Structure and function of Heparin Binding Hemagglutinin from Mycobacterium tuberculosis

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Tuberculosis (TB) is a leading cause of death worldwide due to a single bacterium, Mycobacterium tuberculosis (MTB). Key aspects of TB pathogenesis include the ability of MTB to disseminate from the site of primary infection (primarily the lungs) to potentially any organ (Russel et al, 2010 Science, 328:852-856) via the interaction of MTB with epithelial cells. This process requires a crucial virulence factor called heparin-binding haemagglutinin adhesin (HBHA, Pethe et al., 2001 Nature 412, 190-194), a protein that is localised at the surface of MTB. In addition to the relevant function in TB, HBHA is considered a crucial target for diagnostic and treatment of TB, which is particularly crucial in view of the growing multi-drug resistance of MTB.Currently the structure of HBHA is unknown. The challenging nature of this study is associated with the complex nature of HBHA that has prevented so far the successful employment of methods able to characterise protein structures. This lack of understanding has in turn hampered the characterisation of the mechanisms by which HBHA promotes the extrapulmonary dissemination of TB. The proposal aims at the ambitious target of resolving the structure of HBHA and the functional mechanism by which this protein promotes the adhesion to epithelial cells within the mechanisms of extrapulmunary dissemination of TB. This is a milestone in TB research that requires overcoming significant experimental challenges. Our research proposal comes at a most opportune time since we now have all the tools, materials and background research to achieve this major goal. We will combine our research programmes in biomolecular nuclear magnetic resonance (NMR) spectroscopy and microbiology to generate a multidisciplinary investigation to reveal the structure, dynamics and topology of HBHA at the surface of MTB membranes as well as the details of the mechanism of adhesion to epithelial cells. The impact of our interdisciplinary study will be significant on the wider academic community studying the underlying molecular mechanisms of TB infection and wider disciplines such as protein science, biochemistry, NMR spectroscopy, microbiology, cellular and molecular biophysics. It is anticipated that the outcomes of this research may directly translate into knowledge leading to new therapeutic and diagnostic approaches for TB.