Project Summary. Infection with Mycobacterium tuberculosis (Mtb), the causative agent of the disease tuberculosis (TB), causes ~1.7 million deaths annually. The difficulty of treating Mtb infections with antibiotics and the lack of an effective vaccine fuel the TB pandemic. The development for effective interventions is impeded by the fact that we have very little understanding of the factors that underlie successful immune control of Mtb, or that dictate the heterogenous clinical manifestations observed in human patients. In this proposal we seek to establish that a newly derived collection of genetically diverse wild inbred mice is a powerful tool for dissecting the genetic basis of susceptibly to Mtb. The mouse model is a powerful tool for studying immune responses to Mtb. However, common laboratory strains have very limited genetic diversity. Two collections of mice, the collaborative cross and diversity outbred mice, were established to provide a genetically diverse set of mice that can be used to map the genetic basis of complex traits. Several recent studies have demonstrated the mice from these collections do have heterogenous responses to Mtb infection. Here we describe a new collection of wild-derived inbred mice, all from the Mus musculus domisticus subspecies, that offer several advantages over existing collections. This new collection of mice has the genetic diversity of natural populations, a lack of genomic “blind spots” created by crossing subspecies of mice, and linkage equilibrium that decays over a short genomic interval, facilitating the identification of causal genes. In this exploratory study we propose to infect 40 new lines of these wild-derived mice, and to assess their susceptibility to infection with Mtb using bacterial burden and weight loss studies. In addition, we will perform a preliminary immunological analysis of the most resistant and susceptible strains, to prioritize strains that may reveal new immunological mechanisms for future analysis. We will also attempt to identify strains that recapitulate aspects of human disease not seen in the current mouse models, including the ability to decrease bacterial burdens in the lungs over time, or dissemination to extrapulmonary sites such as the central nervous system. If successful, this study will establish that wild derived mice will be a valuable resource for uncovering novel mechanisms of immunity, and for modeling the heterogenous responses to infection with Mtb observed in humans.