Executive Summary : | Mycobacterium tuberculosis enters macrophages through a complex interplay between mycobacterial factors and host effectors. Cell autonomous defense mechanisms, including phagocytosis, autophagy, and apoptosis, play crucial roles in determining infection fate. Autophagy, a key defense mechanism, can degrade mycobacteria by enhancing lysosomal targeting and overcoming the phagosome maturation block exerted by the pathogen. Autophagy is essential for cellular homeostasis and degrades damaged cellular cargos, such as mitochondria, ER, and protein aggregates, which could damage cellular survival and trigger inflammation. Mitochondria, the most important cargo to be degraded via autophagy, is the most important to be degraded via autophagy. Preliminary investigations suggest that mitochondrial quality control (MQC), which involves processes like mitophagy, proteasomal degradation of mitochondrial proteins, and mitochondria-derived vesicles (MDV), is involved in deciding infection fate and anti-bacterial autophagy (xenophagy). Any shift in mitochondrial dynamics negatively impacts bacterial survival, suggesting that the inherent crosstalk between the host and mitochondria achieves an optimal balance, allowing the pathogen to ensure prolonged survival within macrophages. This proposal aims to investigate mechanisms regulating the dynamic balance between mitophagy and MDV biogenesis, factors regulating their biogenesis and recruitment to bacterial phagosomes, and explore ways to target mitochondrial quality control for enhanced bacterial killing as a host-directed therapy strategy. |