Comprehensive gene expression profiling in lungs of mice infected with Mycobacterium tuberculosis following DNAhsp65 immunotherapy

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Zarate-Blades, Carlos Rodrigo ^[1] ; Deperon-Bonato, Vania Luiza ^[1] ; Volpe da Silveira, Eduardo Lani ^[2] ; Oliveira e Paula, Marina ^{[2, 1]} ; Junta, Cristina Moraes ^[2] ; Sandrin-Garcia, Paula ^[2] ; Fachin, Ana Lucia ^[2] ; Mello, Stephano Spano ^[3] ; Cardoso, Renato Sousa ^[2] ; de Sa Galetti, Fabio Cicero ^[1] ; Martins Coelho-Castelo, Arlete Aparecida ^[1] ; Ramos, Simone Gusmao ^[4] ; Donadi, Eduardo Antonio ^[5] ; Sakamoto-Hojo, Elza Tiemi ^[3] ; da Silva Passos, Geraldo Aleixo ^[2] ; Silva, Celio Lopes ^[1]

Affiliation

^[1] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Bioquim & Imunol, Nucl Pesquisas TB, BR-14049900 Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Fac Med Ribeirao Preto, Immunogenet Mol Lab, Dept Genet, BR-14049900 Ribeirao Preto, SP - Brazil

^[3] Univ Sao Paulo, Fac Med Ribeirao Preto, Lab Citogenet & Mutagenese, Dept Genet, BR-14049900 Ribeirao Preto, SP - Brazil

^[4] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Patol, BR-14049900 Ribeirao Preto, SP - Brazil

^[5] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Clin Med, BR-14049900 Ribeirao Preto, SP - Brazil

• Document type: Journal article
• Source: JOURNAL OF GENE MEDICINE; v. 11, n. 1, p. 66-78, JAN 2009.
• Web of Science Citations: 17

Abstract

Background The continued increase in tuberculosis (TB) rates and the appearance of extremely resistant Mycobacterium tuberculosis strains (XDR-TB) worldwide are some of the great problems of public health. In this context, DNA immunotherapy has been proposed as an effective alternative that could circumvent the limitations of conventional drugs. Nonetheless, the molecular events underlying these therapeutic effects are poorly understood. Methods We characterized the transcriptional signature of lungs from mice infected with M. tuberculosis and treated with heat shock protein 65 as a genetic vaccine (DNAhsp65) combining microarray and real-time polymerase chain reaction analysis. The gene expression data were correlated with the histopathological analysis of lungs. Results The differential modulation of a high number of genes allowed us to distinguish DNAhsp65-treated from nontreated animals (saline and vector-injected mice). Functional analysis of this group of genes suggests that DNAhsp65 therapy could not only boost the T helper (Th)1 immune response, but also could inhibit Th2 cytokines and regulate the intensity of inflammation through fine tuning of gene expression of various genes, including those of interleukin-17, lymphotoxin A, tumour necrosis factor-cl, interleukin-6, transforming growth factor-beta, inducible nitric oxide synthase and Foxp3. In addition, a large number of genes and expressed sequence tags previously unrelated to DNA-therapy were identified. All these findings were well correlated with the histopathological lesions presented in the lungs. Conclusions The effects of DNA therapy are reflected in gene expression modulation; therefore, the genes identified as differentially expressed could be considered as transcriptional biomarkers of DNAhsp65 immunotherapy against TB. The data have important implications for achieving a better understanding of gene-based therapies. Copyright (C) 2008 John Wiley \& Sons, Ltd. (AU)