THE CRUCIAL ROLE OF M TUBERCULOSIS SIGMA-H IN IMMUNOPATHOLOGY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Regulatory cascades involving one of the several different sigma factors likely allows Mycobacterium tuberculosis (Mtb) to efficiently adapt to environmental changes during infection. sigma H is induced in response to heat, thiol-oxidative stress and phagocytosis. The unique "reduced immunopathology in spite of comparable tissue persistence" phenotype associated with the Mtb-sigma H mutant has recently been verified by us in rhesus macaques. Animals infected with Mtb developed active TB, characterized by extensive lung granulomatous histopathology, while animals infected with the sigma H mutant exhibited markedly reduced pathology, in the wake of comparable bacillary burden. We now seek to understand the molecular mechanisms by which sigmaH causes immunopathology during Mtb infection. In absence of sigma H, induction of thioredoxin regulon and Clp proteolytic machinery is compromised. Several Mtb proteins involved in recruiting and activating immune effector cells are damaged by the host oxidative burst. We hypothesize that these oxidized proteins are now inefficient at eliciting effector cells and stimulating cytokine/chemokine-mediated signaling cascades, apparently, due to the lack of induced levels of thioredoxin-thioredoxin reductase and Clp proteases, in the delta-sigma H mutant. We further hypothesize that these deficiencies impair the mutant's ability to cause immunopathology. Conversely, upon infection with Mtb, one or more sigma H-dependent factors interact with and provoke the host immune system into causing immunopathological damage. Studying host-Mtb interactions in the context of the delta-sigma H mutant offer a chance to dissect the signaling cascades that lead to immunopathology. Such knowledge may open new avenues towards the future control and therapeutics of TB.