A single-amino-acid substitution in the HA protein changes the replication and pathogenicity of the 2009 pandemic A (H1N1) influenza viruses in vitro and in vivo

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Abstract
The novel pandemic A (H1N1) virus was first identified in Mexico in April 2009 and since then it spread world wide over a short period of time. Although the virus infection is generally associated with mild disease and a relatively low mortality, it is projected that mutations in specific regions of the viral genome, especially within the receptor binding domain of the hemagglutinin (HA) protein could result in more virulent virus stains, leading to a more severe pandemic. Here, we found that a single amino acid substitution of Asp-to-Gly at position 222 in the HA protein of the A (H1N1) virus occurred after two passage propagation in the allantoic cavities of chicken embryonated eggs, and this single residue variation dramatically increased the viral replication ability in MDCK cells and pathogenicity in BALB/c mice. A substitution of Asp-to-Gly at position 222 in the HA protein was prone to occur under positive selection pressures, and this single amino acid mutation could dramatically increase the virus replication ability in vitro and pathogenicity in vivo. Our finding offers a better understanding of the transmission and evolution of the 2009 pandemic A (H1N1) virus and brings attention to further potentially severe influenza pandemic that may result from cross-host evolution of the influenza viruses.