Complement receptor (CR)-mediated phagocytosis of Mycobacterium tuberculosis by macrophages results in intracellular survival, suggesting that M. tuberculosis interferes with macrophage microbicidal mechanisms. As increases in cytosolic Ca2+ concentration ([Ca2+]c) promote phagocyte antimicrobial responses, we hypothesized that CR phagocytosis of M. tuberculosis is accompanied by altered Ca2+ signaling. Whereas the control complement (C)-opsonized particle zymosan (COZ) induced a 4.6-fold increase in [Ca2+]c in human macrophages, no change in [Ca2+]c occurred upon addition of live, C-opsonized virulent M. tuberculosis. Viability of M. tuberculosis and ingestion via CRs was required for infection of macrophages in the absence of increased [Ca2+]c, as killed M. tuberculosis or antibody (Ab)-opsonized, live M. tuberculosis induced elevations in [Ca2+]c similar to COZ. Increased [Ca2+]c induced by Ab-opsonized bacilli was associated with a 76% reduction in intracellular survival, compared with C-opsonized M. tuberculosis. Similarly, reversible elevation of macrophage [Ca2+]c with the ionophore A23187 reduced intracellular viability by 50%. Ionophore-mediated elevation of [Ca2+]c promoted the maturation of phagosomes containing live C-opsonized bacilli, as evidenced by acidification and accumulation of lysosomal protein markers. These data demonstrate that M. tuberculosis inhibits CR-mediated Ca2+ signaling and indicate that this alteration of macrophage activation contributes to inhibition of phagosome–lysosome fusion and promotion of intracellular mycobacterial survival.
Overexpression of microRNA-340-5p Ameliorates Inflammatory Response and Intracellular Survival of Mycobacterium Tuberculosis in Alveolar Type II Cells
