Abstract
Avian influenza subtypes such as H5, H7 and H9 are yet to adapt to the human host so as to establish airborne transmission between humans. However, lab-generated reassorted viruses possessing hemagglutinin (HA) and neuraminidase (NA) genes from an avian H9 isolate and other genes from a human-adapted (H3 or H1) subtype acquired two amino acid changes in HA and a single amino acid change in NA that confer respiratory droplet transmission in ferrets. We previously demonstrated for human-adapted H1, H2 and H3 subtypes that quantitative binding affinity of their HA to α2→6 sialylated glycan receptors correlates with respiratory droplet transmissibility of the virus in ferrets. Such a relationship remains to be established for H9 HA. In this study, we performed a quantitative biochemical characterization of glycan receptor binding properties of wild-type and mutant forms of representative H9 HAs that were previously used in context of reassorted viruses in ferret transmission studies. We demonstrate here that distinct molecular interactions in the glycan receptor-binding site of different H9 HAs affect the glycan-binding specificity and affinity. Further we show that α2→6 glycan receptor-binding affinity of a mutant H9 HA carrying Thr-189→Ala amino acid change correlates with the respiratory droplet transmission in ferrets conferred by this change. Our findings contribute to a framework for monitoring the evolution of H9 HA by understanding effects of molecular changes in HA on glycan receptor-binding properties.
Highlights
Among subtypes of influenza A viruses isolated from avian species, H5N1, H7N2, H7N3, H7N7 and H9N2 have been known to infect humans but are yet to adapt to human host so as to establish airborne human-to-human transmission
In the past few years, novel influenza strains such as 2009 H1N1 and 2010 H3N2 that naturally emerged from multiple reassortment of viral gene segments between avian, swine and human isolates were able to successfully adapt to human host [1,2]
We focused on investigating the glycan receptorbinding specificity and affinity of H9 HAs from the representative avian isolates WF10 and A/Quail/Hong Kong/A28945/88 (Qa88) that had been recombinantly constructed via reverse genetics for ferret transmissibility studies carried out previously [15,16,17]
Summary
Among subtypes of influenza A viruses isolated from avian species, H5N1, H7N2, H7N3, H7N7 and H9N2 have been known to infect humans but are yet to adapt to human host so as to establish airborne human-to-human transmission. The transmissibility of humanadapted pandemic influenza strains, 1918 H1N1, 1957 H2N2 and 2009 H1N1, in ferrets has been demonstrated to correlate with the specificity and quantitative affinity of the viral surface glycoprotein hemagglutinin (HA) binding to a2R6 sialylated glycans (or human receptors) [7,8,9]. These human receptors are predominantly expressed in the respiratory tract epithelium of humans and ferrets [10,11,12]. The gain in the ability of HA from an avian isolate (such as H5, H7, H9, etc.) to preferentially bind to human receptors (high relative binding affinity to human receptor over avian receptor) is implicated as one of the important factors for the human adaptation of the virus [13]
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