Secondary infections during mycobacterial disease

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DESCRIPTION (provided by applicant): Approximately 30% of the world's population has been infected with Mycobacterium tuberculosis, and tuberculosis has been estimated to be the leading cause of death worldwide. A significant fraction of that mortality is from weakened cellular immunity due to co-infection with other endemic infections. Anti-mycobacterial immunity is mediated primarily by CD4+ T cells, which regulate the formation of protective granulomatous inflammation to restrict pathogen dissemination and protect surrounding healthy tissue. We propose to use a mouse model of chronic tuberculosis, M. bovis strain bacille Calmette Gurin (BCG), to examine the effect of super-infection with influenza virus and the fungus Histoplasma capsulatum. We will genetically mark both the BCG and secondary pathogen with different well-characterized T cell epitopes. Using epitope specific class ll tetramer staining reagents, we can follow the localization and phenotype of TCR-populations specific for either BCG or the secondary pathogen by flow cytometric analysis of granuloma cells. This model will also be used to examine the effect of super-infection upon organ load, the capacity of different TCR-specific T cell populations to produce protective cytokines, and gene-expression changes associated with local antigenic specificity. T cell interactions (help, suppression, competition) have been described with nominal antigens, and our studies will focus on how T cell responses for two infectious agents interfere with each other. We intend to make our observations by infecting animals with a full spectrum of T cells (B10.BR), infecting B10.BR animals into which TCR transgenic T cell populations specific for both epitopes have been adoptively transferred as sentinels, and infecting immunodeficient Rag2-/- after adoptive transfer of TCR transgenic T cells that are specific for the epitope tags expressed by the infectious agents to construct a small T-cell network. Thus we can very precisely study the recruitment and functional qualities of granuloma cells having mycobacterial specificity and those with specificity for other infections. The goal of this research is to understand the interaction of T cell responses controlling different infections. Hopefully, this will lead to better treatments of mycobacterial disease.