The molecular basis of host-microbiota interactions

项目总结 肠道微生物区系和人体免疫系统的失调被认为是导致慢性 炎症性肠病、心脏病、糖尿病和癌症等疾病。更好地理解 微生物区系和宿主免疫系统之间的相互作用应突出新的治疗方法 针对这些慢性疾病的战略，包括直接针对微生物区系而不是宿主的治疗。 最近的研究表明，微生物区系的一个子集定居在健康的人、非人类的灵长类动物和 小鼠淋巴组织。这些细菌被称为淋巴组织驻留共生体或LRC，可诱导出独特的 先天免疫反应，并防止肠道炎症。然而，LRC的分子基础 淋巴组织的定植以及LRC引发的先天免疫反应尚不清楚。初步 该方案中的数据表明，LRC可能通过一种途径抑制树突状细胞中宿主一氧化氮的反应 保守的细菌精氨酸酶。Aim 1将利用LRC的体外和体内定植模型来询问 LRC精氨酸酶与宿主天然免疫系统的相互作用。此外，初步研究 提示宿主铁转运可能在LRC定植和肠道炎症中起积极作用。 AIM 2将利用LRC在体外和体内的定植模型，以及新的小鼠模型 铁运输，以调查LRC定植、宿主铁运输和炎症之间的联系。 总的来说，这两个目标将至关重要地定义LRCs在哺乳动物宿主上定居的分子基础。 并调节肠道炎症。

PROJECT SUMMARY Dysregulation of the intestinal microbiota and the human immune system is thought to contribute to chronic diseases such as inflammatory bowel disease, heart disease, diabetes, and cancer. A better understanding of the interactions between the microbiota and the host immune system should highlight novel therapeutic strategies for these chronic diseases, including therapies directly targeting the microbiota rather than the host. Recent studies have shown that a subset of the microbiota colonizes healthy human, non-human primate, and mouse lymphoid tissues. These bacteria, termed lymphoid tissue-resident commensals or LRCs, elicit unique innate immune responses, and protect against intestinal inflammation. However, the molecular basis of LRC colonization of lymphoid tissues, and LRC-elicited innate immune responses, remains unclear. Preliminary data in this proposal suggests that LRCs may suppress host nitric oxide responses in dendritic cells using a conserved bacterial arginase. Aim 1 will utilize in vitro and in vivo models of LRC colonization to interrogate the interaction between LRC arginases and the host innate immune system. Additionally, preliminary studies suggest that host iron transport may actively contribute to both LRC colonization and intestinal inflammation. Aim 2 will utilize in vitro and in vivo models of LRC colonization, along with novel murine models with modified iron transport, to investigate the connection between LRC colonization, host iron transport, and inflammation. Collectively, these two aims will crucially define the molecular basis by which LRCs colonize mammalian hosts and modulate intestinal inflammation.