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Microbes and microbial toxins: paradigms for microbial-mucosal interactions. VIII. Pathological consequences of
1Department of Integrative Biology, University of Texas at Houston Medical School, Houston, Texas 77030, USA. Andrew.P.Morris@uth.tmc.edu
Abstract:
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.
Insights
Rotavirus infection causes diarrhea in young animals and children, driven by the nonstructural protein NSP4. This protein triggers calcium release in gut cells, leading to fluid secretion and diarrhea.
Area of Science:
- Gastroenterology
- Virology
- Cell Biology
Background:
- Rotavirus infection causes acute, self-limiting diarrhea in neonates and young children.
- Adults are typically asymptomatic, indicating age-dependent disease mechanisms.
- Both viral infection and the nonstructural protein NSP4 mobilize intracellular calcium ([Ca(2+)]i) in gastrointestinal cells.
Purpose of the Study:
- To elucidate the mechanisms of age-dependent rotaviral diarrhea.
- To investigate the role of NSP4 in inducing secretory diarrhea.
- To understand the cellular and neural pathways involved in rotavirus-induced diarrhea.
Main Methods:
- Neonatal mouse pup mucosa models were used to study ion transport.
- Intracellular calcium ([Ca(2+)]i) mobilization was measured in gastrointestinal epithelial cells.
- The role of cyclic nucleotides in the diarrheal response was assessed.
Main Results:
- Elevated [Ca(2+)]i in neonatal models caused age-dependent halide ion movement and transepithelial chloride secretion.
- NSP4 was identified as the likely cause of enterotoxigenic effects, independent of cyclic nucleotides initially.
- A secondary, cyclic nucleotide-dependent phase involving the enteric nervous system sustains diarrhea.
Conclusions:
- Rotavirus-induced diarrhea involves both direct mucosal effects mediated by NSP4 and host-defense mechanisms.
- NSP4-mediated calcium signaling potentiates fluid secretion and inhibits absorption.
- Age-dependent rotaviral disease serves as a model for non-inflammatory diarrhea.