SHIGELLOSIS--ROLE OF INTESTINAL EPITHELIUM

志贺氏菌是一组引起人类急性细菌性痢疾的革兰氏阴性杆菌。这种疾病的标志性特征是临床表现为腹泻的强烈炎症反应。人类和一些非人类灵长类动物，即非洲和亚洲的东半球猴子，是唯一自然容易感染志贺氏菌的宿主。志贺氏菌与人类肠道上皮之间的关系以及随后的炎症反应决定了临床毒力，这无疑是复杂的，有关这一过程的信息很少。因此，利用一个具有良好特性的体外还原系统，这一建议的广泛的长期目标是检查志贺氏菌对人类肠道表现出的物种依赖性的性质，并阐明志贺氏菌诱发急性感染性结肠炎的分子和细胞基础。该提案的特定目标最终旨在实现这一目标，并具有两个方面：特定目标1旨在了解哪些志贺氏菌因子在触发志贺氏菌引起的粘膜炎症反应中是必不可少的。我们将确定志贺氏菌需要哪些遗传决定因素来诱导跨越肠上皮细胞单层的PMN信号。我们还将确定志贺氏菌分泌蛋白在志贺氏菌引起的粘膜炎症中的作用。特异性目标2旨在检测宿主上皮细胞因子对福氏志贺氏菌的反应，这些因素导致肠道炎症的活跃状态。我们将提纯和鉴定一种新的志贺氏菌诱导的中性粒细胞趋化因子，它可以指导中性粒细胞在肠道上皮细胞中的迁移。一旦我们了解了志贺氏菌-肠上皮相互作用协调这种反应的分子机制，就有可能开发出旨在治疗和改善疾病的新的治疗策略。

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.