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

• 批准号: 10426343
• 负责人: Kristin Leigh Patrick
• 金额: $ 52.5万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 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/10426343
• 关键词: Aerosols; Automobile Driving; Bacteria; Bacterial Infections; Biology; Cell Death; Chronic; Communicable Diseases; Crohn' 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

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.

项目摘要 我们对托管线粒体健康和稳态如何调节的理解有根本的差距 传染病结果。该应用的总体目的是定义 病原体诱导的线粒体损伤和宿主线粒体突变在先天免疫结果中。 巨噬细胞中的结核分枝杆菌感染（MTB）在体内和人类疾病的小鼠模型中。 由于线粒体是细菌祖先的，因此它们释放了许多相同的损伤相关的mo- 细菌感染期间激活先天免疫途径的腹膜模式（湿）。尽管他们很清楚 可能调节先天免疫力的潜力，线粒体湿的能力偏向先天免疫反应 在感染期间仍在研究。几条证据强烈认为线粒体稳态 对于控制分枝杆菌感染结果至关重要。首先，全基因组关联研究经常 在线粒体相关基因（例如LRRK2，TFAM，POLG）中鉴定SNP，以赋予对myco-的敏感性 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 与有效的先天免疫反应相关的线粒体潮湿，包括I型干扰素 压力，炎症体激活和炎症细胞死亡。该申请的中心假设 确定（1）MTB已进化为直接损坏线粒体，以增强I型IFN表达和 在富含亮氨酸的重复激酶2（LRRK2）Contry中诱导促细菌免疫重编程和（2）突变 分枝杆菌的敏感性是因为它们会损害线粒体网络稳定性并触发过多的细胞 MTB感染的巨噬细胞死亡，导致体内MTB感染期间过度炎症。完全ap- 在线粒体-MTB界面上进行生物学的良好，需要同时考虑宿主和病原体。 为此，该提案的以病原体为中心的目标1旨在确定新型的MTB毒力因素，这些因素 破坏线粒体稳态，并将线粒体潮湿的释放与I型Interferon生产联系起来 MTB感染的巨噬细胞。 AIM 2转移到主机并研究驱动的分子机制 巨噬细胞中有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，LRR​​K2G2019S。最后，AIM 3将这些巨噬细胞表型与高炎表型联系起来 在MTB感染的LRRK2G2019S小鼠中观察到，并确定是否吸毒线粒体相关因素（例如 LRRK2可以改变MTB感染的结果。该项目很重要，因为阐明了线形的作用 Drial功能障碍在加剧结核病疾病中起作用，可以设计治疗性干预措施 正确的线粒体缺陷和平衡偏斜的免疫反应以改善患者预后。这个ap- PRACH具有创新性，因为它挑战了现有的概念范式，采用了复杂的技术 在MTB研究的尖端，并利用宿主病原体两侧的PI的独特专业知识 界面。