Hypothetical geneRv0495cregulates redox homeostasis inMycobacterium tuberculosis

Abstract

Mycobacterium tuberculosis(Mtb) has evolved sophisticated surveillance mechanisms to regulate and neutralize redox imbalances and associated lethal consequences. Failing this, the accumulated ROS induces toxicity by oxidizing a variety of biological molecules including proteins, nucleic acids and lipids. In the present study we identified Mtb’sRv0495cgene as an important regulator of oxidized cytosolic environment. Compared to wild type Mtb strain lackingthe Rv0495cgene, ΔRv0495c, had increased ROS and NAD+/NADH ratio creating a highly oxidized intracellular environment. ΔRv0495cstrain demonstrated slow growth phenotype underin vitroandex-vivogrowth conditions and demonstrated enhanced susceptibility to drugs, oxidative, nitrosative and hypoxic growth conditions. In addition, the increase in the superoxide radicals triggered a Fenton-like reaction rendering the ΔRv0495csusceptible to free iron. The increase in the intracellular ROS levels of the ΔRv0495cwas further corroborated by an increase in the expression of proteins involved in antioxidant defense and enhanced ROS-mediated oxidation and degradation of mycobacterial lipids. This superoxide-induced lipid degradation resulted in altered colony morphology and loss of membrane integrity in the ΔRv0495c. Surprisingly, despite showing a growth defect phenotype in anex-vivomacrophage infection model, the absence of theRv0495cgene in Mtb enhanced the pathogenicity and augmented the ability of the Mtb to grow inside the host. Gene expression analysis revealed a Rv0495c mediated immunomodulation of the host controls inflammation and helps creates a favorable niche for long-term survival of Mtb inside the host. In summary, the current study underscores the fact that the truce in the war between the host and the pathogen favors long-term disease persistence in tuberculosis. We believe targeting Rv0495c could potentially be explored as a strategy to potentiate the current anti-TB regimen.