TLRs in host-commensal interactions

描述(申请人提供)：Toll样受体(TLRs)在病原体识别和对感染的先天性和获得性免疫反应的激活中发挥关键作用。然而，TLRs识别的微生物配体并不是病原体所特有的，而是由病原微生物和共生微生物产生的。我们最近发现，TLRs对共生细菌的识别对于维持肠道内稳态、组织修复和保护免受损伤至关重要。另一方面，对共生细菌的反应失调会导致炎症性疾病，如炎症性肠病(IBD)。TLRs在IBD发病机制中的作用目前尚不清楚。本研究的目的是研究共系膜-TLR相互作用在维持肠道内环境稳定、组织保护和修复以及IBD发病机制中的作用。我们将培育出肠道中不同细胞类型的TLR信号选择性充足或不足的小鼠。利用这些小鼠，我们将研究不同细胞类型和基因产物在识别共生细菌、宿主防御、肠道稳态以及组织保护和修复方面的作用。我们还将研究TLRs在共系依赖的T细胞介导的结肠炎模型的病因学中的作用，并检查不同细胞类型的TLR信号在发病机制中的作用。我们将分析在结肠中受IL-10负调控的TLR依赖的通路，并研究这些通路的失调如何导致结肠炎的启动和维持。这些研究将提供新的和重要的信息，有助于阐明TLRs在肠道生理学、IBD的发病机制和宿主-共生相互作用的生物学中的作用。

DESCRIPTION (provided by applicant): Toll-like receptors (TLRs) play a crucial role in pathogen recognition and activation of innate and adaptive immune responses to infection. The microbial ligands recognized by TLRs are not unique to pathogens, however, and are produced by both pathogenic and commensal microorganisms. We have recently found that recognition of commensal bacteria by TLRs is critical for the maintenance of intestinal homeostasis, tissue repair and protection from injury. On the other hand, dysregulated responses to commensal bacteria can lead to inflammatory diseases, such as inflammatory bowel disease (IBD). The role of TLRs in the initiation and pathogenesis of IBD is currently unknown. The goal of this proposal is to investigate the role of commensal-TLR interactions in the maintenance of intestinal homeostasis, tissue protection and repair, and the pathogenesis of IBD. We will generate mice that are selectively sufficient or deficient in TLR signaling in different cell types present in the intestine. Using these mice we will investigate the role of different cell types and gene products in recognition of commensal bacteria, host defense, intestinal homeostasis and tissue protection and repair. We will also examine the role of TLRs in the etiology of commensal dependent, T cell mediated colitis model and examine the contribution of TLR signaling by different cell types to pathogenesis. We will analyze the TLR-dependent pathways that are negatively regulated by IL-10 in the colon, and investigate how dysregulation of these pathways leads to initiation and maintenance of colitis. These studies will provide novel and important information that will help elucidate the role of TLRs in intestinal physiology, the pathogenesis of IBD and the biology of host-commensal interactions.