MprA and DosR Coregulate a Mycobacterium tuberculosis Virulence Operon EncodingRv1813candRv1812c

Abstract

ABSTRACTMycobacterium tuberculosisremains a significant global pathogen, causing extensive morbidity and mortality worldwide. This bacterium persists within granulomatous lesions in a poorly characterized, nonreplicating state. The two-component signal transduction systems MprAB and DosRS-DosT (DevRS-Rv2027c) are responsive to conditions likely to be present within granulomatous lesions and mediate aspects ofM. tuberculosispersistencein vitroandin vivo. Here, we describe a previously uncharacterized locus,Rv1813c-Rv1812c, that is coregulated by both MprA and DosR. We demonstrate that MprA and DosR bind to adjacent and overlapping sequences within the promoter region ofRv1813cand direct transcription from an initiation site located several hundred base pairs upstream of theRv1813translation start site. We further show thatRv1813candRv1812care cotranscribed, and that the genomic organization of this operon is specific toM. tuberculosisandMycobacterium bovis. AlthoughRv1813cis not required for survival ofM. tuberculosisin vitro, including under conditions in which MprAB and DosRST signaling are activated, anM. tuberculosisΔRv1813cmutant is attenuated in the low-dose aerosol model of murine tuberculosis, where it exhibits a lower bacterial burden, delayed time to death, and decreased ability to stimulate proinflammatory cytokines interleukin-1β (IL-1β) and IL-12. Interestingly, overcomplementation of these phenotypes is observed in theM. tuberculosisΔRv1813cmutant expressing bothRv1813candRv1812c, but notRv1813calone, intrans. Therefore, Rv1813c and Rv1812c may represent general stress-responsive elements that are necessary for aspects ofM. tuberculosisvirulence and the host immune response to infection.