Modern Clinical Mycobacterium tuberculosis Strains Leverage 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.