Synergy of chemotherapy and immunotherapy revealed by a genome-scale analysis of murine tuberculosis.
J Antimicrob Chemother, 2015;70(6):1774-83.
Rodrigues RF[1], Zárate-Bladés CR[2], Rios WM[1], Soares LS[1], Souza PR[1], Brandão IT[1], Masson AP[1], Arnoldi FG[1], Ramos SG[3], Letourneur F[4], Jacques S[4], Cagnard N[5], Chiocchia G[4], Silva CL[1]
Affiliations
PMID: 25687643DOI: 10.1093/jac/dkv023
Impact factor: 5.758
Abstract
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 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).
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.
Keywords: drug therapy; gene expression profiling; lung transcriptome; vaccine therapy
MeSH terms
Animals; Antitubercular Agents; Combined Modality Therapy; Disease Models, Animal; Drug Therapy; Gene Expression Profiling; Immunotherapy; Isoniazid; Lung; Mice, Inbred BALB C; Mycobacterium tuberculosis; Rifampin; Treatment Outcome; Tuberculosis; Vaccines, DNA
More resources
EndNote: Download