Editing Rotavirus (section)

== Disease mechanisms ==
[[File:Rotavirus infected gut.jpg|thumb|Electron micrograph of a rotavirus infected enterocyte (top) compared to an uninfected cell (bottom). The bar = approx. 500{{nbsp}}nm.|alt=The micrograph at the top shows a damaged cell with a destroyed surface. The micrograph at the bottom shows a healthy cell with its surface intact.]]

Rotaviruses replicate mainly in the [[Gut (zoology)|gut]],<ref name="pmid19457420">{{cite journal |vauthors=Greenberg HB, Estes MK |title=Rotaviruses: from pathogenesis to vaccination |journal=Gastroenterology |volume=136 |issue=6 |pages=1939–1951 |year=2009 |pmid=19457420 |doi=10.1053/j.gastro.2009.02.076 |pmc=3690811 }}</ref> and infect enterocytes of the [[Intestinal villus|villi]] of the [[small intestine]], leading to structural and functional changes of the [[epithelium]].<ref name="pmid8050281">{{cite book |vauthors=Greenberg HB, Clark HF, Offit PA |chapter=Rotavirus Pathology and Pathophysiology |veditors=Ramig RF |series=Current Topics in Microbiology and Immunology|title=Rotaviruses |volume=185 |pages=255–283 |year=1994 |pmid=8050281|publisher=Springer|location=New York|isbn=978-3-540-56761-5}}</ref> There is evidence in humans, and particularly in animal models of extraintestinal dissemination of infectious virus to other organs and macrophages.<ref name="pmid16641274">{{cite journal |vauthors=Crawford SE, Patel DG, Cheng E, Berkova Z, Hyser JM, Ciarlet M, Finegold MJ, Conner ME, Estes MK |title=Rotavirus viremia and extraintestinal viral infection in the neonatal rat model |journal=Journal of Virology |volume=80 |issue=10 |pages=4820–4832 |year=2006 |pmid=16641274 |pmc=1472071 |doi=10.1128/JVI.80.10.4820-4832.2006 }}</ref>

The diarrhoea is caused by multiple activities of the virus.<ref name="pmid15367586">{{cite journal |vauthors=Ramig RF |title=Pathogenesis of intestinal and systemic rotavirus infection |journal=Journal of Virology |volume=78 |issue=19 |pages=10213–10220 |year=2004 |pmid=15367586 |pmc=516399 |doi=10.1128/JVI.78.19.10213-10220.2004 }}</ref> [[Malabsorption]] occurs because of the destruction of gut cells called [[enterocyte]]s. The [[enterotoxin|toxic]] rotavirus protein [[NSP4 (rotavirus)|NSP4]] induces age- and [[calcium]] ion-dependent [[chloride]] secretion, disrupts [[Sodium-glucose transport proteins|SGLT1 (sodium/glucose cotransporter 2)]] [[Membrane transport protein|transporter]]-mediated reabsorption of water, apparently reduces activity of [[Brush border|brush-border membrane]] [[disaccharidase]]s, and activates the calcium ion-dependent [[secretion|secretory]] [[reflex]]es of the [[enteric nervous system]].<ref name="pmid19114772" /> The elevated concentrations of calcium ions in the cytosol (which are required for the assembly of the progeny viruses) is achieved by NSP4 acting as a [[viroporin]]. This increase in calcium ions leads to autophagy (self destruction) of the infected enterocytes.<ref name="pmid21151776">{{cite journal |vauthors=Hyser JM, Collinson-Pautz MR, Utama B, Estes MK |title=Rotavirus disrupts calcium homeostasis by NSP4 viroporin activity |journal=mBio   |volume=1 |issue=5 |year=2010 |pmid=21151776 |pmc=2999940 |doi=10.1128/mBio.00265-10 }}</ref>

NSP4 is also secreted. This extracellular form, which is modified by [[protease]] enzymes in the gut, is an enterotoxin which acts on uninfected cells via [[integrin]] receptors, which in turn cause and increase in intracellular calcium ion concentrations, secretory diarrhoea and autophagy.<ref name="pmid16731945">{{cite journal |vauthors=Berkova Z, Crawford SE, Trugnan G, Yoshimori T, Morris AP, Estes MK |title=Rotavirus NSP4 induces a novel vesicular compartment regulated by calcium and associated with viroplasms |journal=Journal of Virology |volume=80 |issue=12 |pages=6061–6071 |year=2006 |pmid=16731945 |pmc=1472611 |doi=10.1128/JVI.02167-05 }}</ref>

The vomiting, which is a characteristic of rotaviral enteritis, is caused by the virus infecting the [[enterochromaffin cell]]s on the lining of the digestive tract. The infection stimulates the production of 5' hydroxytryptamine ([[serotonin]]). This activates vagal afferent nerves, which in turn activates the cells of the brain stem that control the vomiting reflex.<ref name="pmid22722079">{{cite journal |vauthors=Hagbom M, Sharma S, Lundgren O, Svensson L |title=Towards a human rotavirus disease model |journal=Current Opinion in Virology |volume=2 |issue=4 |pages=408–418 |year=2012 |pmid=22722079 |doi=10.1016/j.coviro.2012.05.006 }}</ref>

Healthy enterocytes secrete [[lactase]] into the small intestine; milk intolerance due to lactase deficiency is a symptom of rotavirus infection,<ref name="pmid18492865">{{cite journal |author=Farnworth ER |title=The evidence to support health claims for probiotics |journal=The Journal of Nutrition |volume=138 |issue=6 |pages=1250S–1254S |year=2008 |pmid=18492865 |doi=10.1093/jn/138.6.1250S |doi-access=free }}</ref> which can persist for weeks.<ref name="pmid12811680">{{cite journal |vauthors=Ouwehand A, Vesterlund S |title=Health aspects of probiotics |journal=IDrugs: The Investigational Drugs Journal |volume=6 |issue=6 |pages=573–580 |year=2003 |pmid=12811680 }}</ref> A recurrence of mild diarrhoea often follows the reintroduction of milk into the child's diet, due to bacterial fermentation of the [[disaccharide]] [[lactose]] in the gut.<ref name="pmid6436397">{{cite journal
|author=Arya SC
|title=Rotaviral infection and intestinal lactase level
|journal=Journal of Infectious Diseases
|volume=150
|issue=5
|page=791
|year=1984
|pmid=6436397
|doi=10.1093/infdis/150.5.791
|doi-access=free
}}</ref>