Differential Roles of the Calcium Ion Channel TRPV4 in Host Responses to Mycobacterium tuberculosis Early and Late in Infection

Abstract

HIGHLIGHTS Mtb down-modulates TRPV4 expression in macrophagesTrpv4 À/À macrophages cannot be activated to drive phagosome maturation and NO production Trpv4-deficient mice are more resistant to Mtb TRPV4-positive macrophages in the periphery of human granuloma but not at the center

Stretching the Function of Innate Immune Cells

“…Increased cytosolic Ca 2+ is necessary for proper phagosome maturation. M. tuberculosis can inhibit TRPV4 expression in macrophages, reducing intracellular Ca 2+ resulting in dysfunctional delivery of mycobacteria to phago-lysosomal components and impaired acidification of phagosomes, which are necessary for effective infection control ( 47 ). TRPV4 -/- mice had higher mycobacterial colony counts after aerosolization into the lung compared with wild-type mice, and hence impaired control of the initial M. tuberculosis infection (24-48 hours after aerosolization) ( 47 ).…”

“…M. tuberculosis can inhibit TRPV4 expression in macrophages, reducing intracellular Ca 2+ resulting in dysfunctional delivery of mycobacteria to phago-lysosomal components and impaired acidification of phagosomes, which are necessary for effective infection control ( 47 ). TRPV4 -/- mice had higher mycobacterial colony counts after aerosolization into the lung compared with wild-type mice, and hence impaired control of the initial M. tuberculosis infection (24-48 hours after aerosolization) ( 47 ). Interestingly, despite worse control of initial infection, TRPV4 -/- mice had improved control of chronic infection at 150 days, as shown by reduced colony forming units compared to wild-type mice ( 47 ).…”

“…TRPV4 -/- mice had higher mycobacterial colony counts after aerosolization into the lung compared with wild-type mice, and hence impaired control of the initial M. tuberculosis infection (24-48 hours after aerosolization) ( 47 ). Interestingly, despite worse control of initial infection, TRPV4 -/- mice had improved control of chronic infection at 150 days, as shown by reduced colony forming units compared to wild-type mice ( 47 ). Improved control of chronic infection was proposed to be secondary to decreased interferon-γ (INF-γ) and diminished neutrophil-driven inflammation in the TRPV4 KO mice ( 47 ).…”

“…Interestingly, despite worse control of initial infection, TRPV4 -/- mice had improved control of chronic infection at 150 days, as shown by reduced colony forming units compared to wild-type mice ( 47 ). Improved control of chronic infection was proposed to be secondary to decreased interferon-γ (INF-γ) and diminished neutrophil-driven inflammation in the TRPV4 KO mice ( 47 ). M. tuberculosis infection results in significant scaring which changes the mechanical properties of the lung.…”

“…Although TRPV4-dependant control of M. tuberculosis in macrophages has not yet been shown to be tissue-stiffness initiated, macrophage function is influenced by a stiffness-dependent mechanism via TRPV4 ( 46 ). Furthermore, M. tuberculosis also induces TRPV4 protein expression in macrophages, suggesting a complex interaction between TRPV4, M. tuberculosis , and the mechanical properties of the lung matrix ( 47 ). This is a fruitful area for future investigation.…”