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（由申请人提供）：本申请是“细胞内病原体和先天免疫”项目资助的竞争性更新，该项目最初于2004年获得资助，并于2009年获得ARRA为期两年的资助。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，反过来，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Project 1中，Portnoy提出扩展他的发现，即单核增生乳杆菌激活宿主胞质监视通路（CSP），导致IFN-¿和共调节基因的表达。在过去的资助期内，细菌配体被鉴定为c-di-AMP，这是一种新发现的细菌小信号分子，似乎对细菌生长至关重要，并通过细菌多药物外排泵分泌。c-di-AMP在感染和免疫中的作用将被探讨。在Project 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，他提出鉴定和表征参与反应的细菌配体和宿主因子。在项目3中，Vance与另外两个小组合作，重点研究控制CSP的宿主因子的识别和表征。他已经建立了ENU诱变程序，并确定宿主蛋白Sting对单核细胞增生乳杆菌、结核分枝杆菌、c-di-AMP、c-di-GMP和DNA的应答是必需的。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个在相关先天免疫途径中具有单、双和三重突变的小鼠菌株。核心还将管理ENU向前遗传筛选，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、组织和管理的领导来确保科学进步和促进协同，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的审查来完成。