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

• Published in: Journal of antimicrobial chemotherapy Vol. 70; no. 6; pp. 1774 - 1783
• Main Authors: Rodrigues, Rodrigo F, Zárate-Bladés, Carlos R, Rios, Wendy M, Soares, Luana S, Souza, Patricia R M, Brandão, Izaíra T, Masson, Ana P, Arnoldi, Frederico G C, Ramos, Simone G, Letourneur, Franck, Jacques, Sébastien, Cagnard, Nicolas, Chiocchia, Gilles, Silva, Celio L
• Format: Journal Article
• Language: English
• Published: England Oxford Publishing Limited (England) 01-06-2015
• Subjects: Animals; Antitubercular Agents - administration & dosage; Bacteria; Chemotherapy; Combined Modality Therapy - methods; Cytokines; Deoxyribonucleic acid; Disease Models, Animal; DNA; Drug Therapy - methods; Gene Expression Profiling; Genes; Immunotherapy; Immunotherapy - methods; Isoniazid - administration & dosage; Lung - microbiology; Lung - pathology; Mice, Inbred BALB C; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - immunology; Rifampin - administration & dosage; Rodents; Treatment Outcome; Tuberculosis - therapy; Vaccines, DNA - administration & dosage; lung transcriptome; drug therapy; gene expression profiling; vaccine therapy
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dkv023

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.
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 μg 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).
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.
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.