Modern Clinical Mycobacterium tuberculosis Strains Leverage Type I IFN Pathway for a Proinflammatory Response in the Host

Abstract

Abstract 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.