Intestinal cell response to bacterial apoptotic signals

描述(申请人提供)：近年来，人们对细菌和真核宿主之间的相互作用越来越感兴趣。这种兴趣主要针对了解传染病的机制，但宿主-微生物相互作用的研究也可能与理解正常生理的许多方面高度相关。这些相互作用最重要的地方是人类的肠道，它受到各种直接影响它的感染的影响。微生物与宿主的相互作用通常会导致炎症反应，而细菌本身在调节这种组织反应方面发挥着核心作用。一个相关的过程是细胞凋亡或程序性细胞死亡。细胞凋亡是个体细胞内在的自我消除，是细菌感染后的常见反应。有趣的是，这种严格调控的过程与促炎症反应一样，分享了许多生化信号通路，炎症效应基因对细胞凋亡施加复杂而严格的调控影响，表明炎症反应的一个组成部分对于控制细胞凋亡的激活是必要的。真核细胞通过保守的模式识别受体家族，如Toll样受体，监测细菌产物或PAMP(病原体相关分子模式)的存在，这些受体能够激活促炎途径。在这个提议中，我们的首要假设是，模式识别受体能够在细菌感染/定植过程中激活细胞保护/抗凋亡程序。我们一直在研究鞭毛蛋白/Toll样受体5作为候选的PAMP/TLR对。我们的研究表明，小鼠伤寒沙门氏菌不能激活上皮细胞的致炎反应，但在体外可导致细胞凋亡增加，并可增加体内组织损伤。我们假设，通过细胞模式识别受体TLR5识别的细菌鞭毛蛋白，作为炎症反应的一个内在和不可分割的方面，激活了抗凋亡/生存基因。我们将利用多种生化、微生物学、组织培养和小鼠系统来研究上皮细胞如何调控沙门氏菌诱导的细胞凋亡的机制和后果。这些研究将增加我们对肠道细菌感染发病机制的理解，并可能阐明共生细菌对胃肠道健康的贡献。

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.