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 我们对宿主线粒体健康和稳态如何调节的理解存在根本性差距 传染病的结果。本申请的总体目标是定义以下的分子贡献： 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 体外巨噬细胞和人类疾病小鼠模型中的结核分枝杆菌（Mtb）感染。 由于线粒体是细菌祖先的起源，它们释放许多相同的损伤相关的mo- 在细菌感染期间激活先天免疫途径的细胞模式（DAMP）。尽管他们的明确 调节先天免疫的潜力，线粒体DAMP扭曲先天免疫反应的能力 在感染过程中的作用还未得到充分研究。有几条证据有力地证明了线粒体内稳态 是控制分枝杆菌感染结果的关键。首先，全基因组关联研究经常 鉴定尿道相关基因（例如LRRK 2、TFAM、POLG）中赋予对真菌易感性的SNP， 细菌感染其次，分枝杆菌感染本身已被证明会破坏线粒体并释放 线粒体DAMP与强效先天免疫应答相关，包括I型干扰素前体， 表达、炎性体活化和炎性细胞死亡。本申请的中心假设是， 结论：（1）Mtb已经进化到直接损伤线粒体以增强I型IFN的表达， 诱导前细菌免疫重编程和（2）富含亮氨酸重复序列激酶2（LRRK 2）突变赋予 分枝杆菌的易感性，因为它们损害线粒体网络的稳定性，并引发过多的细胞 Mtb感染的巨噬细胞死亡，这导致体内Mtb感染期间的过度炎症。为了充分利用- 为了更好地理解宿主-结核分枝杆菌界面的生物学，需要同时考虑宿主和病原体。 为此，本提案的以病原体为重点的目标1旨在鉴定新的Mtb毒力因子， 破坏线粒体内稳态，并将线粒体DAMP的释放与I型干扰素的产生联系起来， 结核杆菌感染的巨噬细胞。目标2将焦点转移到宿主上，并研究了驱动细胞凋亡的分子机制。 线粒体损伤和炎症细胞死亡途径的巨噬细胞， 突变，Lrrk 2G 2019 S。最后，Aim 3将这些巨噬细胞表型与高炎症表型联系起来 在结核分枝杆菌感染的Lrrk 2G 2019 S小鼠中观察，并确定是否给药与肿瘤相关的因素，如 LRRK 2可以改变结核分枝杆菌感染的结果。这个项目是重要的，因为阐明作用mitochon- 骨髓功能障碍在加重结核病中的作用使得能够设计治疗干预措施， 纠正线粒体缺陷和平衡失衡的免疫反应，以改善患者的预后。这个ap- 方法是创新的，因为它挑战现有的概念范式，采用先进的技术， 在结核病研究的前沿，并利用独特的专业知识的PI对每一方的主机病原体 接口.