Project 1: Host Determinants of TB Susceptility Abstract: The outcomes of Mycobacterium tuberculosis (Mtb) infections are extremely diverse. Many infected individuals show no signs of disease. Among those that do become ill, the timing, location, and severity of pathology are remarkably variable. Genetic diversity in the host population is a major contributor to this variability, but the responsible alleles and mechanisms are poorly defined and have been difficult to address experimentally. In this project, we approach this inherently complex problem by modeling host diversity using a highly genetically diverse, but precisely genetically defined, panel of recombinant inbred mice known as the Collaborative Cross. The unique structure of this population allows the sequential evaluation of variable traits that reflect distinct aspects of pathogenesis. We took advantage of this iterative-phenotyping strategy to dissect the genetic basis of TB susceptibility at multiple levels. These prior studies implicated Kit Ligand (KitL) variation as an important determinant of TB disease in mice and humans, suggested that genetic interactions between pathogen and host are a sensitive metric for detecting new genes that alter disease progression, and highlighted the power of using ex vivo systems to dissect the interaction between Mtb and the macrophage. In the proposed project, we will continue to pursue these strategies to: Aim 1: Investigate the mechanism of KitL-linked susceptibility to TB disease in mice and humans. Aim 2: Use combinatorial mouse and bacterial genetics to dissect host-pathogen genetic interactions. Aim 3: Exploit the CC panel to dissect the Mtb-macrophage interaction. In combination, these new resources and approaches promise to provide fundamentally new insight into the role of host and bacterial genetic variation on the outcome of Mtb infection. !