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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

Priscille Brodin,1 Laleh Majlessi,2 Laurent Marsollier,1 Marien I. de Jonge,1 Daria Bottai,1 Caroline Demangel,1 Jason Hinds,3 Olivier Neyrolles,4 Philip D. Butcher,3 Claude Leclerc,2 Stewart T. Cole,1 and Roland Brosch1*

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.

* Corresponding author. Mailing address: Unité de Génétique Moléculaire Bactérienne, Institut Pasteur, 25-28, Rue du Docteur Roux, 75724 Paris Cedex 15, France. Phone: (33) 145688449. Fax: (33) 140613583. E-mail: rbrosch{at}pasteur.fr.

Editor: J. L. Flynn

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.



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