The road to a pandemic - molecular barriers for interspecies transmission of influenza A virus

Influenza A viruses (IAV) intermittently cross species barriers and cause epizootics, epidemics and pandemics.

We will explore and characterize such barriers that can be i) virus related, e.g. host specific signals (HSS) within the virus genome, ii) host related, e.g. intracellular host proteins, or iii) virus-host cell interaction related, e.g. receptor binding.

We will identify HSS associated with avian vs human hosts by training an RNA sequence transformer model and using AI explainability techniques to extract relevant features. We will then study their effect by constructing recombinant viruses and assessing their phenotypes in vitro.

Potential host intracellular species barriers will be identified using single-cell transcriptomics in IAV-infected avian and mammalian primary cells and studied in recombinant cell lines.

IAV-host receptor interactions will be studied using glycoproteomics and adhesion/receptor cleavage assays with defined glycan structures. Finally, phenotypes of recombinant viruses will be assessed in chicken and ferret animal models.

The outcome will increase our understanding of specific species barriers and their interplay in IAV and beyond, and contribute to improved strategies to prevent pandemics.