Intestinal cell response to bacterial apoptotic signals

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DESCRIPTION (provided by applicant): In recent years there has been an increasing interest in the interactions between bacteria and eukaryotic hosts. This interest is targeted largely at understanding mechanisms of infectious disease, but the study of host-microbe interactions are also likely to be highly relevant to understanding many aspects of normal physiology. Nowhere are these interactions as important as in the human gut, which is subject to a wide variety of infections that affect it directly. Microbe-host interactions often result in inflammatory responses, and bacteria themselves play a central role in modulating this tissue response. A related process is apoptosis or programmed cell death. Apoptosis is the intrinsic self-elimination of individual cells and is a common reaction to bacterial infection. Interestingly, this tightly regulated process shares many of the biochemical signaling pathways as do proinflammatory responses, and inflammatory effector genes exert intricate and tight regulatory influences on apoptosis, suggesting that a component of the inflammatory response is necessary to control apoptotic activation. Eukaryotic cells monitor the presence of bacterial products or PAMPs (pathogen associated molecular patterns) by a conserved family of "pattern-recognition receptors" such as the Toll-like receptors, that are capable of activating proinflammatory pathways. In this proposal, our overarching hypothesis is that pattern recognition receptors are able to activate cytoprotective/anti-apoptotic programs during bacterial infection/colonization. We have been studying the flagellin/Toll-like receptor 5 as a candidate PAMP/TLR pair. We have shown that aflagellate Salmonella typhimurium do not activate significant proinflammatory responses in epithelia, however, they do result in increased apoptosis in vitro and increased tissue injury in vivo. We hypothesize that bacterial flagellin, recognized via the cellular pattern recognition receptor TLR5, activates anti-apoptotic/survival genes as an intrinsic and inseparable aspect of the inflammatory response. We will utilize a variety of biochemical, microbiological, tissue culture and murine systems to study the mechanisms and consequences of how epithelial cells regulate apoptosis induced by Salmonella. These studies will increase our understanding of the pathogenesis of enteric bacterial infections, and possibly illuminate means by which commensal bacteria contribute to the health of the Gl tract.