Malat1 and COP1 mediated host responses orchestrate mycobacterial pathogenesis

Abstract

Tuberculosis, which is caused by Mycobacterium tuberculosis (Mtb), is viewed to be the predominant cause of death arising due to bacterial infection. Further, the emergence of MDR/XDR strains and co-infections has compounded the graveness of the disease. In this perspective, the modulation of host signaling pathways and associated epigenetic factors have been widely accepted. The current study focuses on two key regulators, lncRNA Malat1 and E3 ubiquitin ligase COP1 that are modulated during the mycobacterial infection and Mtb-C. albicans co-infection respectively. These studies as detailed, demonstrate the roles for dynamic interplay of signaling pathways and epigenetic factors in governing host-mycobacterial interactions. First part of thesis discusses crucial role of Malat1 during mycobacterial infection. Malat1 mediates differential expression of a distinct repertoire of genes involved in maintaining lipid equilibrium via discrete regulation of the host epigenome. Further, pFAK-pCREB responsive Malat1 expression enhances the recruitment of EZH2 over target genes such as Abca1 and Abcg1. Analysis of the detailed molecular events revealed Mtb-driven association and differential recruitment of Malat1 with specific ATP-dependent chromatin remodeler at the promoters of genes responsible for lipid biosynthesis and uptake. In line with these observations, Malat1 knockout mice were utilized to demonstrate that Malat1 supports the lipid rich environment in macrophages which is conducive for mycobacterial growth. Thus, these findings append critically relevant information to the emerging field of lncRNAs in TB infections; and highlight the prospects of utilizing lncRNAs as potential biomarkers and as efficacious targets to curb tuberculosis alongside conventional anti-TB therapeutics. Second part of the thesis discusses modulation of pyroptosis upon Mycobacterium tuberculosis and Candida albicans coinfection. It reports that IRF9 plays cardinal role in C. albicans induced pyroptosis and prior infection with M. tuberculosis results in inhibition of C. albicans induced pyroptosis. It was observed that COP1 (an E3 ubiquitin ligase) which is induced upon Mtb infection leads to poly-ubiquitination of IRF9 followed by its proteasomal degradation and hence C. albicans infection fails to execute pyroptosis. Further, PKCζ -AMPK-WNT signaling axis was found to be responsible for induction of COP1. Altogether, here the intriguing molecular cross talk during C. albicans and M. tuberculosis coinfection is reported for the first time and pyroptosis is established as an important regulator for host survival during co-infection. Overall, the thesis provides the mechanism of action of Malat1 along with BRG1 and EZH2, in fine tuning host responses during mycobacterial pathogenesis. Further, insights into the extensive implication of signalling cross-talk during the M. tuberculosis and C. albicans co-infection in coining the outcome of C. albicans infections. Such detailed investigations confer a holistic perspective of host-pathogen interactions and bear potential in effective disease control by aiding the search for efficacious therapeutics.