Periodic Reporting for period 1 - HADES (Functional mechanism of heparin-binding hemagglutinin adhesin from Mycobacterium tuberculosis)
Reporting period: 2021-02-01 to 2023-01-31
The HADES project tackles a crucial issue related to the pathogenesis of Tuberculosis (TB), the leading global cause of death from an infectious bacterial agent. Specifically, the project aims to shed light on the poorly understood process of TB extrapulmonary dissemination, which relies on a virulence factor called heparin-binding haemagglutinin adhesin (HBHA).
HBHA is a mycobacterial cell surface protein, and it plays pivotal role in MTB pathogenesis, promoting its adhesion to epithelial cells. Despite its relevance in the dissemination of TB, and as powerful diagnostic antigen or potential therapeutic target, there is only a limited understanding of the biological properties of HBHA.
The project integrates complementary research programmes in structural biology and MTB microbiology, to characterize at high resolution the structural basis of the function of HBHA in different phases of the MTB life cycle and to provide the details of the underlying mechanism by which the extrapulmonary dissemination of TB is originated.
HBHA is a mycobacterial cell surface protein, and it plays pivotal role in MTB pathogenesis, promoting its adhesion to epithelial cells. Despite its relevance in the dissemination of TB, and as powerful diagnostic antigen or potential therapeutic target, there is only a limited understanding of the biological properties of HBHA.
The project integrates complementary research programmes in structural biology and MTB microbiology, to characterize at high resolution the structural basis of the function of HBHA in different phases of the MTB life cycle and to provide the details of the underlying mechanism by which the extrapulmonary dissemination of TB is originated.
The work carried out on HADES project was focused on the characterization of HBHA protein through an integrated approach that combined both solution and solid-state NMR techniques, complemented by biophysical and molecular biology methodologies. Molecular cloning was employed to generate truncated and mutant forms of HBHA, allowing for the assessment of the protein's functionality in various contexts. In order to assess the conformational properties of HBHA protein, during Phase I of the project the Fellow combined solution and solid-state NMR experiments to probe HBHA individual domains. During the Phase II, the Fellow optimized the vesicle reconstitution, in order to characterize by CEST experiments the mechanism of recognition and binding of HBHA in a mycobacteria membrane mimetic system. The data acquired during the Fellowship will be made accessible through publication in an open-access journal. Furthermore, a review article on HBHA has been prepared for submission. Moreover, project aims, goals, results, and MSCA were promoted in dissemination and outreach activities aimed at different target audiences, including researchers, students, policymakers, and school kids.
HADES project aims to achieve a transformative goal in TB research, providing a comprehensive understanding of HBHA’s role in TB extrapulmonary dissemination. Furthermore, given the HBHA role as antigen and as potential therapeutic target, the project holds immense significance for the advancement of diagnostic tools and the exploration of potential therapeutic interventions that target this pivotal protein.
The project’s results will improve the comprehension of TB pathogenesis, that is expected to have a significant socio-economic impact by bolstering our capacity to effectively combat and manage tuberculosis, thereby alleviating the economic burden linked to this infectious disease.
Beyond the direct implications for TB, the project contributes to the broader fields of molecular biology and structural biology, fostering innovation and scientific progress.
The project’s results will improve the comprehension of TB pathogenesis, that is expected to have a significant socio-economic impact by bolstering our capacity to effectively combat and manage tuberculosis, thereby alleviating the economic burden linked to this infectious disease.
Beyond the direct implications for TB, the project contributes to the broader fields of molecular biology and structural biology, fostering innovation and scientific progress.