Modern clinical Mtb strains leverage the type I IFN pathway for a pro-inflammatory response in the host

Host phagocytes respond to infections by innate defense mechanisms through metabolic shuffling in order to restrict the invading pathogen. However, this very plasticity of the host provides an ideal platform for pathogen mediated manipulation. By employing the macrophage model of Mtb infection, we identify an important strategy employed by modern clinical lineages in regulating the host immune-metabolism axis. The potent ability of these strains to specifically elicit a strong and early macrophage type I IFN response (in contrast to the protracted response to ancient Mtb), was dependent on an increased ability to localize in acidified phagosomes; this higher transit via acidified compartments is important for stimulation of the DNA dependent signaling in infected macrophages. The augmented IFN signaling provided a positive regulatory loop for enhanced expression of the cellular oxysterol-CH25H which in turn facilitated higher levels of IL6 in macrophages infected with the modern Mtb strains. Requirement of type I IFN signaling in mycobacterial intracellular growth highlights another unique ability of Mtb to manipulate host cell physiology and proinflammatory responses.\n\nSignificance StatementCo-evolution with humans has enabled the development of novel adaptive mechanisms for survival in host specific environments in the human TB pathogen-Mtb. We present one such mechanism of modern Mtb strains harnessing the type I IFN immune axis to regulate the host pro-inflammatory response. Our results highlight the use of host intracellular endosomal transit as a mechanism by these strains to ensure a strong type I IFN response in macrophages. We also demonstrate the ability of Mtb to regulate macrophage cholesterol metabolism in order to fine tune the host innate responses. These findings lay the foundation of the future development of a host axis directed intervention strategy against this pathogen.