Mitochondrial instruction of antiviral immune responses in macrophages

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Macrophages are innate immune cells found in nearly every tissue of the body. These highly heterogeneous cells regulate inflammation, host defense and homeostatic functions including tissue remodeling and repair. They also express a wide range of pattern recognition receptors (PRR) that recognize pathogen and damage associated molecular pattern (PAMP and DAMP) molecules. This innate recognition activates tissue macrophages, which allows them to respond rapidly to local and systemic perturbations. However, these responses must be tightly regulated to limit damaging inflammation and to maintain tissue homeostasis. Mitochondria have emerged as a central regulator of innate immune function. This regulation is mediated by the dynamic modulation of mitochondrial structure and the flux of mitochondrial metabolites. While it is clear that rewiring of mitochondrial metabolism is required to meet the bioenergetic and biosynthetic demands of the cell, their specific role in regulating antiviral immune effector functions remains incompletely characterized. My research program seeks to understand how innate sensing of viral ligands by PRR rewires mitochondrial metabolism and how this rewiring contributes to the development of tissue specific antiviral responses. We hypothesize that rewiring of mitochondrial metabolism acts as an early rheostat to regulate pathogen specific immune responses, which are optimized based on the local tissue microenvironment. To test this hypothesis we will: 1) Characterize the role of mitochondrial rewiring in driving antiviral immune responses 2) Examine how nutrient availability affects mitochondrial associated antiviral immune responses 3) Evaluate how the brain microenvironment affects mitochondrial associated antiviral immune responses Our proposed work will address key gaps in understanding how cellular metabolism regulates antiviral immune responses and will provide critical insights into how the tissue microenvironment modulates this regulation. We expect to identify tissue specific biochemical targets that can be used to fine tune antiviral responses, which will have important implications for the development of new immunotherapies and to improve vaccine efficacy.