Microbes and microbial toxins: paradigms for microbial-mucosal interactions. VIII. Pathological consequences of rotavirus infection and its enterotoxin.
Rotaviral infection in neonatal animals and young children leads to acute self-limiting diarrhea, but infected adults are mainly asymptomatic. Recently, significant in-roads have been made into our understanding of this disease: both viral infection and virally manufactured nonstructural protein (NSP)4 evoke intracellular Ca(2+) ([Ca(2+)]i) mobilization in native and transformed gastrointestinal epithelial cells. In neonatal mouse pup mucosa models, [Ca(2+)]i elevation leads to age-dependent halide ion movement across the plasma membrane, transepithelial Cl(-) secretion, and, unlike many microbial enterotoxins, initial cyclic nucleotide independence to secretory diarrhea. Similarities between rotavirus infection and NSP4 function suggest that NSP4 is responsible for these enterotoxigenic effects. NSP4-mediated [Ca(2+)]i mobilization may further facilitate diarrhea by signaling through other Ca(2+)-sensitive cellular processes (cation channels, ion and solute transporters) to potentiate fluid secretion while curtailing fluid absorption. Apart from these direct actions in the mucosa at the onset of diarrhea, innate host-mediated defense mechanisms, triggered by either or both viral replication and NSP4-induced [Ca (2+)]i mobilization, sustain the diarrheal response. This secondary component appears to involve the enteric nervous system and may be cyclic nucleotide dependent. Both phases of diarrhea occur in the absence of significant inflammation. Thus age-dependent rotaviral disease represents an excellent experimental paradigm for understanding a noninflammatory diarrhea.
Morris
A P
AP
Department of Integrative Biology, University of Texas at Houston Medical School, Houston, Texas 77030, USA. Andrew.P.Morris@uth.tmc.edu
Estes
M K
MK
D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D003967:Diarrhea / Q000209:etiology / Q000378:metabolism / Q000821:virology*; D017615:Enteric Nervous System / Q000502:physiology; D004768:Enterotoxins / Q000502:physiology*; D005759:Gastroenteritis / Q000378:metabolism / Q000821:virology*; D006023:Glycoproteins / Q000502:physiology*; D006801:Humans; D007223:Infant; D007413:Intestinal Mucosa / Q000098:blood supply / Q000378:metabolism; D017136:Ion Transport; D007511:Ischemia / Q000821:virology; D008954:Models, Biological; D012400:Rotavirus Infections / Q000378:metabolism* / Q000821:virology; D014118:Toxins, Biological; D017361:Viral Nonstructural Proteins / Q000502:physiology*
D001427:Bacterial Toxins; D004768:Enterotoxins; D006023:Glycoproteins; C081369:NS28 protein, rotavirus; D014118:Toxins, Biological; D017361:Viral Nonstructural Proteins; D002118:Calcium