Transmission of human influenza A virus in pigs selects for adaptive mutations on the HA gene

Authors: MO, JONG-SUK - University Of Georgia; Abente, Eugenio; SUTTON, TROY - Pennsylvania State University; FERRERI, LUCAS - University Of Georgia; GEIGER, GINGER - University Of Georgia; GAUGER, PHILLIP - Iowa State University; PEREZ, DANIEL - University Of Georgia; Baker, Amy; RAJAO, DANIELA - University Of Georgia

Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/1/2022
Publication Date: 11/20/2022
Citation: Mo, J., Abente, E.J., Sutton, T.C., Ferreri, L.M., Geiger, G., Gauger, P.C., Perez, D.R., Baker, A.L., Rajao, D.S. 2022. Transmission of human influenza A virus in pigs selects for adaptive mutations on the HA gene. Journal of Virology. 96(22). Article e01480-22. https://doi.org/10.1128/jvi.01480-22.
DOI: https://doi.org/10.1128/jvi.01480-22

Interpretive Summary: People continue to spread seasonal influenza A viruses (IAV) to pigs. This allows exchange of the viral genetic material in 8 gene segments with endemic swine IAV in a process called reassortment. However, little is known about the adaptation processes that are needed for a human-origin IAV to transmit and become established in pigs. We tested a reassorted human H3N2 with 6 of the 8 genes similar to those found in endemic U.S. swine IAV that resulted in transmission from pig to pig. The transmitted virus acquired a change in the hemagglutinin gene, encoding a key protein of the influenza virus, that was associated with increased infectivity and transmission. These results highlight changes needed for a human seasonal IAV to infect and be maintained in swine, with important implications for the swine industry to prevent, identify, and respond to a new introduction before it spreads among pigs.

Technical Abstract: Influenza A viruses (IAV) are known to cause respiratory diseases in many host species, including humans and pigs. The spillover of IAV between swine and humans have been a concern for both public health and the swine industry. With the emergence of the triple reassortant internal gene (TRIG) constellation, establishment of human-origin IAVs in pigs has become more common, leading to increased viral diversity. However, little is known about the adaptation processes that are needed for a human-origin IAV to transmit and become established in pigs. We generated a reassortant IAV containing surface gene segments from a human IAV strain and internal gene segments from the 2009 pandemic and TRIG IAV lineages and demonstrated that it can replicate and transmit in pigs. Deep sequencing and variant calling analysis identified a variant that emerged during replication in pigs, which was mapped to a region near the receptor binding site of the hemagglutinin (HA). The variant was present in all contact pigs and replicated more efficiently in differentiated swine tracheal cells compared to the virus containing the wildtype human-origin HA. These results show that variants are selected quickly after replication of human-origin HA in pigs, leading to improved fitness in the swine host, likely contributing to transmission.