Type II-NDHs in M. tuberculosis respiration and persistence

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 DESCRIPTION (provided by applicant): Mycobacterium tuberculosis is an acid-fast, human-specific pathogen and is the etiological agent of the respiratory disease tuberculosis (TB). Approximately 2 billion individuals are currently predicted to be latently infected with the tuberce bacillus. During latency, M. tuberculosis exists within host-generated granulomatous lesions in a poorly understood physiological state termed non-replicating persistence (NRP). It is generally thought that specific conditions initially encountered within granulomatous lesions, including oxygen-limitation and nitric oxide, inhibit aerobic respiration and induce the transition of M. tuberculosis into NRP for long-term survival during anaerobic dormancy. Aerobic and anaerobic respiration in M. tuberculosis is mediated in part by NADH dehydrogenases (NDH), enzymes which catalyze the oxidation of NADH to NAD+ with concomitant transfer of electrons to respiratory chain components. M. tuberculosis encodes one type-1 NDH and two type-2 NDHs. Recently, we identified a third predicted type-2 NDH (Rv1812c) that is regulated by determinants/conditions associated with M. tuberculosis persistence. Preliminary investigations described in this application indicate that Rv1812c encodes a type-2 NDH and participates in the resuscitation of M. tuberculosis from anaerobic dormancy. In addition, we provide bioinformatic evidence indicating that Rv1812c possesses unique structural, functional, and expression characteristics that distinguish it from the other two established type-2 NDHs (Ndh and NdhA) produced in M. tuberculosis. The two specific aims proposed in this application will allow us to investigate and compare the activities of the three type-2 NDHs produced in M. tuberculosis, and determine whether Rv1812c is required for M. tuberculosis NRP or its resuscitation from latency in vivo.