Project 3: Negative regulation of type I interferons during bacterial infection

项目3：细菌感染过程中I型干扰素的负调控

• 批准号: 10655296
• 负责人: RUSSELL E VANCE
• 金额: $ 43.41万
• 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/10655296
• 关键词: Address; Affect; Anti-Bacterial Agents; Antibacterial Response; Antiviral Response; Bacteria; Bacterial Infections; CRISPR screen; Cells; Chromatin; Collaborations; Complex; Data; Dinucleoside Phosphates; Foundations; Genes; Genetic; Genetic Transcription; Goals; Human; IFNAR1 gene; Immunity; Infection; Innate Immune Response; Interferon Type I; Interferons; Interleukin-1; Interleukin-1 Receptors; Laboratories; Legionella pneumophila; Listeria monocytogenes; Mediating; Modeling; Morbidity - disease rate; Mus; Mycobacterium tuberculosis; Natural Immunity; Nuclear; Nuclear Structure; Pathway interactions; Periodicity; Play; Predisposition; Regulation; Regulatory Pathway; Reporter; Repression; Resistance; Role; Signal Transduction; Testing; Therapeutic Intervention; Therapeutic antibodies; Tuberculosis; Up-Regulation; Vaccine Therapy; Virus; Virus Diseases; Work; adaptive immunity; anakinra; antagonist; antiviral immunity; cytokine; human morbidity; human mortality; mortality; neutrophil; new therapeutic target; novel; pathogen; pathogenic bacteria; prevent; response; restraint

Project Summary/Abstract (Project 3, Vance) Intracellular bacterial pathogens remain a major cause of human mortality and morbidity. By working collaboratively with other P01 Projects, we focus in Project 3 on the role of type I interferons (IFNs) in the innate immune response to three intracellular bacterial pathogens: Listeria monocytogenes, Mycobacterium tuberculosis, and Legionella pneumophila. As we and others have shown previously, all three pathogens induce the expression of type I IFNs via the STING pathway. 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. Indeed, our work and that of other laboratories has shown that type I IFNs tend to exacerbate infection by bacterial pathogens, including M. tuberculosis, L. pneumophila and L. monocytogenes. Our preliminary data suggest 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. Our preliminary data also suggest the existence of regulatory pathways to prevent the adverse induction of type I IFNs during bacterial infections. We identify SP140 and MORC3 as two novel negative regulators of type I IFN expression. We propose three Aims to explain why type I IFNs hinder anti-bacterial immunity and to explain how interferons are normally properly regulated during bacterial infections, in both mice and humans. In Aim 1, we test the hypothesis that type I IFNs antagonize anti-bacterial immunity via induction of IL-1 receptor antagonist, and determine the underlying mechanism. In Aim 2, we dissect the mechanism by which SP140 negatively regulates type I IFN transcription during bacterial infections. In Aim 3, we identify and characterize MORC3 as a novel negative regulator of type I IFN in human cells, and determine its function during bacterial infection.

项目摘要/摘要（Vance项目3） 细胞内细菌病原体仍然是人类死亡率和发病率的主要原因。通过工作 与其他P01项目合作，我们将重点放在项目3中 对三种细胞内细菌病原体的先天免疫反应：单核细胞增生李斯特菌，分枝杆菌 结核病和肺炎军团菌。正如我们和其他人之前所显示的那样，这三种病原体 通过STING途径诱导I型IFN的表达。但是，虽然I型IFN通常是 接受在策划抗病毒免疫中起着至关重要的作用，这是I型IFN在反应中的作用 对细菌很复杂。确实，我们的工作和其他实验室的工作表明，I型IFN倾向于 细菌病原体的加剧感染，包括结核分枝杆菌，肺炎乳杆菌和L. 单核细胞增生。我们的初步数据表明，I型IFN依赖于白介素-1 受体拮抗剂（IL-1RA）是I型IFNS恶化细菌的重要机制 感染。我们的初步数据还表明存在监管途径以防止不利 在细菌感染过程中诱导I型IFN。我们将SP140和MORC3识别为两个新型负面 I型IFN表达的调节剂。我们提出三个目标，以解释为什么I型IFNS阻碍反细菌 免疫力并解释干扰素在细菌感染期间通常如何适当调节 老鼠和人类。在AIM 1中，我们测试了I型IFNS通过抗菌免疫的假设 诱导IL-1受体拮抗剂，并确定基本机制。在AIM 2中，我们剖析了 SP140在细菌感染过程中对I型IFN转录负调节的机制。目标 3，我们将MORC3识别为人类细胞中I型IFN的新型负调节剂，并且 确定其在细菌感染期间的功能。