SHIGELLOSIS--ROLE OF INTESTINAL EPITHELIUM

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Shigella organisms are a group of gram negative bacilli that cause acute bacillary dysentery in humans. The signature feature of this disease is exhibited by an intense inflammatory reaction manifested clinically as diarrhea. 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 very little information is known pertaining to this process. Thus, utilizing a well characterized in vitro reductionistic system, the broad long-term objectives of this proposal are to examine the nature of the species dependency exhibited by Shigella with the human intestine and elucidate the molecular and cellular bases by which Shigella foster acute infectious colitis. The specific aims of this proposal are ultimately directed at achieving this goal, and are two-fold: Specific Aim 1 is designed to understand which Shigella factors are essential in triggering the mucosal inflammatory response induced by S. flexneri. We will determine which genetic determinants are required for Shigella to induce PMN signaling across intestinal epithelial cell monolayers. We will also define the contribution of Shigella secreted proteins in Shigella-induce mucosal inflammation. Specific Aim 2 is designed to examine the host epithelial cell factors that are induced in response to S. flexneri which lead to an active state of intestinal inflammation. We will purify and identify a novel Shigella-elicited neutrophil chemotactic factor which directs PMN migration across the intestinal epithelium. Once we understand the molecular mechanisms by which Shigella-intestinal epithelial interactions orchestrate this response it may be possible to develop novel therapeutic strategies aimed at treatments for and ameliorating disease.