Determinants of Influenza a Diffusion Through the Mucus Barrier to Infection

Abstract

Lung airway mucus is the first line of defense against inhaled infectious materials. A breakdown in mucus barrier function can lead to increased infections by respiratory viruses like influenza as they are not effectively removed from the airway. Thus, the infectivity of these viruses will depend on if these particles are capable of maneuvering through the mucus barrier to infection. In this study, influenza A virus (IAV) and nanoparticle diffusion in human mucus was quantified using multiple particle tracking. In previous work, it was determined mucin-associated sialic acid (SA) may act as decoy receptors for hemagglutinin binding by IAVs, but its passage through the mucus gel layer is facilitated through the sialic-acid cleaving enzyme, neuraminidase (NA), also abundant on the IAV capsid surface. We investigated the impact of inhibition of neuraminidase (NA) on IAV diffusion through mucus. Our current data suggests the mobility of IAV in mucus is primarily influenced by the mesh structure of the gel, as measured by nanoparticle probes, and NA activity is unlikely sufficient to facilitate their passage through more densely cross-linked mucus barriers. Given the enhanced susceptibility to infection of patients with airway diseases (e.g. bronchitis, asthma), we examined if the composition of mucus observed in diseases influenced its barrier function. IAV was introduced into a synthetic mucus (SM) model, allowing for direct control of mucin composition. Interestingly, our initial findings show that in SM with composition similar to individuals with airway disease that IAV diffuse more rapidly than in ‘healthy-like’ SM. This study provides important insights on how IAV initiates infection in the airway. In future work, we aim to study virus-associated factors (e.g. glycan binding preference, pleomorphism) that confer IAV with the ability to diffuse and penetrate through airway mucus.