I am investigating immunologic mechanisms of disease pathogenesis with an emphasis on genetic, cellular, and molecular studies of the innate immune response. My primary interest is to understand why individuals have different susceptibility to infections and whether these insights can lead to novel treatment and vaccine strategies. In particular, I examine tuberculosis due to its global health importance, lack of an effective vaccine, and our ignorance about what constitutes a protective immune response to TB. We use ex vivo and in vitro immunologic, cellular and molecular assays to understand how innate immune response genes and their variants mediate a protective immune response. We attempt to discover human deficiency in these genes and to understand the clinical implications with case-control genetic studies examining associations of polymorphisms in these genes with disease susceptibility. Finally, we are complementing these studies with in vivo infection models in mice with targeted gene deletions to elucidate mechanisms of disease pathogenesis. We use these methods to study the pulmonary innate immune response to Mycobacterium tuberculosis and Legionella pneumophila as well as immunity to M. leprae. We compare and contrast the host immune response to these different pathogens to gain a better understanding of immunogenetics and human susceptibility to infections.