Mitochondria as crucial regulators of innate immune outcomes during Mycobacterium tuberculosis infection

线粒体作为结核分枝杆菌感染期间先天免疫结果的关键调节因子

基本信息

批准号：
10298524
负责人：
Kristin Leigh Patrick
金额：
$ 66.31万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-10 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10298524
关键词：
Aerosols Automobile Driving Bacteria Bacterial Infections Biology Cell Death Chronic Communicable Diseases Crohn&apos s disease Cytosol Data Defect Disease Disease Outcome Dose ELF3 gene Ectopic Expression Environment Equilibrium Genes Genetic Predisposition to Disease Guanosine Triphosphate Phosphohydrolases Health Homeostasis Human IRF3 gene Immune Immune response Infection Inflammasome Inflammation Inflammatory Innate Immune Response Interferon Type I Interferons Knock-in Mouse Knowledge LRRK2 gene Ligands Link Mediating Mitochondria Mitochondrial DNA Modeling Molecular Mus Mutation Mycobacterium Infections Mycobacterium tuberculosis Natural Immunity Nature Outcome Outer Mitochondrial Membrane PARK2 gene PINK1 gene Parkinson Disease Pathogenesis Pathogenicity Pathway interactions Patient-Focused Outcomes Patients Pattern Phagosomes Pharmaceutical Preparations Pharmacology Phenotype Phosphotransferases Play Predisposition Production Proteins Research Role Severities Severity of illness Side Stimulator of Interferon Genes System Technology Therapeutic Therapeutic Intervention Tuberculosis Tweens Virulence Factors base design ds-DNA experimental study genome wide association study human disease human model improved in vivo innate immune pathways innovation insight interest leucine-rich repeat protein macrophage mitochondrial dysfunction mouse model mutant mycobacterial novel pathogen response sensor synergism therapeutic target treatment planning

项目摘要

PROJECT SUMMARY There is a fundamental gap in our understanding of how host mitochondrial health and homeostasis modulate infectious disease outcomes. The overall objective of this application is to define the molecular contributions of pathogen-induced mitochondrial damage and host mitochondrial mutations to innate immune outcomes during Mycobacterium tuberculosis (Mtb) infection in macrophages ex vivo and in mouse models of human disease. Because mitochondria are of bacterial ancestral origin, they release many of the same damage-associated mo- lecular patterns (DAMPs) that activate innate immune pathways during bacterial infection. In spite of their clear potential to regulate innate immunity, the ability of mitochondrial DAMPs to skew innate immune responses during infection remains understudied. Several lines of evidence strongly argue that mitochondrial homeostasis is crucial for controlling mycobacterial infection outcomes. First, genome-wide association studies frequently identify SNPs in mitochondrial-associated genes (e.g. LRRK2, TFAM, POLG) that confer susceptibility to myco- bacterial infection. Second, mycobacterial infection itself has been shown to damage mitochondria and release mitochondrial DAMPs that are associated with potent innate immune responses, including type I interferon ex- pression, inflammasome activation, and inflammatory cell death. The central hypotheses of this application pre- dict that (1) Mtb has evolved to damage mitochondria directly in order to enhance type I IFN expression and induce pro-bacterial immune reprogramming and (2) mutations in leucine rich repeat kinase 2 (LRRK2) confer mycobacterial susceptibility because they compromise mitochondria network stability and trigger excessive cell death in Mtb-infected macrophages, which leads to hyperinflammation during Mtb infection in vivo. To fully ap- preciate the biology at the mitochondrial-Mtb interface, one needs to consider both the host and the pathogen. To this end, pathogen-focused Aim 1 of this proposal is designed to identify novel Mtb virulence factors that disrupt mitochondrial homeostasis and link the release of mitochondrial DAMPs to type I interferon production in Mtb-infected macrophages. Aim 2 shifts focus to the host and investigates the molecular mechanisms that drive mitochondrial damage and inflammatory cell death pathways in macrophages that harbor a common human mutation, Lrrk2G2019S. Lastly, Aim 3 will link these macrophage phenotypes to the hyperinflammatory phenotype observed in Mtb-infected Lrrk2G2019S mice and determine whether drugging mitochondrial-associated factors like LRRK2 can alter the outcome of Mtb infection. This project is significant because elucidating the role mitochon- drial dysfunction plays in exacerbating tuberculosis disease enables the design of therapeutic interventions that correct mitochondrial defects and balance skewed immune responses to improve patient outcomes. This ap- proach is innovative because it challenges existing conceptual paradigms, employs sophisticated technologies at the cutting-edge of Mtb research, and leverages the unique expertise of PIs on each side of the host-pathogen interface.

项目概要我们对宿主线粒体健康和体内平衡如何调节的理解存在根本差距传染病的结果。该应用程序的总体目标是定义分子贡献病原体诱导的线粒体损伤和宿主线粒体突变对先天免疫结果的影响离体巨噬细胞和人类疾病小鼠模型中的结核分枝杆菌 (Mtb) 感染。因为线粒体是细菌祖先起源的，所以它们释放许多与损伤相关的相同分子在细菌感染期间激活先天免疫途径的分子模式（DAMP）。尽管他们明确调节先天免疫的潜力，线粒体 DAMP 扭曲先天免疫反应的能力感染期间的情况仍有待研究。几条证据有力地证明线粒体稳态对于控制分枝杆菌感染结果至关重要。首先，全基因组关联研究频繁识别线粒体相关基因（例如 LRRK2、TFAM、POLG）中赋予真菌易感性的 SNP 细菌感染。其次，分枝杆菌感染本身已被证明会损害线粒体并释放线粒体 DAMP 与有效的先天免疫反应相关，包括 I 型干扰素前体压力、炎症小体激活和炎症细胞死亡。本申请的中心假设是指出 (1) Mtb 已进化为直接损伤线粒体，以增强 I 型 IFN 表达，并且诱导亲细菌免疫重编程和 (2) 富含亮氨酸重复激酶 2 (LRRK2) 的突变分枝杆菌易感性，因为它们会损害线粒体网络稳定性并引发过多的细胞 Mtb感染的巨噬细胞死亡，从而导致体内Mtb感染期间的过度炎症。为了充分应用为了阐明线粒体-结核分枝杆菌界面的生物学特性，需要同时考虑宿主和病原体。为此，本提案以病原体为重点的目标 1 旨在确定新型 Mtb 毒力因子，破坏线粒体稳态并将线粒体 DAMP 的释放与 I 型干扰素的产生联系起来 Mtb 感染的巨噬细胞。目标 2 将焦点转移到宿主并研究驱动的分子机制含有共同人类的巨噬细胞中的线粒体损伤和炎症细胞死亡途径突变，Lrrk2G2019S。最后，目标 3 将这些巨噬细胞表型与高炎症表型联系起来在 Mtb 感染的 Lrrk2G2019S 小鼠中观察到，并确定是否给线粒体相关因子（如 LRRK2 可以改变 Mtb 感染的结果。该项目意义重大，因为阐明了线粒体的作用干燥功能障碍会加剧结核病，因此可以设计治疗干预措施纠正线粒体缺陷并平衡倾斜的免疫反应，以改善患者的治疗结果。这个应用程序 Proach 具有创新性，因为它挑战了现有的概念范式，采用了先进的技术处于 Mtb 研究的前沿，并利用 PI 在宿主病原体各方面的独特专业知识界面。