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. TB is a global health emergency of mammoth proportions, annually causing the death of almost two million people. AIDS continues to wreak havoc on a global scale, having caused 25 million deaths. The combined toll of AIDS and TB is devastating. New and efficient vaccines and drugs are urgently needed to control these pandemics. It is necessary to understand the molecular mechanisms of TB/AIDS co-infection. Nonhuman primates (NHPs) have long been recognized as excellent models of AIDS. We have established an NHP model of TB/AIDS co-infection via natural routes of infection. The immune system responds to Mtb infection by inducing granulomatous pulmonary pathology. This response is coordinated by CD4+ T lymphocytes, which are selectively depleted in mucosal immune sites including the lung during AIDS (a.k.a SIV infection of nonhuman primates). The regulation of granulomatous response is a key event, since its dysregulation can result in over-exuberant inflammation and tissue damage (immunopathology). miRNAs are small RNA molecules that act as regulators of gene-expression. Our preliminary data shows that the granulomatous immune response to Mtb infection in NHPs is accompanied by changes in the global miRNA profile, including the induction of miR-223 and miR-21 - which play roles in suppression of premature neutrophil activation and polarization of the Th immune response. Similarly miR-155, involved in the initiation of potent innate immune responses is repressed in NHP TB granulomas. We hypothesize that these changes in miRNA expression profiles regulate the granuloma response and pathology. We will study miRNA expression profiles in the lungs of NHPs exposed to low and high doses of Mtb as well as those co-infected with SIV.
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