Probing the mysteries of sweet “on-off” switches of the human immune system: toward the development of novel glycomimetics against bacterial infections

Project Information

GLYCOSWITCH

Grant agreement ID: 851356

DOI

10.3030/851356

EC signature date 10 October 2019

Start date 1 February 2020

End date 31 January 2027

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 994 117,50

EU contribution

€ 1 994 117,00

Coordinated by

UNIVERSITA DEGLI STUDI DI NAPOLI FEDERICO II
Italy

Periodic Reporting for period 3 - GLYCOSWITCH (Probing the mysteries of sweet “on-off” switches of the human immune system: toward the development of novel glycomimetics against bacterial infections)

Reporting period: 2023-02-01 to 2024-07-31

Summary of the context and overall objectives of the project

GLYCOSWITCH project is aimed to the analysis of structural requisites for recognition and binding between eukaryotic host immune proteins and pathogen cell surface glycoconjugates. These latter represent the keywords of the molecular cross-talk between microbes and eukaryotic host. Actually, complex glycans decorate the cell surface of all living organisms mediating and/or modulating almost all the biological events. They are directly involved in the etiology of several major diseases, spanning from bacterial and viral infections through to cancer and autoimmune disorders. Thus, deciphering the glycome, beyond the current knowledge, holds huge promise to provide new targets and diagnostics for human health and could represent the key to look ‘outside the box’ of current antibiotic paradigms.

Despite the great advances in medicine, infections and their secondary effects remain one of the leading causes of human mortality in the developing world. Considering the increasing number of reported resistant microbial strains, it has been estimated that the deaths attributable to AMR (antimicrobial resistance) every year will be of 10 million in 2050, exceeding all the other major causes of death. As mentioned above, it is nowadays well known that glycans are the principal actors in the interaction of bacteria with host, however the molecular details of several host-pathogen interactions are still not well understood, precluding us the possibility to modulate them in beneficial ways to mankind. In spite of the tremendous advance of knowledge in the field of Glycoscience during the last decade, the comprehension at high resolution of the molecular basis of many pathogen-mediated diseases is still incomplete.
GLYCOSWITCH project strategically combines expertise in distinct aspects of Glycoscience, whose core is organic chemistry and including biochemistry, molecular biology, biophysics and bioinformatics, to explain essential aspects of bacterial glycans recognition by the host immune system, paving the way to the development of novel and effective therapeutic strategies against bacterial infections.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

We used a concerted approach of modern NMR methods, assisted by several other biophysical techniques, taking advantage of progresses in synthesis and protein expression, to investigate the recognition of bacterial glycans by different host immune proteins. The acquired knowledge will open new avenues for modulating and interfering with pivotal pathways of host immune system unlocking attractive opportunities for the development of host-directed strategies to boost the immune response or reverse pathogen-induced immunosuppression.
Of course, given the time period covered in this report, some research activities have been impacted by the ongoing COVID-19 pandemic; for instance, practical research in the laboratory was hampered for several months during 2020. We have however adapted to ensure progress of the project, moving meetings and trainings to online and adapting some of the plans to accommodate this situation.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The application of an inter-disciplinary and unique approach, harnessing the synergy of combining chemical, biological and biophysics research strategies, allowed us to achieve an unprecedented knowledge of different molecular aspects at the basis of bacterial glycans recognition and binding by host immune proteins.
We are expecting that our results will greatly contribute to improve the understanding of the role of bacterial glycans in the interaction with host immune proteins, in the frame of human health and disease, and to gain deep insights into their mechanisms. The results we expect to obtain will be also crucial in inspiring the development of alternative strategies for the treatment of clinically relevant bacterial diseases improving human health.

Probing the mysteries of sweet “on-off” switches of the human immune system