Synergy of chemotherapy and immunotherapy revealed by a genome-scale analysis of murine tuberculosis.

Objectives: Although TB immunotherapy improves the results of conventional drug treatment, the effects of combining chemotherapy and immunotherapy have never been systematically evaluated. We used a comprehensive lung transcriptome analysis to directly compare the activity of combined chemotherapy and immunotherapy with that of single treatments in a mouse model of TB. Methods: Mycobacterium tuberculosis-infected mice in the chronic phase of the disease (day 30) received: (i) isoniazid and rifampicin (drugs) daily for 30 days; (ii) DNA immunotherapy (DNA), consisting of four 100 mu g injections at 10 day intervals; (iii) both therapies (DNA+ drugs); or (iv) saline. The effects were evaluated 10 days after the end of treatment (day 70 post-infection). Results: In all groups a systemic reduction in the load of bacilli was observed, bacilli became undetectable in the drugs and DNA+ drugs groups, but the whole lung transcriptome analysis showed 867 genes exclusively modulated by the DNA+ drugs combination. Gene enrichment analysis indicated that DNA+ drugs treatment provided synergistic effects, including the down-regulation of proinflammatory cytokines and mediators of fibrosis, as confirmed by real-time PCR, ELISA, histopathology and hydroxyproline assay. Conclusions: Our results provide a molecular basis for the advantages of TB treatment using combined chemotherapy and DNA immunotherapy and demonstrate the synergistic effects obtained with this strategy.