How do the rotavirus NSP4 and bacterial enterotoxins lead differently to diarrhea?

Lorrot, Mathie; Vasseur, Monique

doi:10.1186/1743-422x-4-31

Cited by 87 publications

(72 citation statements)

References 39 publications

(67 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The cholinergic agonist carbachol was included in our assessment because, similarly to NSP4, it causes chloride secretion through a calcium-mediated pathway (44)(45)(46)(47). In addition, to evaluate the specificity of the response, we measured changes in the HIE lumenal area after administration of a mutant enterotoxin peptide (NSP4 peptide spanning aa 95 to 146 with an E120A/Q123A mutation) that does not increase intracellular calcium concentrations in vitro or induce diarrhea in neonatal mice (48).…”

Section: Resultsmentioning

confidence: 99%

Human Intestinal Enteroids: a New Model To Study Human Rotavirus Infection, Host Restriction, and Pathophysiology

Saxena

Blutt

Ettayebi

et al. 2016

J Virol

329

435

View full text Add to dashboard Cite

Human gastrointestinal tract research is limited by the paucity of in vitro intestinal cell models that recapitulate the cellular diversity and complex functions of human physiology and disease pathology. Human intestinal enteroid (HIE) cultures contain multiple intestinal epithelial cell types that comprise the intestinal epithelium (enterocytes and goblet, enteroendocrine, and Paneth cells) and are physiologically active based on responses to agonists. We evaluated these nontransformed, three-dimensional HIE cultures as models for pathogenic infections in the small intestine by examining whether HIEs from different regions of the small intestine from different patients are susceptible to human rotavirus (HRV) infection. Little is known about HRVs, as they generally replicate poorly in transformed cell lines, and host range restriction prevents their replication in many animal models, whereas many animal rotaviruses (ARVs) exhibit a broader host range and replicate in mice. Using HRVs, including the Rotarix RV1 vaccine strain, and ARVs, we evaluated host susceptibility, virus production, and cellular responses of HIEs. HRVs infect at higher rates and grow to higher titers than do ARVs. HRVs infect differentiated enterocytes and enteroendocrine cells, and viroplasms and lipid droplets are induced. Heterogeneity in replication was seen in HIEs from different patients. HRV infection and RV enterotoxin treatment of HIEs caused physiological lumenal expansion detected by time-lapse microscopy, recapitulating one of the hallmarks of rotavirus-induced diarrhea. These results demonstrate that HIEs are a novel pathophysiological model that will allow the study of HRV biology, including host restriction, cell type restriction, and virus-induced fluid secretion. IMPORTANCEOur research establishes HIEs as nontransformed cell culture models to understand human intestinal physiology and pathophysiology and the epithelial response, including host restriction of gastrointestinal infections such as HRV infection. HRVs remain a major worldwide cause of diarrhea-associated morbidity and mortality in children <5 years of age. Current in vitro models of rotavirus infection rely primarily on the use of animal rotaviruses because HRV growth is limited in most transformed cell lines and animal models. We demonstrate that HIEs are novel, cellularly diverse, and physiologically relevant epithelial cell cultures that recapitulate in vivo properties of HRV infection. HIEs will allow the study of HRV biology, including human hostpathogen and live, attenuated vaccine interactions; host and cell type restriction; virus-induced fluid secretion; cell-cell communication within the epithelium; and the epithelial response to infection in cultures from genetically diverse individuals. Finally, drug therapies to prevent/treat diarrheal disease can be tested in these physiologically active cultures. K nowledge of the human small intestine has been limited by the lack of in vitro systems that recapitulate its complex nature and functions. In ...

show abstract

Section: Resultsmentioning

confidence: 99%

Human Intestinal Enteroids: a New Model To Study Human Rotavirus Infection, Host Restriction, and Pathophysiology

Saxena

Blutt

Ettayebi

et al. 2016

J Virol

329

435

View full text Add to dashboard Cite

show abstract

“…(d) A subset of human cystic fibrosis patients exhibit residual colonic Cl -conductance that is likely mediated by CaCCs (39). (e) Rotavirus infection produces diarrhea by stimulating Ca 2+ -dependent Cl -secretion from crypts (40), and the rotavirus toxin NSP4 induces Ca 2+ -mediated Cl -secretion in both WT and CFTR-knockout crypts (41).…”

