Mycobacterium tuberculosis enhances macrophage P-glycoprotein (MDR-1) expression and activity to promote intracellular survival

Abstract

Tuberculosis (TB) is a communicable disease caused by Mycobacterium tuberculosis (M.tb), a serious problem worldwide with over one third of the global population being infected; resulting in 1.3 million deaths. TB treatment includes a combination of 3 or more anti-TB drugs over a prolonged period of time. In the last few decades, multi drug resistant (MDR-TB) and extensively drug resistant TB (XDR-TB) strains have emerged due to the mismanaged use of anti-TB drugs. In this study, we discovered that M.tb infection increases the expression of macrophage drug efflux pump P-Glycoprotein (MDR-1) to extrude various chemical substances including the anti-TB drugs to benefit the M.tb survival. M.tb infection in macrophages suppresses the heat shock factor-1 (HSF1), a transcriptional regulator of MDR-1 through the up regulation of miR-431. Notably, the non pathogenic mycobacterium M. smegmatis or BCG did not increase the MDR-1 expression in human macrophages. Additionally, the inhibition of M.tb phoPR secretion system by pharmacological inhibitor reverses the M.tb mediated up regulation of MDR-1 in macrophages. Finally, inhibition of MDR-1 in macrophages enhances the anti TB drug mediated killing of M.tb. In conclusion, we report a novel finding that M.tb up regulates the MDR-1 in macrophages which limits the exposure of M.tb to sub-lethal concentrations of drugs that promotes M.tb survival and emergence of resistant variants.