Inhibition of Ca(2+) signaling by Mycobacterium tuberculosis is associated with reduced phagosome-lysosome fusion and increased survival within human macrophages

• Published in: The Journal of experimental medicine Vol. 191; no. 2; pp. 287 - 302
• Main Authors: Malik, Z A, Denning, G M, Kusner, D J
• Format: Journal Article
• Language: English
• Published: United States 17.01.2000
• Subjects: Adult; Antibodies, Bacterial - immunology; Calcium - metabolism; Calcium Signaling; Cells, Cultured; Cytosol - metabolism; Humans; Lysosomes; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Macrophages - microbiology; Membrane Fusion; Mycobacterium tuberculosis - immunology; Mycobacterium tuberculosis - physiology; Phagocytosis; Phagosomes; Receptors, IgG - immunology; Zymosan - pharmacology
• ISSN: 0022-1007
• DOI: 10.1084/jem.191.2.287

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 Ca(2+) concentration (¿Ca(2+)(c)) promote phagocyte antimicrobial responses, we hypothesized that CR phagocytosis of M. tuberculosis is accompanied by altered Ca(2+) signaling. Whereas the control complement (C)-opsonized particle zymosan (COZ) induced a 4.6-fold increase in ¿Ca(2+)(c) in human macrophages, no change in ¿Ca(2+)(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 ¿Ca(2+)(c), as killed M. tuberculosis or antibody (Ab)-opsonized, live M. tuberculosis induced elevations in ¿Ca(2+)(c) similar to COZ. Increased ¿Ca(2+)(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 ¿Ca(2+)(c) with the ionophore A23187 reduced intracellular viability by 50%. Ionophore-mediated elevation of ¿Ca(2+)(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 Ca(2+) signaling and indicate that this alteration of macrophage activation contributes to inhibition of phagosome-lysosome fusion and promotion of intracellular mycobacterial survival.