HA and NA balance and role of mucus in influenza A virus infection

This project is aimed at better understanding the interaction of respiratory viruses with their glycan receptors and how they navigate through the heavily sialylated mucus barrier overlaying the epithelial cells of the respiratory tract, focussing on influenza A viruses and enterovirus-D68 (EV-D68).

Influenza A viruses infect birds and mammals such as swine and humans. They have sialic acid receptor-binding hemagglutinin (HA) and receptor-cleavage neuraminidase (NA) proteins. The functional balance between these proteins is thought to be important for host tropism and pathogenesis. This balance is poorly characterized and molecular details are largely lacking. In this project, we will focus on the HA-NA balance of human and swine influenza A viruses and the importance thereof for host tropism, with particular focus on the interaction of these viruses with the heavily sialylated mucus barrier overlaying the epithelial cells of the respiratory tract. The HA-NA balance of human and swine viruses will be studied for different functional and decoy receptors including mucus by using innovative biolayer interferometry assays (Guo et al., PLoS Pathog. 2018. 14(8):e1007233).

EV-D68 is an emerging respiratory virus that is also associated with paralysis. It also relies on sialic acid to infect cells, but this non-enveloped virus lacks a receptor-destroying enzyme. Whether mucus enhances or inhibits infection of epithelial cells is unknown. The role of sialic acid receptors as well as protein receptors for infection will be studied as well as the identity of the cell types that are infected with different EV-D68 strains.

For this project, we will establish airway epithelial cell cultures, of human and swine origin, which will be used for infection studies and for harvesting of mucus. Mucus samples will also be characterized in detail for their protein and glycan content and for their ability to inhibit virus infection.

Louisa Wallace