 47 (10): 1169–80. PMC 1749961. PMID 4329549.
  6. ↑ 6.0 6.1 JENKIN CR, ROWLEY D (1959). "Possible factors in the pathogenesis of cholera". Br J Exp Pathol. 40: 474–81. PMC 2082309. PMID 14407057.
  7. ↑ 7.0 7.1 DiRita V, Parsot C, Jander G, Mekalanos J (1991). "Regulatory cascade controls virulence in Vibrio cholerae". Proc Natl Acad Sci U S A. 88 (12): 5403–7. PMID 2052618.
  8. ↑ 8.0 8.1 Taylor RK, Miller VL, Furlong DB, Mekalanos JJ (1987). "Use of phoA gene fusions to identify a pilus colonization factor coordinately regulated with cholera toxin". Proc Natl Acad Sci U S A. 84 (9): 2833–7. PMC 304754. PMID 2883655.
  9. ↑ 9.0 9.1 Cassel D, Pfeuffer T (1978). "Mechanism of cholera toxin action: covalent modification of the guanyl nucleotide-binding protein of the adenylate cyclase system". Proc Natl Acad Sci U S A. 75 (6): 2669–73. PMC 392624. PMID 208069.
  10. ↑ 10.0 10.1 Waldor MK, Mekalanos JJ (1996). "Lysogenic conversion by a filamentous phage encoding cholera toxin". Science. 272 (5270): 1910–4. PMID 8658163.


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