The alternative sigma factor SigH regulates major components of oxidative and heat stress responses in Mycobacterium tuberculosis

Mycobacterium tuberculosis is a specialized intracellular pathogen that mus t regulate gene expression to overcome stresses produced by host defenses d uring infection. SigH is an alternative sigma factor that we have previousl y shown plays a role in the response to stress of the saprophyte Mycobacter ium smegmatis. In this work we investigated the role of sigH in the M. tube rculosis response to heat and oxidative stress. We determined that a M. tub erculosis sigH mutant is more susceptible to oxidative stresses and that th e inducible expression of the thioredoxin reductase/thioredoxin genes trxB2 /trxC and a gene of unknown function, Rv2466c, is regulated by sigH via exp ression from promoters directly recognized by SigH. We also determined that the sigH mutant is more susceptible to heat stress and that inducible expr ession of the heat shock genes dnaK and clpB is positively regulated by sig H. The induction of these heat shock gene promoters but not of other SigH-d ependent promoters was markedly greater in response to heat versus oxidativ e stress, consistent with their additional regulation by a heat-labile repr essor. To further understand the role of sigH in the M. tuberculosis stress response, we investigated the regulation of the stress-responsive sigma fa ctor genes sigE and sigB. We determined that inducible expression of sigE i s regulated by sigH and that basal and inducible expression of sigB is depe ndent on sigE and sigH. These data indicate that sigH plays a central role in a network that regulates heat and oxidative-stress responses that are li kely to be important in M. tuberculosis pathogenesis.