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Abstract
H9N2 avian influenza viruses circulate worldwide in poultry and have sporadically infected humans, raising concern whether H9N2 viruses have pandemic potential. Here, we use a guinea pig model to examine whether serial passage results in adaptive viral changes that confer a transmissible phenotype to a wild-type H9N2 virus. After nine serial passages of an H9N2 virus through guinea pigs, productive transmission by direct contact occurred in 2/3 guinea pig pairs. The efficiency of transmission by direct contact increased following the fifteenth passage and occurred in 3/3 guinea pig pairs. In contrast, airborne transmission of the passaged virus was less efficient and occurred in 1/6 guinea pig pairs and 0/6 ferret pairs after the fifteenth passage. Three amino acid substitutions, HA1-Q227P, HA2-D46E, and NP-E434K, were sufficient for contact transmission in guinea pigs (2/3 pairs). The two HA amino acid substitutions enhanced receptor binding to α2,3-linked sialic acid receptors. Additionally, the HA2-D46E substitution increased virus thermostability whereas the NP-E434K mutation enhanced viral RNA polymerase activity in vitro. Our findings suggest that adaptive changes that enhance viral receptor binding, thermostability, and replicative capacity in mammalian cells can collectively enhance the transmissibility of H9N2 AIVs by direct contact in the guinea pig model.
Highlights
These findings suggest that mammalian adaptation of H9N2 viruses may generate viruses capable of transmission by direct contact in mammals, additional amino acid substitutions are likely required for efficient airborne transmission
Three amino acid substitutions introduced into the H9N2 avian influenza virus (AIV) during serial passage (HA1-Q227P, HA2-D46E, and NP-E434K or HA1-Q227P, NP-E434K, and PB2-D195N) were sufficient to increase contact transmission efficiency between guinea pigs (2/3 pairs)
We explored the mechanistic basis by which these three amino acid substitutions may contribute to the ability of the adapted H9N2 virus to transmit by direct contact
Summary
Several experimental approaches have been used to explore the capacity of avian influenza subtypes to acquire a transmissible phenotype These approaches rely upon the genetic reassortment of an avian subtype virus with a human influenza virus, the adaptation of an avian subtype virus in mammals through serial passage, or a combination of both of the above. These approaches have been used to demonstrate that reassortant H5N1 viruses containing 2009/H1N1 genes were capable of respiratory droplet-mediated transmission in guinea pigs and ferrets[16,17,18]. These findings suggest that mammalian adaptation of H9N2 viruses may generate viruses capable of transmission by direct contact in mammals, additional amino acid substitutions are likely required for efficient airborne transmission
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