Role of Alkylhydroperoxidase Rv2159c in the Oxidative Stress Response and Virulence of Mycobacterium tuberculosis

<p><em>Mycobacterium tuberculosis</em>, which&nbsp;causes tuberculosis, is one of the leading infectious agents worldwide with a high rate of mortality. Following aerosol inhalation,&nbsp;<em>M. tuberculosis</em>&nbsp;primarily infects the alveolar macrophages, which results in a host immune response that gradually activates various antimicrobial mechanisms, including the production of reactive oxygen species (ROS), within the phagocytes to neutralize the bacteria.&nbsp;<em>OxyR</em>&nbsp;is the master regulator of oxidative stress response in several bacterial species. However,&nbsp;due to the absence of a functional&nbsp;<em>oxyR&nbsp;</em>locus in&nbsp;<em>M. tuberculosis,</em>&nbsp;the peroxidase stress is controlled by alkylhydroperoxidases.&nbsp;<em>M. tuberculosis&nbsp;</em>expresses alkylhydroperoxide reductase to counteract the toxic effects of ROS.&nbsp;In the current study, we report the functional characterization of an ortholgue of alkylhydroperoxidase family member, Rv2159c, a conserved protein with putative peroxidase activity, during stress response and virulence of&nbsp;<em>M. tuberculosis</em><em>.&nbsp;</em>We generated a&nbsp;gene knockout mutant of&nbsp;<em>M. tuberculosis&nbsp;</em>Rv2159c (Mtb&Delta;2159) by specialized transduction. The Mtb&Delta;2159&nbsp;was sensitive to oxidative stress and exposure to toxic transition metals. In a human monocyte (THP-1) cell infection model,&nbsp;Mtb&Delta;2159 showed reduced intracellular survival and increased expression of pro-inflammatory molecules, includingIL-1&beta;, IP-10 and MIP-1&alpha;, compared to the wild type&nbsp;<em>M. tuberculosis</em>&nbsp;and&nbsp;Rv2159c-complemented&nbsp;Mtb&Delta;2159 strains. Similarly, in a guinea pig model of pulmonary infection, Mtb&Delta;2159 displayed growth attenuation in the lungs, compared to the wild type&nbsp;<em>M. tuberculosis</em>&nbsp;and&nbsp;Rv2159c-complemented&nbsp;Mtb&Delta;2159 strains<em>.&nbsp;</em>Our study suggests that Rv2159c has a significant role in maintaining the cellular homeostasis during stress and virulence of&nbsp;<em>M. tuberculosis</em>.&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</p>