Identifying innate immune regulators of Mycobacterium tuberculosis pathogenesis in macrophages

Abstract

Abstract Tuberculosis (TB) is a leading infectious disease that contributes to approximately 1.4 million deaths annually worldwide. In the present situation of the COVID-19 pandemic and disrupted healthcare services, mathematical modelling predicts that there will be an additional 6.3 million new cases and 1.4 million more TB deaths by the end of 2025. Innate immune cells like macrophages are the frontline responders in host defense against Mycobacterium tuberculosis (MTB) and may also play a major role in disease establishment. A major roadblock in developing effective strategies against TB is the inability of current anti-TB drugs to target both replicating and non-replicating bacteria. We have found that lack of specific components of the host innate sensing machinery has a major impact on intracellular bacterial growth and the production of IL-1β and IFN-β during MTB infection of macrophages; the latter cytokines play major roles in host-protective and host-detrimental outcomes of infection respectively. RNA seq reveals that these innate immune modules differentially control the expression of genes implicated in host protein synthesis and MTB dissemination and escape from the granuloma. Ongoing work is utilizing Path-Seq for quantitative profiling of the MTB transcriptome within infected macrophages and investigating macrophage-dependent mechanisms of MTB restriction and persistence in vivo. Our study will potentially identify immune regulators that make the macrophage environment either permissive or restrictive for intracellular replication of MTB with important implications for developing combinatorial targeting approaches for host-directed treatment of TB.