Elucidating the molecular mechanism by which BTN3A3 mediates host restriction against zoonotic influenza virus infection.

Avian influenza viruses (AIV) pose a constant socio-economic threat to humanity due to their potential to cause novel pandemics. This risk is underscored by recent reports of mammalian species infected with highly pathogenic strains of AIV. To develop effective drugs and improve risk assessment, a detailed understanding of the molecular mechanisms of AIV infection is crucial. AIV are typical emerging zoonotic pathogens capable of crossing into new species. This depends on two factors: i) the new host must support viral replication, and ii) restrictive factors that inhibit infection must be evaded. One significant barrier to AIV infections in humans is the limited activity of avian-adapted viral ribonucleoprotein complexes. These complexes consist of one genomic RNA segment, nucleoproteins, and a viral polymerase. Recently, the host factor BTN3A3 was identified as a critical restriction element for zoonotic AIV, influencing cross-species viral evolution. However, the exact mechanisms through which BTN3A3 restricts the virus, and how the virus evades this restriction, remain unclear. This study involves structural investigations conducted directly within infected cells at nanometer resolution by in situ cryo-electron tomography, an approach that is significantly pushing beyond the current state-of-the-art thereby setting new paradigms in the understanding of molecular infection mechanisms. The primary objective is to elucidate how viral host-adaptation mutations evade BTN3A3 restriction with the overarching goals to i) improve pandemic risk assessment tools, ii) reveal new drug targets, and iii) serve as a proof-of-principle for studying restriction factors during infection with other zoonotic viruses. This research will be conducted under the supervision of Dr. Petr Chlanda at Heidelberg University, where I will have access to world-class facilities and training opportunities, supporting my growth as an independent researcher.