Shigella organisms are a group of Gram-negative enteric bacilli that cause acute bacillary dysentery in humans. The signature feature of this disease is exhibited by an intense inflammatory reaction manifestec clinically as passage of bloody stools. Humans and some non-human primates, namely Old World monkeys in Africa and Asia serve as the only hosts that are naturally susceptible to Shigella infection. The relationship between Shigella and the human intestinal epithelium and the subsequent inflammatory response, which determines clinical virulence, is undoubtedly complicated and relatively little information is known pertaining to this process. During the previous funding period we have identified key components of the Shigella-host relationship related to the polarity of the intestinal epithelium that might explain not only some of the host adaptation exhibited by this organism but also some of the strategic mechanisms underlying Shigella flexneri pathogenicity. Based on new information as a direct outgrowth from our preliminary observations we hypothesize that the elucidation of specific host-Shigella interactions that occur at either the apical or basolateral membrane domain will improve our understanding of both the immunology of mucosal surfaces and bacterial pathogenecity. The long-term goal of this project is to understand the molecular mechanisms underlying S. flexneri-intestinal epithelial interactions, which lead to acute infectious colitis so that novel therapeutic strategies for the treatment of this disease can be developed.
The specific aims of this proposal are ultimately aimed at achieving this goal and are three-fold:
Specific Aim 1 is designed to understand the molecular mechanisms by which S.flexneri regulates the tight junctional complex, by specifically examining the regulation of claudin-1, ZO-1, and ZO-2.
Specific Aim 2 is designed to examine key interactions at the host-basolateral interface that play a critical role in the ability of S. flexneri to mediate pro-inflammatory events that govern PMN movement across intestinal epithelia. In particular, we will examine the role of Shigella lipopolysaccharide and host cell ERK activation. Having established key S. flexneri interactions that occur at the apical and basolateral intestinal epithelial surface, Specific Aim 3 will determine the functional consequence of these interactions in an in vivo model of shigellosis that we have recently developed. Finally, we will examine the immunomodulatory role played by Saccharomyces bouldari during Shigella infection.
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