Enterotoxin

Enterotoxins have a particularly marked effect upon the gastrointestinal tract, causing traveler's diarrhea and food poisoning. The action of enterotoxins leads to increased chloride ion permeability of the apical membrane of intestinal mucosal cells. These membrane pores are activated either by increased cAMP or by increased calcium ion concentration intracellularly. The pore formation has a direct effect on the osmolarity of the luminal contents of the intestines. Increased chloride permeability leads to leakage into the lumen followed by sodium and water movement. This leads to a secretory diarrhea within a few hours of ingesting enterotoxin. Several microbial organisms contain the necessary enterotoxin to create such an effect, such as Staphylococcus aureus and E. coli.

The drug linaclotide, used to treat some forms of constipation, is based on the mechanism of enterotoxins.{{cite journal|last1=Hornby|first1=PJ|title=Drug discovery approaches to irritable bowel syndrome.|journal=Expert Opinion on Drug Discovery|date=2015|volume=10|issue=8|pages=809–24|doi=10.1517/17460441.2015.1049528|pmid=26193876|s2cid=207494271}}

Enterotoxins can be formed by the bacterial pathogens Staphylococcus aureus and Bacillus cereus and can cause Staphylococcal Food Poisoning and Bacillus cereus diarrheal disease, respectively. Staphylococcal enterotoxins and streptococcal exotoxins constitute a family of biologically and structurally related pyrogenic superantigens.{{Cite journal|last1=Dinges|first1=M. M.|last2=Orwin|first2=P. M.|last3=Schlievert|first3=P. M.|date=2000|title=Exotoxins of Staphylococcus aureus|journal=Clinical Microbiology Reviews|volume=13|issue=1|pages=16–34, table of contents|issn=0893-8512|pmid=10627489|pmc=88931|doi=10.1128/CMR.13.1.16}} 25 staphylococcal enterotoxins (SEs), mainly produced by Staphylococcus aureus, have been identified to date and named alphabetically (SEA – SEZ).{{cite journal |last1=Etter |first1=Danai |last2=Schelin |first2=Jenny |last3=Schuppler |first3=Markus |last4=Johler |first4=Sophia |title=Staphylococcal Enterotoxin C—An Update on SEC Variants, Their Structure and Properties, and Their Role in Foodborne Intoxications |journal=Toxins |date=2020-09-10 |volume=12 |issue=9 |pages=584 |doi=10.3390/toxins12090584 |pmid=32927913 | pmc=7551944 |hdl=20.500.11850/441345 |hdl-access=free |doi-access=free }} It has been suggested that staphylococci other than S. aureus can contribute to Staphylococcal Food Poisoning by forming enterotoxins.{{Cite journal|last1=Fetsch|first1=Alexandra|last2=Johler|first2=Sophia|date=2018-04-27|title=Staphylococcus aureus as a Foodborne Pathogen|journal=Current Clinical Microbiology Reports|language=en|volume=5|issue=2|pages=88–96|doi=10.1007/s40588-018-0094-x|s2cid=13668423|issn=2196-5471}} Streptococcal exotoxins are produced by Streptococcus pyogenes.{{cite journal | author = Iandolo JJ | title = Genetic analysis of extracellular toxins of Staphylococcus aureus | journal = Annu. Rev. Microbiol. | volume = 43 | pages = 375–402 | year = 1989 | pmid = 2679358 | doi = 10.1146/annurev.mi.43.100189.002111 }}{{cite journal |vauthors=Marrack P, Kappler J | title = The staphylococcal enterotoxins and their relatives | journal = Science | volume = 248 | issue = 4956 | pages = 705–11 |date=May 1990 | pmid = 2185544 | doi = 10.1126/science.2185544| bibcode = 1990Sci...248..705M | s2cid = 33752378 }} These toxins share the ability to bind to the major histocompatibility complex proteins of their hosts. A more distant relative of the family is the S. aureus toxic shock syndrome toxin, which shares only a low level of sequence similarity with this group.

All of these toxins share a similar two-domain fold (N and C-terminal domains) with a long alpha-helix in the middle of the molecule, a characteristic beta-barrel known as the "oligosaccharide/oligonucleotide fold" at the N-terminal domain and a beta-grasp motif at the C-terminal domain. An example is staphylococcal enterotoxin B. Each superantigen possesses slightly different binding mode(s) when it interacts with MHC class II molecules or the T-cell receptor.{{cite journal |vauthors=Papageorgiou AC, Tranter HS, Acharya KR | title = Crystal structure of microbial superantigen staphylococcal enterotoxin B at 1.5 A resolution: implications for superantigen recognition by MHC class II molecules and T-cell receptors | journal = J. Mol. Biol. | volume = 277 | issue = 1 | pages = 61–79 |date=March 1998 | pmid = 9514739 | doi = 10.1006/jmbi.1997.1577 }}

The beta-grasp domain has some structural similarities to the beta-grasp motif present in immunoglobulin-binding domains, ubiquitin, 2Fe-2 S ferredoxin and translation initiation factor 3 as identified by the SCOP database.

