Rv0687 a Putative Short-Chain Dehydrogenase is indispensable for pathogenesis ofMycobacterium tuberculosis

Abstract

AbstractMycobacterium tuberculosis (Mtb),a successful human pathogen, resides in host sentinel cells and combats the stressful intracellular environment induced by reactive oxygen and nitrogen species during infection.Mtbemploys several evasion mechanisms in the face of the host as a survival strategy, including detoxifying enzymes as short-chain dehydrogenases/ reductases (SDRs) to withstand host-generated insults. In this study, using specialized transduction we have generated a Rv0687 deletion mutant and its complemented strain and investigated the functional role of Rv0687, a member of SDRs family genes inMtbpathogenesis. Wildtype (WT) and mutantMtbstrain lacking Rv0687 (RvΔ0687) were tested forin-vitrostress response andin-vivosurvival in macrophages and mice models of infection. The study demonstrates that Rv0687 is crucial for sustaining bacterial growth in nutrition-limited conditions. The deletion of Rv0687 elevated the sensitivity ofMtbto oxidative and nitrosative stress-inducing agents. Furthermore, the lack of Rv0687 compromised the survival ofMtbin primary bone marrow macrophages and led to an increase in the levels of the secreted proinflammatory cytokines TNF-α, and MIP-1α. Interestingly, the growth of WT and RvΔ0687 was similar in the lungs of infected immunocompromised mice however, a significant reduction in RvΔ0687 growth was observed in the spleen of immunocompromised Rag-/-mice at 4 weeks post-infection. Moreover Rag-/-mice infected with RvΔ0687 survived longer compared to WTMtbstrain. Additionally, we observed significant reduction in bacterial burden in spleens and lungs of immunocompetent C57BL/6 mice infected with RvΔ0687 compared to complemented and WTMtbstrains. Collectively, this study reveals that Rv0687 plays a role inMtbpathogenesis.