| Over one-third of the world's population is infected with Mycobacterium tuberculosis, and the disease kills an estimated 2 million people annually. Remarkably, 90–95% of those infected never develop active tuberculosis. The factors that predispose 5–10% of infected people to develop disease are unknown in the majority of cases, however there is clear evidence that resistance to M. tuberculosis infection is under genetic control. Mice that vary in their susceptibility to tuberculosis infection can be used to model human susceptibility to the disease. By identifying immunological correlates of susceptibility and resistance in mice, we can begin to define what constitutes a protective versus a non-protective response to infection, and identify the genetic loci that control these phenotypes.; The studies in this dissertation investigate differences in the generation of immunity to M. tuberculosis in resistant and susceptible inbred strains of mice. Our experiments define several immunological correlates of resistance and susceptibility. First, we show that susceptible mice have a severe defect in generating a protective immune response in the lung. This deficit is characterized by a delayed and reduced recruitment of IFNγ-producing CD4+ and CD8+ T cells into the lungs. As a result, the susceptible mice fail to contain bacterial growth and succumb very early after infection. Second, we show that resistant mice demonstrate earlier extrapulmonary dissemination of M. tuberculosis than susceptible mice. We define the kinetics of early dissemination and show that dissemination of M. tuberculosis to the draining pulmonary lymph node precedes the initiation of an antigen-specific CD4+ T cell response. Thus, resistant mice are able to generate an earlier adaptive immune response than susceptible mice. Third, we present several experiments that investigate the host factors involved in dissemination, and we show that inducing early dissemination can protect susceptible mice from infection. Finally, we demonstrate that by modulating the immune response in susceptible mice by activating NKT cells, we are able to protect them from M. tuberculosis infection. Taken together, these studies provide us with a clearer picture of the factors governing resistance and susceptibility to M. tuberculosis infection. |
