Genetic variation of the host significantly contributes to dramatic differences in the outcomes of natural infection with virulent Mycobacterium tuberculosis (MTB) in humans, as well as in experimental animal models. Host resistance to tuberculosis is a complex multifactorial genetic trait in which many genetic polymorphisms contribute to the phenotype, while their individual contributions are influenced by gene-gene and gene-environment interactions. The most epidemiologically significant form of tuberculosis infection in humans is pulmonary tuberculosis. Factors that predispose immunocompetent individuals to this outcome, however, are largely unknown. Using an experimental mouse model of infection with virulent MTB for the genetic analysis of host resistance to this pathogen, we have identified several tuberculosis susceptibility loci in otherwise immunocompetent mice. The sst1 locus has been mapped to mouse chromosome 1 and shown to be especially important for control of pulmonary tuberculosis. Rampant progression of tuberculosis infection in the lungs of the sst1-susceptible mouse was associated with the development of necrotic lung lesions, which was prevented by the sst1-resistant allele. Using a positional cloning approach, we have identified a novel host resistance gene, Ipr1, which is encoded within the sst1 locus and mediates innate immunity to the intracellular bacterial pathogens MTB and Listeria monocytogenes. The sst1 locus and the Ipr1 gene participate in control of intracellular multiplication of virulent MTB and have an effect on the infected macrophages' mechanism of cell death. The Ipr1 is an interferon-inducible nuclear protein that dynamically associates with other nuclear proteins in macrophages primed with interferons or infected with MTB. Several of the Ipr1-interacting proteins are known to participate in regulation of transcription, RNA processing, and apoptosis. Further biochemical analysis of the Ipr1-mediated pathway will help delineate a mechanism of innate immunity that is especially important for control of tuberculosis progression in the lungs.