Host phagocytes respond to infections by innate defense mechanisms through metabolic shuffling to restrict the invading pathogen. However, this very plasticity of the host provides an ideal platform for pathogen-mediated manipulation. In the human (THP1/THP1 dual/PBMC-derived monocyte-derived macrophages) and mouse (RAW264.7 and C57BL/6 bone marrow-derived) macrophage models of Mycobacterium tuberculosis infection, we have identified an important strategy employed by clinical lineages in regulating the host immune-metabolism axis. We show greater transit via the macrophage phagosomal compartments by Mycobacterium tuberculosis strains of lineage: M. tuberculosis lineage 3 is associated with an ability to elicit a strong and early type I IFN response dependent on DNA (in contrast with the protracted response to lineage: M. tuberculosis lineage 1). This augmented IFN signaling supported a positive regulatory loop for the enhanced expression of IL-6 consequent to an increase in the expression of 25-hydroxycholesterol in macrophages. This amplification of the macrophage innate response-metabolic axis incumbent on a heightened and early type I IFN signaling portrays yet another novel aspect of improved intracellular survival of clinical M. tuberculosis strains.
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