Bacterial-induced changes in intestinal epithelial cell gene expression play a pivotal role in host defense and may also drive the seemingly inappropriate inflammation associated with Crohn's disease. Accordingly, investigation of the mechanisms governing such bacterial-epithelial interactions has revealed some of the key host and bacterial determinants that mediate mucosal inflammation in the gut. Although much less studied, changes in epithelial cell gene expression can also be induced by viruses, which like bacteria often first colonize their hosts via the mucosal epithelium. Importantly, although not yet well defined, the specific genes upregulated upon epithelial colonization by viruses appear to be markedly distinct than that induced by bacteria. We hypothesize that, analogous to the case for bacteria, viral-induced intestinal epithelial gene expression, mediated by epithelial pattern recognition receptors, plays an important role in both innate and adaptive immune responses to ingested viral pathogens. Such host responses are likely an important component of host defense and may also be associated with viral pathogenesis. While we anticipate that developing this hypothesis will be a long term endeavor, the focused goal of this 2-year R21 proposal is to begin to explore this under-investigated area by examining mechanisms that mediate innate immune responses to rotavirus in intestinal epithelia.
The goal of this project is to understand the means by which the intestine clears viral infections and how such clearance results in protection against subsequent infection. The specific virus on which we will focus is rotavirus, which is one of the world's most common causes of gastroenteritis. The knowledge yielded by this project should aid the design of strategies to treat and prevent mucosally acquired viral infections in humans.
| Frias, Amena H; Jones, Rheinallt M; Fifadara, Nimita H et al. (2012) Rotavirus-induced IFN-? promotes anti-viral signaling and apoptosis that modulate viral replication in intestinal epithelial cells. Innate Immun 18:294-306 |
| Frias, A H; Vijay-Kumar, M; Gentsch, J R et al. (2010) Intestinal epithelia activate anti-viral signaling via intracellular sensing of rotavirus structural components. Mucosal Immunol 3:622-32 |
