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

Abstract

Recent developments in TB treatment have identified an enormous potential of host targeting entities (host directed therapies-HDT) in achieving better and faster control of infection. We have previously demonstrated the synergistic effect of sertraline with frontline TB drugs in clearing infection in murine tissues. We surmised that understanding the mechanism of sertraline mediated enhancement of antibiotic efficacy would help identify novel pathways of pathogen control. Here, we have used sertraline as a probe to identify host signaling pathways that are important for bacterial control. We identify a role for sertraline mediated modulation of macrophage mitochondrial physiology in this process. We show that the resultant ROS generated in cells acts as the secondary signal for host cell inflammasome activation catalyzing the greater release of IL1beta; and significant efflux of K+ from the SRT treated macrophages. We thus highlight an important relationship between mitochondrial physiology in regulating the activation of the inflammasome to achieve better control of Mtb by infected macrophages.