Abstract
The 2009 H1N1 influenza A virus continues to circulate among the human population as the predominant H1N1 subtype. Epidemiological studies and airborne transmission studies using the ferret model have shown that the transmission efficiency of 2009 H1N1 viruses is lower than that of previous seasonal strains and the 1918 pandemic H1N1 strain. We recently correlated this reduced transmission efficiency to the lower binding affinity of the 2009 H1N1 hemagglutinin (HA) to α2→6 sialylated glycan receptors (human receptors). Here we report that a single point mutation (Ile219→Lys; a base pair change) in the glycan receptor-binding site (RBS) of a representative 2009 H1N1 influenza A virus, A/California/04/09 or CA04/09, quantitatively increases its human receptor-binding affinity. The increased human receptor-affinity is in the same range as that of the HA from highly transmissible seasonal and 1918 pandemic H1N1 viruses. Moreover, a 2009 H1N1 virus carrying this mutation in the RBS (generated using reverse genetics) transmits efficiently in ferrets by respiratory droplets thereby reestablishing our previously observed correlation between human receptor-binding affinity and transmission efficiency. These findings are significant in the context of monitoring the evolution of the currently circulating 2009 H1N1 viruses.
Highlights
On June 11, 2009, the World Health Organization raised the global pandemic alert to phase 6, the pandemic phase [1], in response to the emergence and global spread of a novel H1N1 influenza A virus
Using prototypic pandemic strains, such as 1918 H1N1 and 1957-58 H2N2, we have previously demonstrated that the binding affinity of HA to human receptors is one important factor that correlates with the transmissibility of the virus via respiratory droplets in ferrets [10,11,12]
We demonstrate that a single Ile219RLys mutation in the receptor-binding site (RBS) of 2009 H1N1 HA (CA04/09mut1) substantially increases its human receptor affinity in comparison with that of CA04/09 HA
Summary
On June 11, 2009, the World Health Organization raised the global pandemic alert to phase 6, the pandemic phase [1], in response to the emergence and global spread of a novel H1N1 influenza A virus (referred to as 2009 H1N1). Using prototypic pandemic strains, such as 1918 H1N1 and 1957-58 H2N2, we have previously demonstrated that the binding affinity of HA to human receptors is one important factor that correlates with the transmissibility of the virus via respiratory droplets in ferrets [10,11,12]. We extended this finding to 2009 H1N1 by characterizing the glycan-receptor binding specificity and affinity of the CA04/09 HA These studies demonstrated that CA04/09 HA bound to human receptors on a glycan array platform and on human upper respiratory epithelia, and showed no detectable binding to a2R3 sialylated glycans (referred to as avian receptors) [9]. Our approach to identify HA mutations that improve human receptor affinity and transmissibility of the virus is significant in the context of surveillance of the evolution of the currently circulating 2009 H1N1 virus
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