Intracellular pathogens and innate immunity

细胞内病原体和先天免疫

• 批准号: 8507131
• 负责人: DANIEL A PORTNOY
• 金额: $ 176.59万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8507131
• 关键词: Adjuvant; Adjuvanticity; Affect; Binding; Biochemical; Biochemistry; Bone Marrow; Breeding; Cells; Communities; Computer software; Cytosol; DNA; Data; Data Set; Defect; Disease; Ensure; Ethylnitrosourea; Focus Groups; Francisella tularensis; Funding; Genes; Genetic; Genetic Screening; Goals; Growth; Health; IRF3 gene; Immune; Immune response; Immune system; Immunity; In Vitro; Infection; Integration Host Factors; Interferons; International; Investigation; Lead; Leadership; Legionella pneumophila; Ligands; Listeria monocytogenes; Maps; Methodology; Microbe; Modeling; Molecular; Molecular Models; Monitor; Mouse Strains; Mus; Mutagenesis; Mutation; Mycobacterium tuberculosis; Natural Immunity; Nucleic Acids; Nucleotides; Pathogenesis; Pathway interactions; Phagosomes; Phosphotransferases; Prevention; Program Research Project Grants; Proteins; RNA; Reporting; Role; Signal Transduction; Signaling Molecule; System; TBK1 gene; Testing; Therapeutic; Time; Type IV Secretion System Pathway; Vaccines; biodefense; bis(3' ,5' )-cyclic diguanylic acid; clinically relevant; efflux pump; genetic analysis; global health; in vivo; macrophage; meetings; member; microbial; molecular modeling; mutant; novel; nucleotide receptor; pathogen; programs; response

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.

描述（由应用程序提供）：此应用程序是对计划项目赠款的竞争续签，标题为“细胞内病原体和先天免疫学”，最初于2004年资助，并于2009年续签，并从ARRA获得了两年的资金。正在研究的中心问题是宿主先天免疫学系统如何识别细胞内病原体，相反，病原体如何避免和/或操纵宿主反应以促进其发病机理。该计划由三个项目和两个核心组成。在项目1中，Portnoy提出的提议扩展了他发现单核细胞增生李斯特氏菌会激活宿主胞质监测途径（CSP），从而导致IFN- - 表达和共同调节基因的表达。在过去的资金期间，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，并通过细菌多泡外排泵分泌。将探索C-DI-AMP在感染和免疫力中的作用。在项目2中，Cox发现结核分枝杆菌需要ESX-1辅助分泌系统激活CSP，他提出识别和表征细菌配体和宿主因子的宿主因素，并表征有助于反应的宿主。在项目3中，万斯与其他两个组合作，并着重于控制CSP的宿主因素的识别和表征。他已经建立了一个ENU诱变程序，并确定宿主蛋白刺是对单核细胞增生李斯特氏菌，结核分枝杆菌，C-DI-AMP，C-DI-AMP，C-DI-GMP和DNA的反应所必需的。此外，在初步数据中，STING似乎是环状核苷酸接收器。由Barton管理的Core B是一种小鼠和ENU核心，它将继续产生并繁殖大约25种具有相关先天免疫途径的单，双重和三重突变的小鼠。核心还将管理ENU的前向遗传筛查和分配潜在的突变巨噬细胞到其他项目领导者，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，这将通过对所有实验室组的每月会议进行广泛审查来实现科学进步。