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The heparin-binding haemagglutinin of M. tuberculosis is required for extrapulmonary dissemination

Nature volume 412, pages 190–194 (2001)Cite this article

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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Figure 1: Genotype and phenotype analyses of hbhA::aph strains.
Figure 2: Effect of the hbhA::aph mutation on the interaction of M. tuberculosis 103 with phagocytic and non-phagocytic cells.
Figure 3: Effect of the hbhA::aph mutation on survival and multiplication of M. bovis BCG (left panels) and M. tuberculosis 103 (right panels).
Figure 4: Influence of anti-HBHA antibodies on dissemination.

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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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Authors and Affiliations

  1. Unité INSERM U447, Institut Pasteur de Lille, 1 rue du Prof. Calmette, Lille Cedex, F-59019, France

    Kevin Pethe, Sylvie Alonso, Franck Biet, Camille Locht & Franco D. Menozzi

  2. Laboratory of Mycobacterial Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, 29 Lincoln Drive, Building 29, Room 502, Bethesda, 20892, Maryland, USA

    Giovanni Delogu & Michael J. Brennan

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  1. Kevin Pethe
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Correspondence to Camille Locht.

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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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