• Clostridioides difficile
• Clostridium perfringens (Clostridium enterotoxin){{cite journal |vauthors=Katahira J, Sugiyama H, Inoue N, Horiguchi Y, Matsuda M, Sugimoto N |title=Clostridium perfringens enterotoxin utilizes two structurally related membrane proteins as functional receptors in vivo |journal=The Journal of Biological Chemistry |volume=272 |issue=42 |pages=26652–8 |date=October 1997 |pmid=9334247 |doi= 10.1074/jbc.272.42.26652|doi-access=free }}
• Vibrio cholerae (Cholera toxin){{MeshName|Enterotoxins}}
• Staphylococcus aureus (Staphylococcal enterotoxin B){{EMedicine|article|830715|CBRNE - Staphylococcal Enterotoxin B}}
• Yersinia enterocolitica
• Shigella dysenteriae (Shiga toxin)

Viruses in the families Reoviridae, Caliciviridae, and Astroviridae are responsible for a huge percentage of gastrointestinal disease worldwide. Rotaviruses (of Reoviridae) have been found to contain an enterotoxin which plays a role in viral pathogenesis. NSP4, is a protein that is made during the intracellular phase of the virion's life cycle and is known to have a primary function in intracellular virion maturation.{{cite journal |last1=Crawford |first1=Sue E. |last2=Ramani |first2=Sasirekha |last3=Tate |first3=Jacqueline E. |last4=Parashar |first4=Umesh D. |last5=Svensson |first5=Lennart |last6=Hagbom |first6=Marie |last7=Franco |first7=Manuel A. |last8=Greenberg |first8=Harry B. |last9=O'Ryan |first9=Miguel |last10=Kang |first10=Gagandeep |last11=Desselberger |first11=Ulrich |last12=Estes |first12=Mary K. |title=Rotavirus infection |journal=Nature Reviews Disease Primers |date=9 November 2017 |volume=3 |issue=1 |page=17083 |doi=10.1038/nrdp.2017.83 |pmid=29119972 |pmc=5858916 }} However, when NSP4 from group A Rotaviruses was purified (4 alleles tested), concentrated, and injected into a mouse model, diarrheal disease mimicking that caused by Rotavirus infection commenced.{{cite journal |last1=Horie |first1=Y. |last2=Nakagomi |first2=O. |last3=Koshimura |first3=Y. |last4=Nakagomi |first4=T. |last5=Suzuki |first5=Y. |last6=Oka |first6=T. |last7=Sasaki |first7=S. |last8=Matsuda |first8=Y. |last9=Watanabe |first9=S. |title=Diarrhea Induction by Rotavirus NSP4 in the Homologous Mouse Model System |journal=Virology |date=September 1999 |volume=262 |issue=2 |pages=398–407 |doi=10.1006/viro.1999.9912 |pmid=10502518 |doi-access=free }} A putative mode of toxicity is that NSP4 activates a signal transduction pathway that ultimately results in an increased cellular concentration of calcium and subsequent chloride secretion from the cell.{{cite journal |last1=Zhang |first1=Mingdong |last2=Zeng |first2=Carl Q.-Y. |last3=Morris |first3=Andrew P. |last4=Estes |first4=Mary K. |title=A Functional NSP4 Enterotoxin Peptide Secreted from Rotavirus-Infected Cells |journal=Journal of Virology |date=15 December 2000 |volume=74 |issue=24 |pages=11663–11670 |doi=10.1128/JVI.74.24.11663-11670.2000 |pmid=11090165 |pmc=112448 }} Secretion of ions from villi lining the gut alter normal osmotic pressures and prevent uptake of water, eventually causing diarrhea.

• Rotavirus (NSP4)

• Endotoxin
• Exotoxin

{{Reflist}}

• {{cite journal | journal = Public Health Rep | date = Mar 1959 | volume = 74 | issue = 3 | pages = 265–270 | pmc = 1929208 | title = Two poisoning outbreaks in Puerto Rico from salt preserved codfish |author1=Alfonse T. Masi |author2=Rafael A. Timothee |author3=Rolando Armijo |author4=Darwin Alonso |author5=Luis E. Mainardi | doi=10.2307/4590423 | pmid=13634314| jstor = 4590423 }}

{{Toxins}}

{{InterPro content|IPR006123}}

Category:Toxins by organ system affected

Category:Peripheral membrane proteins

Category:Protein families