Systems Genetics of Tuberculosis: Program Abstract: Mycobacterium tuberculosis (Mtb) infection outcomes are highly variable, creating a great challenge in TB control; how do we identify those that are genuinely at risk and deliver an intervention that will be effective for that individual? The biological determinants of Mtb infection outcome have been difficult to define largely because multiple variables are involved, which include genetic variation in host and pathogen and non-genetic environmental factors. To overcome this complexity, we leveraged new mammalian and bacterial genetic resources to create a model system that can be used to study the effect of each of these variables in isolation and in combination. Host diversity is incorporated using mice from the “Collaborative Cross” (CC), a newly generated reference panel of inbred mice that reflects the diversity of an outbred population. Bacterial variation is incorporated using large panels of Mtb strains that reflect both naturally- and experimentally-generated diversity. Using this highly-tractable system, the effect of controlled interventions can be assessed, and high-resolution phenotyping can be applied to differentiate different TB-related disease states. Three inter-related scientific projects will use this uniquely tractable experimental system to: 1) Define host determinants of TB susceptibility, 2) Identify bacterial determinants of host-pathogen preference. 3) Investigate the basis for TB vaccine efficacy in genetically-diverse populations Through collaboration with two essential Scientific Cores focused on Mouse and Human genetics and one Administrative Core, we will accomplish our ultimate scientific goals: to characterize the mechanisms underlying tuberculosis pathogenesis, extend these observations to human clinical cohorts, and use these insights to rationally-design more effective vaccines. !