The intersection of innate and adaptive immunity to intracellular pathogens

项目概要/摘要（总体） 这个应用程序是一个有竞争力的更新计划项目赠款题为“的交集，先天和 对细胞内病原体的适应性免疫”本P01的主要目标是识别和表征先天性 由细胞内病原体触发、避免或操纵的免疫途径， 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病原体的微生物学和免疫生物学;李斯特菌 单核细胞增多症，嗜肺军团菌，重要的是，M.结核这是一个整体主题， 应用是先天免疫系统检测细胞内的关键代谢物和毒力活性， 细菌病原体，包括胞质侵入或通过专用细菌分泌系统进入。为 例如，研究中的所有三种病原体都激活STING，无论是通过直接分泌环状二聚体， 核苷酸（CDN）或通过响应细菌DNA激活宿主细胞cGAS，以激活STING， 最终导致关键的宿主应答，包括I型IFN的活化和自噬。在项目1中， Portnoy通过研究c-di-AMP分泌如何影响c-di-AMP和STING的作用， 影响L.单核细胞增多症的发病机制和传播到胎盘和脑在一个口服模型， 感染在项目2中，考克斯问M.结核病利用其ESX-1 VII型分泌系统来抑制 吞噬体膜，激活STING并诱导I型IFN的产生，其促进感染，但 还激活泛素介导的自噬反应，从而限制感染。然而，当类型 I型干扰素通常被认为在协调抗病毒免疫中起着至关重要的作用，I型干扰素的作用 IFN对细菌的反应是复杂的，通常会加剧细菌病原体的感染。在 项目3，万斯提出的初步数据表明，I型IFN依赖性诱导的 白细胞介素-1受体拮抗剂（IL-1 Ra）是I型干扰素加重 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， 通过分析其他两种细菌代谢物，导致激活什么是细菌代谢物， 分类为先天或不变T细胞，包括MAIT细胞和Vg 9Vd 2 T细胞。我们将确定 这些代谢产物在L.单核细胞增多症和M.结核病感染（项目1、2和 4）。在项目4中，Stanley建议继续研究她的初步数据，这些数据显示了基于CDN的蛋白质 疫苗导致稳健和持久的结核病疫苗，特别是当鼻内引入时， 与诱导保护性Th 17应答相关。斯坦利建议评估一些疫苗 使用CDN与修饰的BCG和L.单核细胞生成载体。

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.