The intersection of innate and adaptive immunity to intracellular pathogens

针对细胞内病原体的先天免疫和适应性免疫的交叉点

• 批准号: 10400179
• 负责人: DANIEL A PORTNOY
• 金额: $ 233.32万
• 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: 2004-09-30 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10400179
• 关键词: Address; Adjuvant; Affect; Antibacterial Response; Antibodies; Autophagocytosis; Bacteria; Bacterial DNA; Bacterial Infections; Brain; Cells; Communicable Diseases; Communities; Complex; Cytosol; DNA; Data; Defense Mechanisms; Disease; ELF3 gene; Engineering; Enzymes; Foundations; Future; Goals; Immune; Immune response; Immune system; Immunity; Immunobiology; Infection; Innate Immune Response; Innate Immune System; Interferon Type I; Interferons; Interleukin-1; International; Investigation; Knowledge; Lead; Legionella pneumophila; Listeria monocytogenes; Mediating; Membrane; Microbiology; Modeling; Mycobacterium tuberculosis; Natural Immunity; Nucleotides; Oral; Pathogenesis; Pathway interactions; Periodicity; Phagosomes; Placenta; Play; Positioning Attribute; Production; Program Research Project Grants; Proteins; Research; Research Support; Resources; Role; System; T-Lymphocyte; Therapeutic; Translating; Tuberculosis; Tuberculosis Vaccines; Ubiquitin; Vaccines; Virulence; Virulence Factors; Virulent; Virus Diseases; adaptive immune response; adaptive immunity; anakinra; antiviral immunity; base; biosafety level 3 facility; burden of illness; collaborative approach; design; extracellular; follow-up; global health; immunogenicity; improved; innate immune pathways; innovation; insight; meetings; mutant; novel therapeutic intervention; novel vaccines; pathogen; pathogenic bacteria; prevent; programs; receptor; response; success; synergism; targeted treatment; vaccination outcome; vaccine development; vaccine strategy; vector; Address; Adjuvant; Affect; Antibacterial Response; Antibodies; Autophagocytosis; Bacteria; Bacterial DNA; Bacterial Infections; Brain; Cells; Communicable Diseases; Communities; Complex; Cytosol; DNA; Data; Defense Mechanisms; Disease; ELF3 gene; Engineering; Enzymes; Foundations; Future; Goals; Immune; Immune response; Immune system; Immunity; Immunobiology; Infection; Innate Immune Response; Innate Immune System; Interferon Type I; Interferons; Interleukin-1; International; Investigation; Knowledge; Lead; Legionella pneumophila; Listeria monocytogenes; Mediating; Membrane; Microbiology; Modeling; Mycobacterium tuberculosis; Natural Immunity; Nucleotides; Oral; Pathogenesis; Pathway interactions; Periodicity; Phagosomes; Placenta; Play; Positioning Attribute; Production; Program Research Project Grants; Proteins; Research; Research Support; Resources; Role; System; T-Lymphocyte; Therapeutic; Translating; Tuberculosis; Tuberculosis Vaccines; Ubiquitin; Vaccines; Virulence; Virulence Factors; Virulent; Virus Diseases; adaptive immune response; adaptive immunity; anakinra; antiviral immunity; base; biosafety level 3 facility; burden of illness; collaborative approach; design; extracellular; follow-up; global health; immunogenicity; improved; innate immune pathways; innovation; insight; meetings; mutant; novel therapeutic intervention; novel vaccines; pathogen; pathogenic bacteria; prevent; programs; receptor; response; success; synergism; targeted treatment; vaccination outcome; vaccine development; vaccine strategy; vector

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.

项目摘要/摘要（总体） 该申请是对计划项目赠款的竞争性续签，标题为“先天和 对细胞内病原体的适应性免疫学。”该P01的主要目标是识别和表征先天 通过细胞内病原体触发，避免或操纵的免疫途径，并确定 这些途径在感染和免疫力中的作用。更具体地说，在此P01中，我们专注于 三种潜水员的细胞内细菌病原体的微生物学和免疫生物学；李斯特菌 单核细胞增生，肺炎军团菌，重要的是结核分枝杆菌。总体主题 应用是先天免疫系统检测到细胞内的关键代谢物和病毒活性 细菌病原体，包括胞质侵袭或通过专用细菌分泌系统进入。为了 例如，在投资下的所有三种病原体都通过直接分泌环状分泌激活刺痛 核苷酸（CDN）或通过响应细菌DNA激活宿主细胞CGA，以激活刺痛， 最终在关键的宿主反应中达到包括I型IFN和自噬的激活。在项目1中 Portnoy通过检查C-Di-Amp分泌如何扩展了他对C-DI-AMP和Sting的作用的研究 在口头模型中影响单核细胞增生李斯特氏菌的发病机理，并将 在项目2中，考克斯询问结核分枝杆菌如何使用其ESX-1型VII分泌系统穿孔 吞噬机制，激活刺痛并诱导I型IFN的产生，这会促进感染，但 还激活泛素介导的自噬反应，这有限于限制感染。但是，类型 我普遍认为，IFN在策划抗病毒免疫（I型的角色）中起着至关重要的作用 对细菌的反应中的IFN是复杂的，通常会因细菌病原体而加剧感染。在 项目3，万斯介绍了初步数据，表明I型IFN依赖性诱导 白介素-1受体拮抗剂（IL-1RA）是I型IFNS加剧的重要机制 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 细菌代谢产物通过分析其他两种导致激活的细菌代谢产物 分类为先天或不变的T细胞，包括Mait细胞和VG9VD2 T细胞。我们将确定 这些代谢物在单核细胞增生李斯特氏菌和结核分枝杆菌感染期间的相关性（项目1、2和 4）。在项目4中，斯坦利提议跟进她的初步数据，显示基于CDN的蛋白质 疫苗会导致坚固耐用的结核病疫苗，尤其是在鼻内引入的疫苗 与诱导受保护的TH17响应有关。斯坦利的提议评估多种疫苗 使用CDN结合改良的BCG和基于单核细胞增生的载体的策略。