Reactivation Tuberculosis in A/J Mice

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DESCRIPTION (provided by applicant) One quarter of the world's population is infected with M. tuberculosis resulting in approximately 2.9 million deaths each year. Reactivation tuberculosis is the major cause of adult tuberculosis today although the mechanisms that predispose to reactivation are complex and enigmatic. Since animal models are useful for understanding pathogenesis of tuberculosis, we performed a series of studies to standardize murine models of acute, chronic and reactivation tuberculosis by varying the mouse strain, route and dose of infection. We then found that A/J mice were highly susceptible while C57Bl/6 mice were relatively resistant to progressive disease when infected either i.v. or via aerosol routes. A/J mice were unable to form granulomas in lungs and their macrophages were defective in killing MTB. Unlike C57Bl/6 mice, A/J mice also underwent an early and near uniform reactivation of tuberculosis following the Cornell model. A/J mice have a deletion in the gene encoding for Complement C5 which in intact mice yields the C5a anaphylatoxin, a known regulator of cytokine and chemokine synthesis of macrophages. Therefore, in this investigation, we will examine the hypothesis that the lack of C5a compromises the immune responses in mice allowing the reactivation of tuberculosis through the following aims. Specific Aim I will investigate whether the deletion in C5 gene affects the synthesis of cytokines (TNF alpha, IL1-beta and IL-6), prevents macrophage activation and thereby macrophage mediated killing of MTB in A/J mice. Specific Aim II will investigate the effects of the deletion in C5 gene to the secretion of chemokines by MTB infected A/J macrophages and evaluate whether they are important in causing influx of immune cells into the lungs and formation of granulomas. Specific Aim III will characterize histological, cytokine and chemokine responses of lungs in A/J mice to determine the type of immune response (Th1 vs Th2) that dominates during the reactivation of tuberculosis. These studies are anticipated to enhance our understanding on putative mechanisms that precede the reactivation of tuberculosis in the lungs of mice and ultimately help us to develop better strategies to prevent tuberculosis in man.