Intracellular pathogens and innate immunity

描述（由申请人提供）：本申请是题为“细胞内病原体和先天免疫”的计划项目拨款的竞争性更新，最初于 2004 年资助，并于 2009 年更新，由 ARRA 提供两年的资助。正在研究的中心问题是宿主先天免疫系统如何识别细胞内病原体，以及病原体如何避免和/或操纵宿主反应以促进其发病机制。该计划由三个项目和两个核心组成。在项目 1 中，Portnoy 提议扩展他的发现，即单增李斯特菌激活宿主胞质监视途径 (CSP)，从而导致 IFN-¿ 和共同调节基因的表达。在过去的资助期间，细菌配体被鉴定为c-di-AMP，这是一种新发现的小细菌信号分子，似乎对细菌生长至关重要，并通过细菌多药外排泵分泌。将探讨 c-di-AMP 在感染和免疫过程中的作用。在项目 2 中，Cox 发现结核分枝杆菌需要 ESX-1 辅助分泌系统来激活 CSP，他建议识别和表征有助于反应的细菌配体和宿主因子。在项目 3 中，Vance 与其他两个小组合作，重点研究控制 CSP 的宿主因素的识别和表征。他已经建立了 ENU 诱变程序，并确定宿主蛋白 Sting 对于对单核细胞增生李斯特菌、结核分枝杆菌、c-di-AMP、c-di-GMP 和 DNA 的反应是必需的。此外，在初步数据中，Sting 似乎是环二核苷酸受体。由 Barton 管理的 Core B 是一个小鼠和 ENU 核心，将继续产生和繁殖大约 25 种小鼠，这些小鼠在相关先天免疫途径中具有单、双和三突变。该核心还将管理 ENU 正向遗传筛选，并将潜在的突变巨噬细胞分配给其他项目负责人，以筛选先天免疫途径中的宿主缺陷。核心 A 的目的是通过提供科学、组织和行政领导来确保科学进步并促进协同作用，这将通过在所有实验室小组的月度会议上对科学进展进行广泛审查来实现。

DESCRIPTION (provided by applicant): This application is a competitive renewal of a Program Project Grant entitled, "Intracellular pathogens and innate immunity," originally funded in 2004 and renewed in 2009 with two years of funding from the ARRA. The central problem under investigation is how intracellular pathogens are recognized by the host innate immune system and conversely, how pathogens avoid and/or manipulate the host response to promote their pathogenesis. The program consists of three projects and two cores. In Project 1, Portnoy proposes to extend his discovery that L. monocytogenes activates a host cytosolic surveillance pathway (CSP) leading to the expression of IFN-¿ and co-regulated genes. During the past funding period, the bacterial ligand was identified as c-di-AMP, a newly discovered small bacterial signaling molecule that appears to be essential for bacterial growth, and is secreted through a bacterial multidrug efflux pump. The role of c-di-AMP during infection and immunity will be explored. In Project 2, Cox found that M. tuberculosis requires the ESX-1 auxiliary secretion system to activate the CSP, and he proposes to identify and characterize the bacterial ligand(s) and host factors that contribute to the response. In Project 3, Vance collaborates with the other two groups and focuses on the identification and characterization of host factors that control the CSP. He has already established a program of ENU mutagenesis and identified that the host protein Sting is necessary for the response to L. monocytogenes, M. tuberculosis, c-di-AMP, c-di-GMP, and DNA. Furthermore, in preliminary data, Sting appears to be the cyclic-di-nucleotide receptor. Core B, managed by Barton, is a mouse and ENU core that will continue to generate and breed approximately 25 strains of mice with single, double and triple mutations in relevant innate immune pathways. The core will also manage the ENU forward genetic screen and dispense potential mutant macrophages to the other project leaders to screen for host defects in innate immune pathways. The purpose of Core A is to ensure scientific progress and promote synergy by providing scientific, organizational, and administrative leadership, which will be accomplished by extensive review of scientific progress during monthly meetings of all the lab groups.