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

Author:

Rodrigues Rodrigo F.1,Zárate-Bladés Carlos R.1,Rios Wendy M.1,Soares Luana S.1,Souza Patricia R. M.1,Brandão Izaíra T.1,Masson Ana P.1,Arnoldi Frederico G. C.1,Ramos Simone G.2,Letourneur Franck3,Jacques Sébastien3,Cagnard Nicolas34,Chiocchia Gilles3,Silva Celio L.1

Affiliation:

1. 1  The Centre for Tuberculosis Research, Department of Biochemistry and Immunology, Ribeirão Preto School of Medicine, University of São Paulo, São Paulo, Ribeirao Preto, 14049-900, Brazil

2. 2  Department of Pathology, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirao Preto, São Paulo, 14049-900, Brazil

3. 3  Université Paris-Descartes, Institut Cochin and INSERM U1016, CNRS (CMRS 8104), Paris, 75014, France

4. 4  Hôpital Necker, Paris, 75015, France

Abstract

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.

Publisher

Oxford University Press (OUP)

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology,Microbiology (medical)

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