This proposal describes a 5 year training program designed to provide the education and laboratory experience required for a successful academic career in basic science research in infectious diseases. This multidisciplinary program will include formal coursework in immunology and basic science fundamentals as well as an extensive lab experience encompassing cellular, molecular and immunologic techniques. Dr. JoAnne Flynn, an internationally recognized expert in host defenses in Mycobacterium tuberculosis (Mtb) infection, will mentor the principal investigator. Research progress and career development will be reviewed quarterly by an advisory committee. Tumor necrosis factor-alpha(TNF) neutralization in acute and chronic Mtb-infected mice results in poor granuloma structure, disseminated disease and poor survival. Similar results have been observed in patients treated with anti-TNF antibody. We hypothesize that TNF neutralization dysregulates cell migration factors critical to granuloma formation and maintenance. This proposal seeks to determine the role of TNF and its influence on chemokines, chemokine receptors and adhesion molecules in the context of granuloma structure in the lungs during primary and latent Mtb infection. We will focus on chemokines, chemokine receptors and adhesion molecules induced in TH1 immune responses in the lung. We will determine how Mtb-induced production of TNF alters expression of chemokines, chemokine receptors and adhesion molecules using both in vitro and in vivo models; in this latter part we will examine changes in granuloma histology, immune phenotype and function in animal models of primary and latent Mtb infection treated with TNF neutralizing antibody. These changes will be analyzed the context of granuloma structure and host response to infection. The University of Pittsburgh provides an ideal research environment to support this training program.
