Intracellular pathogens and innate immunity

描述（由申请人提供）：本申请是一个名为“细胞内病原体和先天免疫”的计划项目资助的竞争性更新，最初于2004年资助，并于2009年更新，由ARRA提供两年的资助。研究的中心问题是细胞内病原体如何被宿主先天免疫系统识别，以及相反，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提出扩展他的发现，即L。单核细胞增多症激活宿主胞质监视途径（CSP），导致IFN-γ和共调节基因的表达。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，考克斯发现M.结核病需要ESX-1辅助分泌系统来激活CSP，他建议鉴定和表征有助于应答的细菌配体和宿主因子。在项目3中，万斯与其他两个小组合作，重点是确定和表征控制CSP的宿主因子。他已经建立了一个ENU诱变程序，并确定宿主蛋白Sting是对L.单核细胞增多症M.结核病、c-di-AMP、c-di-GMP和DNA。此外，在初步数据中，Sting似乎是环状二核苷酸受体。由巴顿管理的核心B是一个小鼠和ENU核心，将继续产生和繁殖大约25个品系的小鼠，这些小鼠在相关的先天免疫途径中具有单突变、双突变和三突变。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和促进协同作用，这将通过在所有实验室小组的月度会议上广泛审查科学进展来实现。

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.