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

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 systematicall...

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Bibliographic Details
Published in:Infection and Immunity 2006, Vol.74 (1), p.88-98
Main Authors: Brodin, Priscille, Majlessi, Laleh, Marsollier, Laurent, de Jonge, Marien I, Bottai, Daria, Demangel, Caroline, Hinds, Jason, Neyrolles, Olivier, Butcher, Philip D, Leclerc, Claude, Cole, Stewart T, Brosch, Roland
Format: Article
Language:English
Subjects:
Animals
Antigens, Bacterial - physiology
Bacterial Infections
Bacterial Proteins - metabolism
Biological and medical sciences
Female
Fundamental and applied biological sciences. Psychology
Macrophages - immunology
Macrophages - microbiology
Male
Mice
Mice, Inbred C57BL
Mice, SCID
Microbiology
Mycobacterium bovis
Mycobacterium bovis - immunology
Mycobacterium microti
Mycobacterium tuberculosis
Mycobacterium tuberculosis - growth & development
Mycobacterium tuberculosis - immunology
Mycobacterium tuberculosis - pathogenicity
Transcription, Genetic - immunology
Virulence - immunology
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Summary: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.
ISSN:0019-9567
1098-5522
DOI:10.1128/IAI.74.1.88-98.2006