This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Regulatory cascades involving one of the several different delta factors allows Mycobacterium tuberculosis (Mtb) to efficiently adapt to environmental changes during infection. SigmaH is induced in response to heat, thiol-oxidative stress and phagocytosis. The Mtb delta-sigH mutant is attenuated for growth in mice. We seek to understand the molecular mechanisms by which delta SigmaH causes immunopathology during Mtb infection. We showed that SigH forms a transcriptional network with SigE, SigB and ClgR, the regulator for Clp gene regulon in Mtb (1). This network responds to cell-envelope damage. Mtb, but not the delta sigH and delta sigE mutants are able to resist this envelope damage (1). Chemical over-expression of SigB is able to reverse the hyper-susceptibility to envelope damage (1). We also show that the expression of SigH is not only induced in response to heat and oxidative stress but also in response to a non-antibiotic compound, thioridazine (THZ), which causes envelope damage (2). The induction is nullified in the delta-sigH mutant (2). Studying host-Mtb interactions in the context of the mutant offers a chance to dissect the signaling cascades that lead to immunopathology. We also show that infection of rhesus derived bone marrow macrophages (BMDMs) with the delta-sigH mutant results in higher apoptosis and delta chemokine secretion relative to infection with Mtb. In-vivo infection of rhesus macaques with the aerosols of Mtb causes rapid pulmonary TB. The pro-inflammatory cytokine and chemokine response to this infection peaks at 4 weeks and reprograms by week 13 (3). However, the animals don't survive beyond week 13. We show that animals comparably infected with the delta-sigH mutant exhibit a completely attenuated phenotype. We are now studying the immune response to this infection.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Primate Research Center Grants (P51)
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Special Emphasis Panel (ZRR1-CM-8 (01))
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Tulane University
Obstetrics & Gynecology
Schools of Medicine
New Orleans
United States
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