Commensal-dependent induction of protective immunity

摘要 几千年来，人类和他们的微生物群共同进化出一种互利的关系。许多 宿主生理的基本方面，包括免疫系统发育和肠道内环境平衡， 依赖于肠道细胞、肠道免疫系统和微生物区系之间的相互作用。为 肠道免疫系统，这些相互作用要求它在提供强大的抗- 微生物对病原微生物的反应，同时限制对微生物区系的炎症反应。至 了解这种平衡是如何实现和维持的，了解肠道微生物是至关重要的， 免疫细胞群，以及所涉及的信号通路。我们的工作和其他人的数据表明 表达单核巨噬细胞(MNPs)的CX3CR1检测来自微生物区系的信号并协调 肠道免疫反应，促进上皮完整性，减少肠道炎症。这群人 大多数MNPs具有高度的吞噬功能，并能分泌促炎和抗炎细胞因子。此外, 这种细胞群在炎症性肠病(IBD)患者的结肠中被发现是扩张的 在结肠炎的小鼠模型中也是如此。我们假设CX3CR1+MNPs识别 微生物区系，这反过来决定了它们调节保护性或病理反应的能力。变化 因此，在CX3CR1+MNPs遇到的共生微生物中，预计会影响 这些MNPs的功能。作为炎症性疾病(如IBD)的标志是生物失调，或 微生物群的组成，CX3CR1+MNPs遇到的共生微生物的变化将 直接影响到它们的功能。我们已经鉴定出属于小鼠微生物区系的正常成员的大肠杆菌 对结肠炎小鼠模型提供不同程度的保护。我们将利用这种鼠标共生以及 大肠杆菌人类临床分离株以了解这些微生物定植对效应器功能的影响 CX3CR1+MNPs。我们将进一步确定这些分离株是如何支持免疫保护的。 结肠炎。最后，为了确定诱导免疫保护的微生物遗传因素，我们将 利用基于比较基因组学的分析来识别和随后针对微生物基因簇 这些与保护性免疫相关的大肠杆菌分离株。我们的总体目标是确定具体到什么程度 微生物区系成员影响肠道免疫是了解肠道免疫调节的第一步。 肠道动态平衡由微生物区系决定。

Summary Over the millennia, humans and their microbiota have coevolved a mutually beneficial relationship. Many essential aspects of host physiology, including immune system development and intestinal homeostasis, depend on interactions between cells of the intestine, the intestinal immune system, and the microbiota. For the intestinal immune system, these interactions require that it strike a balance between providing robust anti- microbial responses to pathogenic microbes while limiting inflammatory responses against the microbiota. To understand how this balance is achieved and maintained, it is critical to understand the intestinal microbes, immune cell populations, and signaling pathways involved. Data from our work and others suggest that CX3CR1 expressing mononuclear phagocytes (MNPs) detect signals from the microbiota and coordinate intestinal immune responses to promote epithelial integrity and reduce intestinal inflammation. This population of MNPs is highly phagocytic and is known to secrete both pro- and anti-inflammatory cytokines. In addition, this cell population has been found to be expanded in the colon of inflammatory bowel disease (IBD) patients as well as in mouse models of colitis. We hypothesize that CX3CR1+ MNPs recognize specific members of the microbiota, which in turn dictates their ability to mediate either protective or pathological responses. Changes in the commensal microbes encountered by CX3CR1+ MNPs would therefore be predicted to impact the function of these MNPs. As a hallmark of inflammatory conditions such as IBD is dysbiosis, or a shift in the composition of the microbiota, changes in the commensal microbes encountered by CX3CR1+ MNPs would directly impact their function. We have identified E. coli that are normal members of the mouse microbiota and offer different degrees of protection in mouse models of colitis. We will utilize this mouse commensal as well as E. coli human clinical isolates to understand how colonization with these microbes impacts the effector function of CX3CR1+ MNPs. We will further determine how these isolates support immune protection in models of colitis. Finally, with the goal of identifying microbial genetic elements which induce immune protection, we will utilize comparative genomics-based analysis to identify and subsequently target microbial gene clusters in these E. coli isolates that correlate with protective immunity. Our overall objective is to determine how specific members of the microbiota impacts intestinal immunity as the first step in understanding the regulation of intestinal homeostasis by the microbiota.