Immunological parameters to define infection progression and therapy response in a well-defined tuberculosis model in mice

Abstract

To evaluate novel approaches for tuberculosis (TB) diagnostics and treatment, well-validated animal TB models are needed. Especially the emergence and spread of drug resistant TB requires innovative therapy and accurate parameters for monitoring success or failure of therapy. We developed a TB model in BALB/c mice, in which Mycobacterium tuberculosis (Mtb) infection was induced through the natural respiratory route, mimicking human TB infection. The lung showed a mild inflammatory infiltrate consisting of granulomas in the first phase of infection, followed by progressive increase of pneumonic lesions resulting in extensive lung consolidation in the chronic phase. Dissemination to the extra-pulmonary sites was observed. The model was validated in terms of therapeutic outcome. The 26-week standard therapy administered in human pharmacokinetic-equivalent doses, resulted in complete elimination of Mtb in all infected organs, without relapse of infection in the post-treatment period. However, a 13-week therapy, simulating patient non-adherence resulted in relapse of infection. In our quest to find biomarkers for monitoring success or failure of therapy, the concentrations of various cytokines in serum and lung, determined by cytometric bead array (CBA), were evaluated in relation to the in situ cytokine expression in the lung, assessed by immunohistochemistry. The level of IFN-gamma concentration in serum increased with infection progression, and decreased during effective therapy, and as such appeared to be an appropriate immunological parameter for success or failure of therapy. Relapse of infection, after inappropriate therapy, manifested as an increase in the serum IFN-gamma concentration.