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. Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is an infectious disease emergency. Each year an estimated 8 million people develop, and ~ 2 million people die of TB. New drugs and vaccines are urgently needed to effectively control TB. This requires a better understanding of how Mtb adapts to a wide-variety of environmental conditions, inevitably faced by it during the various stages of infection. Nonhuman Primates (NHPs), arguably, best model critical aspects of TB. Analysis of the mechanisms employed by Mtb to successfully infect and persist in NHP lungs would therefore be very useful. We studied genes essential for growth/survival of Mtb in the NHP lungs experimentally exposed to high doses of Mtb transposon mutants. In this acute model of TB, 33.13% of all tested mutants were attenuated for in-vivo growth compared to the mouse model where only ~6% of all mutants are attenuated. The Mtb mutants attenuated for in-vivo survival in primates were involved in the transport of lipid virulence factors;biosynthesis of cell-wall arabinan and peptidoglycan, fatty-acids and polyketides;DNA repair;sterol metabolism and mammalian cell-entry (mce). Our study highlights the various virulence-mechanisms employed by Mtb for infection and to overcome the hostile environment encountered during infection of NHP lungs. We would like to leverage our ability to model the various clinical phases of human TB - acute, pulmonary TB, chronic-progressive TB and latent, asymptomatic TB in NHPs - to study the growth/survival phenotype profiles of Mtb mutants. Further, we would like to understand the role of two Mtb pathways crucial for virulence, using the NHP model. These include the mce1/mce4 operons, whose members were among mutants that were attenuated for growth in NHP lungs;and members of the dos regulon, which were surprisingly not attenuated in NHP lungs, in-spite of their well-defined roles in latency, persistence and defense against hypoxia.
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