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Infection and Immunity, January 2006, p. 88-98, Vol. 74, No. 1
0019-9567/06/$08.00+0     doi:10.1128/IAI.74.1.88-98.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Dissection of ESAT-6 System 1 of Mycobacterium tuberculosis and Impact on Immunogenicity and Virulence

Unité de Génétique Moléculaire Bactérienne,¹ Unité de Biologie des Régulations Immunitaires-INSERM E352,² Unité de Génétique Mycobactérienne-CNRS URA 2172, Institut Pasteur, 25-28, Rue du Docteur Roux, 75724 Paris Cedex 15, France,⁴ Bacterial Microarray Group, Medical Microbiology, Department of Cellular and Molecular Medicine, St. George's Hospital Medical School, Cranmer Terrace, London SW17 0RE, United Kingdom³

Received 8 June 2005/ Returned for modification 14 July 2005/ Accepted 18 September 2005

The dedicated secretion system ESX-1 of Mycobacterium tuberculosis encoded by the extended RD1 region (extRD1) assures export of the ESAT-6 protein and its partner, the 10-kDa culture filtrate protein CFP-10, and is missing from the vaccine strains M. bovis BCG and M. microti. Here, we systematically investigated the involvement of each individual ESX-1 gene in the secretion of both antigens, specific immunogenicity, and virulence. ESX-1-complemented BCG and M. microti strains were more efficiently engulfed by bone-marrow-derived macrophages than controls, and this may account for the enhanced in vivo growth of ESX-1-carrying strains. Inactivation of gene pe35 (Rv3872) impaired expression of CFP-10 and ESAT-6, suggesting a role in regulation. Genes Rv3868, Rv3869, Rv3870, Rv3871, and Rv3877 encoding an ATP-dependent chaperone and translocon were essential for secretion of ESAT-6 and CFP-10 in contrast to ppe68 Rv3873 and Rv3876, whose inactivation did not impair secretion of ESAT-6. A strict correlation was found between ESAT-6 export and the generation of ESAT-6 specific T-cell responses in mice. Furthermore, ESAT-6 secretion and specific immunogenicity were almost always correlated with enhanced virulence in the SCID mouse model. Only loss of Rv3865 and part of Rv3866 did not affect ESAT-6 secretion or immunogenicity but led to attenuation. This suggests that Rv3865/66 represent a new virulence factor that is independent from ESAT-6 secretion. The present study has allowed us to identify new aspects of the extRD1 region of M. tuberculosis and to explore its role in the pathogenesis of tuberculosis.

Editor: J. L. Flynn

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