Abstract
Tuberculosis remains the world's leading cause of death due to a single infectious agent, Mycobacterium tuberculosis, with 3 million deaths and 10 million new cases per year1. The infection initiates in the lungs and can then spread rapidly to other tissues2. The availability of the entire M. tuberculosis genome sequence3 and advances in gene disruption technologies4 have led to the identification of several mycobacterial determinants involved in virulence5,6,7,8. However, no virulence factor specifically involved in the extrapulmonary dissemination of M. tuberculosis has been identified to date. Here we show that the disruption of the M. tuberculosis or Mycobacterium bovis Bacille Calmette–Guérin (BCG) hbhA gene encoding the heparin-binding haemagglutinin adhesin (HBHA) markedly affects mycobacterial interactions with epithelial cells, but not with macrophage-like cells. When nasally administered to mice, the mutant strains were severely impaired in spleen colonization, but not in lung colonization. Coating wild-type mycobacteria with anti-HBHA antibodies also impaired dissemination after intranasal infection. These results provide evidence that adhesins such as HBHA are required for extrapulmonary dissemination, and that interactions with non-phagocytic cells have an important role in the pathogenesis of tuberculosis. They also suggest that antibody responses to HBHA may add to immune protection against tuberculosis.
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Acknowledgements
We thank W. R. Jacobs Jr for the gift of pYUB415; B. Gicquel for the gift of pPR27 and M. tuberculosis 103; J. P. Decavel for help in animal handling; and S. T. Cole, P. Bifani and A. R. Baulard for critically reading the manuscript. This work was supported by INSERM, Institut Pasteur de Lille, Région Nord-Pas de Calais, and the Ministère de la Recherche. K.P. and S.A. were supported by a fellowship from the Ministère de la Recherche and Aventis-Pasteur, respectively.
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Pethe, K., Alonso, S., Biet, F. et al. The heparin-binding haemagglutinin of M. tuberculosis is required for extrapulmonary dissemination. Nature 412, 190–194 (2001). https://doi.org/10.1038/35084083
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DOI: https://doi.org/10.1038/35084083
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