Interferons shape the interface between macrophages and Mycobacterium tuberculosis: lessons from latency and metabolic mechanisms

Abstract

Humans and Mycobacterium tuberculosis (Mtb) have been co-evolving for tens of thousands of years. Although Mtb remains the deadliest bacterial infection globally, most exposed individuals control the infection either through clearance or containment and never develop disease. While a quarter of the entire human population has been exposed to Mtb, how a contained Mtb infection (CMTB) alters the biology of the host remains poorly understood. The beginning of this dissertation investigates how CMTB alters immune responses in a mouse model. CMTB rapidly and durably reduces tuberculosis disease burden after re-exposure through aerosol challenge and also protects against heterologous challenges with Listeria monocytogenes or metastatic melanoma. Protection is associated with activation of alveolar macrophages, the first cells that respond to inhaled Mtb, and accelerated recruitment of Mtb-specific T cells to the lung parenchyma. RNA sequencing, ex vivo functional assays, and in vivo infections demonstrate that CMTB reconfigures tissue resident alveolar macrophages via exposure to low-grade interferon γ, a type II interferon (IFN). These studies demonstrate that under certain circumstances, the continuous interaction of the immune system with Mtb is beneficial to the host by maintaining elevated innate immune responses. To better understand the molecular interface between macrophages and Mtb, we turn to a more tractable in vitro model of Mtb infection. Metabolic reprogramming powers and polarizes macrophage functions, but the nature and regulation of this response during infection with pathogens remain controversial. We characterize the metabolic and transcriptional responses of murine macrophages to Mtb in order to disentangle the underlying mechanisms. We find that type I IFN signaling correlates with the decreased glycolysis and mitochondrial damage that is induced by live, but not killed, Mtb. Macrophages lacking the type I IFN receptor maintain glycolytic flux and mitochondrial function during Mtb infection in vitro and, importantly, in vivo. IFNβ itself restrains the glycolytic shift of inflammatory macrophages and initiates mitochondrial stress. We confirm that type I IFN acts upstream of mitochondrial damage using macrophages lacking the protein STING. We suggest that a type I IFN – mitochondrial feedback loop controls macrophage responses to mycobacteria and that this could contribute to pathogenesis across a range of diseases. Overall, this dissertation provides new insights into the interface between the immune system and Mtb at both the organismal and molecular scales. The evidence of beneficial effects of CMTB on organismal health raises many questions about how the immune system responds to contained or latent Mtb. We posit that extending the molecular mechanisms controlling the macrophage metabolic response described here will be a critical first step in addressing these questions.