Inflammasome activation dictates the efficacy of antimycobacterial activity of frontline TB drugs

Abstract

Recent developments in tuberculosis (TB) treatment have identified an enormous potential of host-directed therapies (HDT) in achieving better and faster control of infection. We have previously demonstrated the synergistic effect of sertraline (SRT) with frontline TB drugs in clearing infection in murine tissues. Our attempts to uncover the mechanistic basis of this enhancement, using sertraline as a probe, help identify host signalling pathways critical for controlling Mycobacterium tuberculosis (Mtb). We identify a significant role for sertraline-mediated modulation of mitochondrial physiology and consequent reactive oxygen species (ROS) generation as a secondary signal, leading to greater IL-1β release and K+ efflux from macrophages via NLRP3 inflammasome activation. We thus highlight an important relationship between mitochondrial physiology and inflammasome activation, enabling infected macrophages to better control Mtb.