The intersection of innate and adaptive immunity to intracellular pathogens

项目摘要/摘要(总体) 这项申请是一项计划项目拨款的竞争性续订，其名称为“先天与 对细胞内病原体的适应性免疫。本P01的一个主要目标是识别和表征先天 由细胞内病原体触发、避免或操纵的免疫通路，并确定 这些途径在感染和免疫过程中的作用。更具体地说，在本P01中，我们重点关注 三种不同兼性胞内细菌的微生物学和免疫生物学研究 单核细胞增多症、嗜肺军团菌，以及重要的结核分枝杆菌。这是一个总的主题 应用是先天免疫系统检测细胞内的关键代谢物和毒力活动 细菌病原体，包括胞浆侵入或通过专门的细菌分泌系统进入。为 例如，研究中的所有三种病原体都激活了叮咬，要么是通过直接分泌环状二聚体，要么是通过直接分泌 核苷酸(CDN)或通过宿主细胞cGAs对细菌DNA的反应而激活，以激活刺痛， 最终导致关键的宿主反应，包括激活I型干扰素和自噬。在项目1中， 波特诺伊通过研究c-diAMP如何分泌来扩展他对c-diAMP和STING作用的研究。 影响单核细胞增多性李斯特菌的发病机制，并在口服模型期间扩散到胎盘和脑 感染。在项目2中，考克斯询问结核分枝杆菌是如何利用其ESX-1型VII型分泌系统穿孔的 吞噬体膜，激活刺痛并诱导I型干扰素的产生，从而促进感染，但 还能激活泛素介导的自噬反应，从而限制感染。但是，在键入 I型IFN被普遍认为在协调抗病毒免疫方面发挥着关键作用，I型IFN的作用 在对细菌的反应中，干扰素是复杂的，通常会加剧细菌病原体的感染。在……里面 项目3，万斯提出的初步数据表明，I型干扰素依赖的诱导 白细胞介素1受体拮抗剂(IL-1ra)是I型IFN加重的重要机制 细菌感染。我们还探讨了CDN只是免疫刺激的一个例子的想法 细菌代谢物通过分析另外两种导致激活的细菌代谢物 被归类为天然T细胞或不变T细胞，包括MAIT细胞和Vg9Vd2 T细胞。我们将确定 单核细胞增多性乳杆菌和结核分枝杆菌感染期间这些代谢物的相关性(项目1、2和 4)。在项目4中，斯坦利提议跟进她的初步数据，显示基于CDN的蛋白质 疫苗产生了一种强健和持久的结核病疫苗，特别是当经鼻注射时，即 与诱导保护性Th17反应有关。斯坦利建议评估一些疫苗 将CDNS与改良的卡介苗和单核细胞增多性乳杆菌载体相结合的策略。

Project Summary/Abstract (Overall) This application is a competitive renewal of a program project grant entitled, “The intersection of innate and adaptive immunity to intracellular pathogens.” A major goal of this P01 is to identify and characterize innate immune pathways that are triggered, avoided, or manipulated by intracellular pathogens and to determine the role of these pathways during infection and immunity. More specifically, in this P01 we focus on the microbiology and immunobiology of three diverse facultative intracellular bacterial pathogens; Listeria monocytogenes, Legionella pneumophila, and importantly, M. tuberculosis. An overall theme of this application is that the innate immune system detects key metabolites and virulence activities of intracellular bacterial pathogens, including cytosolic invasion or access via dedicated bacterial secretion systems. For example, all three pathogens under investigation activate STING, either by direct secretion of a cyclic-di- nucleotide (CDN) or by activation of host cell cGAS in response to bacterial DNA, to activate STING, culminating in critical host responses including activation of a type I IFN and autophagy. In Project 1, Portnoy extends his studies on the roles of c-di-AMP and STING by examining how c-di-AMP secretion affects L. monocytogenes pathogenesis and dissemination to the placenta and brain during an oral model of infection. In Project 2, Cox asks how M. tuberculosis uses its ESX-1 type VII secretion system to perforate phagosomal membranes, activate STING and induce production of type I IFN, which promotes infection, but also activates ubiquitin-mediated autophagy responses, which serves to limit infection. However, while type I IFNs are generally accepted to play a crucial role in orchestrating anti-viral immunity, the roles of type I IFNs in the responses to bacteria are complex and often exacerbate infection by bacterial pathogens. In Project 3, Vance presents preliminary data suggesting that type I IFN-dependent induction of the interleukin-1 receptor antagonist (IL-1Ra) is an important mechanism by which type I IFNs exacerbate bacterial infections. We also explore the idea that CDNs are just one example of immunostimulatory bacterial metabolites by analyzing two other bacterial metabolites that lead to the activation of what are classified as innate or invariant T-cells, including MAIT cells and Vg9Vd2 T-cells. We will ascertain the relevance of these metabolites during L. monocytogenes and M. tuberculosis infection (Projects 1, 2 and 4). In Project 4, Stanley propose to follow up on her preliminary data showing the CDN-based protein vaccines result in a robust and durable tuberculosis vaccines especially when introduced intranasally that is associated with induction of a protective Th17 response. Stanley proposes to evaluate a number of vaccine strategies using CDNs in combination with modified BCG and L. monocytogenes-based vectors.