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

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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.