Dissecting the role of the HA1-226 leucine residue in the fitness and airborne transmission of an A(H9N2) avian influenza virus

Although the capacity for human-like receptor binding is a key prerequisite for non-human origin influenza A virus (IAV) to become airborne transmissible in mammalian hosts, the underlying molecular basis is not well understood. In this study, we investigated a naturally occurring substitution (leucine to glutamine) at residue 226 in the HA of an avian-origin A(H9N2) virus and assessed the impact on virus replication and airborne transmission in the ferret model. We demonstrate that the enhanced airborne transmission associated with the HA1-L226 virus was mainly due to the increased infectivity of the virus. Interestingly, we found that, unlike most sites in the ferret respiratory tract, ferret ethmoid turbinate lined with olfactory epithelium favors replication of the AL/39-HA1-L226Q virus, suggesting that this site may serve as a unique niche for IAV with avian-like receptor binding specificity to potentially allow the virus to spread to extrapulmonary tissues and to facilitate adaptation of the virus to human hosts.