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

Autor(es):Mostrar menos -

Rodrigues, Rodrigo F. ^[1] ; Zarate-Blades, Carlos R. ^[1] ; Rios, Wendy M. ^[1] ; Soares, Luana S. ^[1] ; Souza, Patricia R. M. ^[1] ; Brandao, Izaira T. ^[1] ; Masson, Ana P. ^[1] ; Arnoldi, Frederico G. C. ^[1] ; Ramos, Simone G. ^[2] ; Letourneur, Franck ^{[3, 4]} ; Jacques, Sebastien ^{[3, 4]} ; Cagnard, Nicolas ^{[3, 4, 5]} ; Chiocchia, Gilles ^{[3, 4]} ; Silva, Celio L. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Ctr TB Res, Dept Biochem & Immunol, Ribeirao Preto Sch Med, BR-14049900 Ribeirao Preto - Brazil

^[2] Univ Sao Paulo, Ribeirao Preto Sch Med, Dept Pathol, BR-14049900 Sao Paulo - Brazil

^[3] Univ Paris 05, Inst Cochin, F-75014 Paris - France

^[4] CNRS CMRS 8104, INSERM U1016, F-75014 Paris - France

^[5] Hop Necker Enfants Malad, F-75015 Paris - France

• Tipo de documento: Artigo Científico
• Fonte: Journal of Antimicrobial Chemotherapy; v. 70, n. 6, p. 1774-1783, JUN 2015.
• Citações Web of Science: 2

Resumo

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. (AU)

• Processo FAPESP: 07/54880-0 - Identificacao de biomarcadores durante a terapia tuberculose.
• Beneficiário: Rodrigo Ferracine Rodrigues
• Modalidade de apoio: Bolsas no Brasil - Doutorado