Cell death at the cross roads of host-pathogen interaction in Mycobacterium tuberculosis infection

Tuberculosis (TB) continues to be the leading cause of death by any single infectious agent, accounting for around 1.7 million annual deaths globally, despite several interventions and support programs by national and international agencies. With the development of drug resistance in Mycobacterium tuberculosis (M. tb), there has been a paradigm shift in TB research towards host-directed therapy. The potential targets include the interactions between host and bacterial proteins that are crucial for pathogenesis. Hence, collective efforts are being made to understand the molecular details of host-pathogen interaction for possible translation into host-directed therapy. The present review focuses on 'host cell death modalities' of host-pathogen interaction, which play a crucial role in determining the outcome of TB disease progression. Several cell death modalities that occur in response to mycobacterial infection have been identified in human macrophages either as host defences for bacterial clearance or as pathogen strategies for multiplication and dissemination. These cell death modalities include apoptosis, necrosis, pyroptosis, necroptosis, pyronecrosis, NETosis, and autophagy. These processes are highly overlapping with several mycobacterial proteins participating in more than one cell death pathway. Until now, reviews in M. tb and host cell death have discussed either focusing on host evasion strategies, apoptosis, autophagy, and necrosis or describing all these forms with limited discussions of their role in host-pathogen interactions. Here, we present a comprehensive review of various mycobacterial factors modulating host cell death pathways and the cross-talk between them. Besides this, we have discussed the networking of host cell death pathways including the interference of host miRNA during M. tb infection with their respective targets. Through this review, we present the host targets that overlap across several cell death modalities and the technical limitations of methodology in cell death research. Given the compelling need to discover alternative drug target(s), this review identifies these overlapping cell death factors as potential targets for host-directed therapy.