Moo-tating Threats: Decoding HA and NA functionalities to unmask H5Nx infections in novel hosts

• Applicant: Privatdozent Dr. El-Sayed Mohammed Abd El-Whab
• Subject Area: Virology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 566164996

H5Nx viruses have taken over the world in the last decade. Unprecedentedly transmitting to new regions such as the Antarctic and infecting novel hosts, including many carnivores and ruminants. Influenza A virus (IAV) has two major antigens, hemagglutinin (HA) and neuraminidase (NA), which are further distinguished into 19 and 11 antigenic subtypes. Both viral envelope proteins continuously evolve when transmitting from and to novel host species. Humans are immunologically naïve to H5Nx viruses, which pose a significant pandemic threat. The risks are at an all-time high with the establishment of an IAV lineage in cows, a major livestock species, and the virus's recent incursion into pigs. Not too long ago, ruminants were considered not to be hosts of IAV; thus, H5Nx influenza A viruses are outsmarting us. While outsmarting us, these viruses change receptor-binding properties, creating significant challenges in surveillance and analyses into interspecies transmission and adaptation to humans. It is paramount to understand how influenza viruses change their receptor interaction phenotypes. This will lead to an increased understanding of receptor binding and release of ever-changing pre-pandemic H5Nx viruses and will aid in better surveillance systems, novel opportunities for the development of antivirals, vaccines, diagnostics, and biologics, including monoclonal antibodies, antigens, and modified cell lines. IAV binds glycans to infect cells; these are omnipresent on eukaryotic cells and are differentially expressed between cells, tissues, and species. Glycan interactions of IAV are directly linked to their biological phenotypes. Yet, we only have a rudimentary understanding of which glycans are bound and which are eventually cleaved, leaving major biological questions to be answered. Therefore, this proposal aims to interrogate the multiple complexities of IAV glycan specificity. To achieve this goal, we strive to understand the molecular determinants of receptor specificity by H5 and Nx. Next, we will apply novel glycoscience tools to challenge the dogma of HA/NA balance profiles. The HAs and NAs in our studies will be interrogated using glycan and tissue arrays, elucidating receptor binding and release patterns. Understanding NA phenotypes has been a major afterthought but is essential to viral pathogenesis. Therefore, we will investigate NA's role in modulating receptor availability, facilitating zoonotic transmission, and influencing viral competition and the persistence of emerging H5Nx subtypes. We expect that these approaches will reveal the complexities of pathobiology related to glycan-binding and release of the virus to improve predictive models and additional tools as options for the control of influenza.

• DFG Programme: Research Grants
• International Connection: Netherlands
• Cooperation Partner: Professor Robert P. de Vries