A Mathematical Model of the Human Immune Response to Mycobacterium Tuberculosis Infection

Wigginton, J. and D. Kirschner University of Michigan Medical School

A key issue for the study of tuberculosis (TB) infection is to understand the immunologic mechanisms involved in disease resolution, and those that lead to the development of active disease. An enormous body of literature exists regarding individual elements of both pathogenic mechanisms and the immune response to TB; however, little is known about combined interactions or the balance between these processes. In light of the observation that pathology in {\it Mycobacterium tuberculosis} infection may be due to an imbalance between TH1-type T cell responses that act to clear bacteria, but cause tissue damage, and TH2-type T cell responses that downregulate these potent responses, an understanding of TH1/TH2 T cell cross-regulation may be particularly relevant to any investigation of the pathogenesis of M. tuberculosis infection. To this end, we have developed a mathematical model that qualitatively and quantitatively characterizes aspects of the cytokine control network that is operational during TB infection. We are now using this model to explore the hypothesis that the outcomes of infection with {\it M. tuberculosis} depend on the TH1 or TH2 cytokine profile generated during the immune response to {\it M. tuberculosis}. In addition, we identify key interactions among the immune mechanisms critical to the clinical outcome in tuberculosis and explore the effects of perturbing different factors in this system including expression of cytokines/cytokine receptors, activation, deactivation and recruitment of macrophages, T cell and macrophage effector mechanisms, T cell recruitment and differentiation, as well as bacterial growth and mechanisms of immune evasion.