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Infection and Immunity, December 2009, p. 5311-5321, Vol. 77, No. 12
0019-9567/09/$08.00+0     doi:10.1128/IAI.00580-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Mycobacterium tuberculosis Culture Filtrate Proteins plus CpG Oligodeoxynucleotides Confer Protection to Mycobacterium bovis BCG-Primed Mice by Inhibiting Interleukin-4 Secretion{triangledown}

Denise Morais da Fonseca,1 Celio Lopes Silva,1 Pryscilla Fanini Wowk,1 Marina Oliveira e Paula,1 Simone Gusmão Ramos,2 Cynthia Horn,3 Gilles Marchal,4 and Vânia Luiza Deperon Bonato1*

Núcleo de Pesquisas em Tuberculose, Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil,1 Departamento de Patologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil,2 Laboratório de Imunologia e Imunogenética, Instituto de Pesquisa Clínica Evandro Chagas, Fundação Osvaldo Cruz, Rio de Janeiro, RJ, Brazil,3 Laboratoire d'Immunothérapie, Institut Pasteur, Paris, France4

Received 24 May 2009/ Returned for modification 2 July 2009/ Accepted 6 September 2009

Culture filtrate proteins (CFP) are potential targets for tuberculosis vaccine development. We previously showed that despite the high level of gamma interferon (IFN-{gamma}) production elicited by homologous immunization with CFP plus CpG oligodeoxynucleotides (CFP/CpG), we did not observe protection when these mice were challenged with Mycobacterium tuberculosis. In order to use the IFN-{gamma}-inducing ability of CFP antigens, in this study we evaluated a prime-boost heterologous immunization based on CFP/CpG to boost Mycobacterium bovis BCG vaccination in order to find an immunization schedule that could induce protection. Heterologous BCG-CFP/CpG immunization provided significant protection against experimental tuberculosis, and this protection was sustained during the late phase of infection and was even better than that conferred by a single BCG immunization. The protection was associated with high levels of antigen-specific IFN-{gamma} and interleukin-17 (IL-17) and low IL-4 production. The deleterious role of IL-4 was confirmed when IL-4 knockout mice vaccinated with CFP/CpG showed consistent protection similar to that elicited by BCG-CFP/CpG heterologous immunization. These findings show that a single dose of CFP/CpG can represent a new strategy to boost the protection conferred by BCG vaccination. Moreover, different immunological parameters, such as IFN-{gamma} and IL-17 and tightly regulated IL-4 secretion, seem to contribute to the efficacy of this tuberculosis vaccine.

* Corresponding author. Mailing address: Núcleo de Pesquisas em Tuberculose, Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo. Av. Bandeirantes, 3900, CEP 14049-900, Ribeirão Preto, SP, Brazil. Phone: 55-16 3602 3089. Fax: 55-16 3602 4590. E-mail: vlbonato{at}fmrp.usp.br

{triangledown} Published ahead of print on 14 September 2009.

Editor: J. L. Flynn

Infection and Immunity, December 2009, p. 5311-5321, Vol. 77, No. 12
0019-9567/09/$08.00+0     doi:10.1128/IAI.00580-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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