Section: Discussionmentioning

confidence: 99%

Bestrophin-2 mediates bicarbonate transport by goblet cells in mouse colon

et al. 2010

View full text Add to dashboard Cite

Anion transport by the colonic mucosa maintains the hydration and pH of the colonic lumen, and its disruption causes a variety of diarrheal diseases. Cholinergic agonists raise cytosolic Ca 2+ levels and stimulate anion secretion, but the mechanisms underlying this effect remain unclear. Cholinergic stimulation of anion secretion may occur via activation of Ca 2+ -activated Cl -channels (CaCCs) or an increase in the Cl -driving force through CFTR after activation of Ca 2+ -dependent K + channels. Here we investigated the role of a candidate CaCC protein, bestrophin-2 (Best2), using Best2 -/-mice. Cholinergic stimulation of anion current was greatly reduced in Best2 -/-mice, consistent with our proposed role for Best2 as a CaCC. However, immunostaining revealed Best2 localized to the basolateral membrane of mucin-secreting colonic goblet cells, not the apical membrane of Cl --secreting enterocytes. In addition, in the absence of HCO 3 -, cholinergic-activated current was identical in control and Best2 -/-tissue preparations, which suggests that most of the Best2 current was carried by HCO 3 -. These data delineate an alternative model of cholinergic regulation of colonic anion secretion in which goblet cells play a critical role in HCO 3 -homeostasis. We therefore propose that Best2 is a HCO 3 -channel that works in concert with a Cl:HCO 3 -exchanger in the apical membrane to affect transcellular HCO 3 -transport. Furthermore, previous models implicating CFTR in cholinergic Cl -secretion may be explained by substantial downregulation of Best2 in Cftr -/-mice.

show abstract

“…Rotavirus protein NSP4 induces a Ca ion-dependent chloride secretion, disrupts Na þ -dependent GLUT1 transporter-mediated reabsorption of water, causes maldigestion of carbohydrates and probably activates the Ca ion-dependent secretory reflexes of the enteric nervous system (69) . The malabsorption of nutrients in the intestine is associated with inhibited water reabsorption and can lead to diarrhoea and malnutrition (69) . Shigellosis is one of the major causes of diarrhoea-related morbidity and mortality in developing countries, transmitted through contaminated food and water as well as through person-to-person contact (70,71) .…”

Section: Antisecretory Factor and Gut Healthmentioning

confidence: 99%

Antisecretory factor as a potential health-promoting molecule in man and animals

2010

View full text Add to dashboard Cite

Antisecretory factor (AF) is a protein secreted in plasma and other tissue fluids in mammals with proven antisecretory and anti-inflammatory activity; its immunohistological distribution suggests a role in the immune system. The expression level and the distribution of AF protein are altered during an immunological response. Exposure to bacterial toxins induces secretion of AF in plasma, probably reflecting a natural defence mechanism to agents causing diarrhoea, thereby contributing to a favourable clinical outcome and disease termination. An increase of AF levels in plasma by dietary means, such as specially processed cereals (SPC), has been demonstrated in human subjects and animals. Administration of SPC to patients affected by inflammatory bowel disease, gastroenteritis and Ménière's disease relieved symptoms and improved quality of life. A recent study showed the positive effect of SPC diet supplementation on prevention of the effects of exposure to low levels of blast overpressure in rats, reducing the extent of intracranial pressure increase and cognitive function impairment. AF-rich egg yolk powder improved health status in children suffering acute and chronic diarrhoea, reducing the frequency and increasing the consistency of stools. This kind of functional food could be used for prophylaxis in populations exposed to a high risk of morbidity and mortality caused by diarrhoea and as a complementary therapy in patients affected by chronic intestinal inflammatory disease to improve well-being. In pig husbandry AF-inducing diets, owing to their antisecretory activity and anti-inflammatory action, are a suitable option as an alternative to antibiotic growth promoters to counteract post-weaning diarrhoea.

show abstract

How do the rotavirus NSP4 and bacterial enterotoxins lead differently to diarrhea?

Cited by 87 publications

References 39 publications

Human Intestinal Enteroids: a New Model To Study Human Rotavirus Infection, Host Restriction, and Pathophysiology

Human Intestinal Enteroids: a New Model To Study Human Rotavirus Infection, Host Restriction, and Pathophysiology

Bestrophin-2 mediates bicarbonate transport by goblet cells in mouse colon

Antisecretory factor as a potential health-promoting molecule in man and animals

Contact Info

Product

Resources

About