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Infection and Immunity, February 2007, p. 941-949, Vol. 75, No. 2
0019-9567/07/$08.00+0     doi:10.1128/IAI.01137-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Immunogenicity of Eight Dormancy Regulon-Encoded Proteins of Mycobacterium tuberculosis in DNA-Vaccinated and Tuberculosis-Infected Mice

Virginie Roupie,^1, Marta Romano,^1, Lei Zhang,² Hannelie Korf,¹ May Young Lin,³ Kees L. M. C. Franken,³ Tom H. M. Ottenhoff,³ Michèl R. Klein,^3, and Kris Huygen^1*

Mycobacterial Immunology, WIV-Pasteur Institute, B1180 Brussels, Belgium,¹ Department of International Business and Cooperation, Chengdu Institute of Biological Products, Waidong Baojiangqiao, Sichuan Province, Chengdu 610023, People's Republic of China,² Leiden University Medical Center, 2333 ZA Leiden, The Netherlands³

Received 20 July 2006/ Returned for modification 25 August 2006/ Accepted 15 November 2006

Hypoxia and low concentrations of nitric oxide have been reported to upregulate in vitro gene expression of 48 proteins of the dormancy (DosR) regulon of Mycobacterium tuberculosis. These proteins are thought to be essential for the survival of bacteria during persistence in vivo and are targeted by the immune system during latent infection in humans. Here we have analyzed the immunogenicity of eight DosR regulon-encoded antigens by plasmid DNA vaccination of BALB/c and C57BL/6 mice, i.e., Rv1733c, Rv1738, Rv2029c (pfkB), Rv2031c/hspX (acr), Rv2032 (acg), Rv2626c, Rv2627c, and Rv2628. Strong humoral and/or cellular Th1-type (interleukin-2 and gamma interferon) immune responses could be induced against all but one (Rv1738) of these antigens. The strongest Th1 responses were measured following vaccination with DNA encoding Rv2031c and Rv2626c. Using synthetic 20-mer overlapping peptides, 11 immunodominant, predicted major histocompatibility complex class II-restricted epitopes and one K^d-restricted T-cell epitope could be identified. BALB/c and (B6D2)F₁ mice persistently infected with M. tuberculosis developed immune responses against Rv1733c, Rv2031c, and Rv2626c. These findings have implications for proof-of-concept studies in mice mimicking tuberculosis (TB) latency models and their extrapolation to humans for potential new vaccination strategies against TB.

Published ahead of print on 4 December 2006.

Editor: W. A. Petri, Jr.

Both authors contributed equally to this work.

Present address: RIVM-National Institute of Public Health and the Environment, Center for Infectious Disease Control, Diagnostic Laboratory for Infectious Diseases and Perinatal Screening, Antonie van Leeuwenhoeklaan 9, 3721 MA, Postbus 1, 3720 BA, Bilthoven, The Netherlands.

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