Inflammatory, transcriptomic, and cell fate responses underlying the mammalian transmission of avian influenza viruses.

Airborne transmissibility of avian influenza viruses (AIVs) in humans is considered an essential component of their pandemic risk. Although several viral factors regulating airborne transmission (AT) have been delineated, it is not known what, if any, responses at the respiratory epithelia are determinants of AIV AT. Using responses in the ferret nasal epithelium to a panel of H1N1 AIVs, we describe host responses that segregate with AT phenotypes. AIV infection upregulated interferon alpha and gamma responses and IL-6 JAK-STAT signaling and downregulated oxidative phosphorylation. Single-cell transcriptomics revealed that cellular genotoxic stress and NF-kB, interferon, and cell fate pathways differentiated host responses to AIVs with different transmissibilities. These responses culminated in greater AIV antigen-containing exudate and debris in the respiratory spaces of the nasal epithelium of ferrets inoculated with AT AIVs. More abundant CMPK2, SP100, and CXCL10 transcription in infected epithelia was a hallmark of AT viruses. Overall, our study reveals host responses associated with AIV infection and transmission in the nasal epithelium, the determinant anatomical site of influenza virus transmission.IMPORTANCEAirborne transmission (AT) is a critical component of the pandemic risks posed by avian influenza A viruses (AIVs). However, the host responses ultimately dictating transmissibility elicited by AIVs in the upper respiratory tract of mammals, the determinant site of influenza virus AT, are largely unknown. We identified host responses in the nasal epithelium of the upper respiratory tract differentially expressed in response to infection by AIVs of different mammalian ATs. Our data indicate that a definable host response was associated with AT of AIVs. These data would serve as an important basis for future mechanistic studies of AIV zoonosis and potentially have implications for understanding the mechanisms of transmission of respiratory viruses between humans.