Three mutations switch H7N9 influenza to human-type receptor specificity

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Abstract
The avian H7N9 influenza outbreak in 2013 resulted from an unprecedented incidence of influenza transmission to humans from infected poultry. The majority of human H7N9 isolates contained a hemagglutinin (HA) mutation (Q226L) that has previously been associated with a switch in receptor specificity from avian-type (NeuAcα2-3Gal) to human-type (NeuAcα2-6Gal), as documented for the avian progenitors of the 1957 (H2N2) and 1968 (H3N2) human influenza pandemic viruses. While this raised concern that the H7N9 virus was adapting to humans, the mutation was not sufficient to switch the receptor specificity of H7N9, and has not resulted in sustained transmission in humans. To determine if the H7 HA was capable of acquiring human-type receptor specificity, we conducted mutation analyses. Remarkably, three amino acid mutations conferred a switch in specificity for human-type receptors that resembled the specificity of the 2009 human H1 pandemic virus, and promoted binding to human trachea epithelial cells. Influenza A virus of the H7N9 subtype continues to cross the species barrier from poultry to humans. This zoonotic ability is remarkable as the virus retains specificity to avian-type receptors. To effectively transmit between humans, the virus needs to acquire human-type receptor specificity. In this study, we show that recombinant H7 proteins need three amino acid mutations to change specificity to human-type receptors. Although we are not allowed to assess if these mutations would lead to efficient transmission in the ferret model, this knowledge will aid in surveillance. If these amino acid mutations are observed to arise during natural selection in humans, timely actions could be taken.
Funding Information
  • National Institutes of Health (AI114730)
  • National Institutes of Health (AI117675)
  • National Institutes of Health (GM103390)
  • National Institutes of Health (GM100058)
  • National Institutes of Health (GM62116)
  • Rubicon and VENI (Netherlands Organization for Scientific Research (NWO))
  • Kwang Hua Education Foundation
  • European Molecular Biology Organization (ALTF 963-2014)