Compatibility of H9N2 avian influenza surface genes and 2009 pandemic H1N1 internal genes for transmission in the ferret model

Department of Veterinary Medicine, University of Maryland, College Park, MD 20742, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 07/2011; 108(29):12084-8. DOI: 10.1073/pnas.1108058108
Source: PubMed


In 2009, a novel H1N1 influenza (pH1N1) virus caused the first influenza pandemic in 40 y. The virus was identified as a triple reassortant between avian, swine, and human influenza viruses, highlighting the importance of reassortment in the generation of viruses with pandemic potential. Previously, we showed that a reassortant virus composed of wild-type avian H9N2 surface genes in a seasonal human H3N2 backbone could gain efficient respiratory droplet transmission in the ferret model. Here we determine the ability of the H9N2 surface genes in the context of the internal genes of a pH1N1 virus to efficiently transmit via respiratory droplets in ferrets. We generated reassorted viruses carrying the HA gene alone or in combination with the NA gene of a prototypical H9N2 virus in the background of a pH1N1 virus. Four reassortant viruses were generated, with three of them showing efficient respiratory droplet transmission. Differences in replication efficiency were observed for these viruses; however, the results clearly indicate that H9N2 avian influenza viruses and pH1N1 viruses, both of which have occasionally infected pigs, have the potential to reassort and generate novel viruses with respiratory transmission potential in mammals.

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    • "Based on this information, Kimble et al. (2011) generated reassortants composed of 2009 pandemic H1N1 vRNA segments and the HA or HA/NA vRNA segments of the H9N2 ferret-transmissible virus, or the parent of the ferret-transmissible virus. Three of four reassortant viruses transmitted via respiratory droplets to naïve ferrets (Kimble et al., 2011), further demonstrating the potential of avian/human reassortants to transmit among mammals via respiratory droplets. "
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    ABSTRACT: Influenza A viruses cause respiratory infections that range from asymptomatic to deadly in humans. Widespread outbreaks (pandemics) are attributable to 'novel' viruses that possess a viral hemagglutinin (HA) gene to which humans lack immunity. After a pandemic, these novel viruses form stable virus lineages in humans and circulate until they are replaced by other novel viruses. The factors and mechanisms that facilitate virus transmission among hosts and the establishment of novel lineages are not completely understood, but the HA and basic polymerase 2 (PB2) proteins are thought to play essential roles in these processes by enabling avian influenza viruses to infect mammals and replicate efficiently in their new host. Here, we summarize our current knowledge of the contributions of HA, PB2, and other viral components to virus transmission and the formation of new virus lineages. Copyright © 2015 Elsevier Inc. All rights reserved.
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    • "However a natural variant of 1918 H1N1 HA isolated from humans which has a single amino acid mutation in the RBS (A/New York/1/18) shows a similar relative binding affinity as that of the mCC:LS and mFC: LS HAs. This observation warrants further investigation of the aerosol transmission in ferrets of reassorted viruses carrying these mutant H7 HAs in context of other human adapted genes similar to the previous studies carried out for H9 and H5 subtypes [7], [8]. "
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    ABSTRACT: In the context of recently emerged novel influenza strains through reassortment, avian influenza subtypes such as H5N1, H7N7, H7N2, H7N3 and H9N2 pose a constant threat in terms of their adaptation to the human host. Among these subtypes, it was recently demonstrated that mutations in H5 and H9 hemagglutinin (HA) in the context of lab-generated reassorted viruses conferred aerosol transmissibility in ferrets (a property shared by human adapted viruses). We previously demonstrated that the quantitative binding affinity of HA to α2→6 sialylated glycans (human receptors) is one of the important factors governing human adaptation of HA. Although the H7 subtype has infected humans causing varied clinical outcomes from mild conjunctivitis to severe respiratory illnesses, it is not clear where the HA of these subtypes stand in regard to human adaptation since its binding affinity to glycan receptors has not yet been quantified. In this study, we have quantitatively characterized the glycan receptor-binding specificity of HAs from representative strains of Eurasian (H7N7) and North American (H7N2) lineages that have caused human infection. Furthermore, we have demonstrated for the first time that two specific mutations; Gln226→Leu and Gly228→Ser in glycan receptor-binding site of H7 HA substantially increase its binding affinity to human receptor. Our findings contribute to a framework for monitoring the evolution of H7 HA to be able to adapt to human host.
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    • "It was demonstrated that among different avian H9N2 isolates, those with Leu-226 in the RBS showed a similar tropism of preferentially infecting non-ciliated human airway epithelial cells (characteristic of human-adapted viruses) [14]. Although the H9N2 virus is yet to adapt to a human host, reassorted viruses carrying HA and NA from a H9N2 virus isolated from a wild terrestrial bird (A/Guinea Fowl/Hong Kong/WF10/99 or WF10) and other genes from human-adapted H3N2 [15] or 2009 pandemic H1N1 [16] have been able to transmit via respiratory droplet in ferrets by acquiring as few as two amino acid changes in the HA, Thr-189→Ala in the RBS and Gly-192→Arg in the HA2 subunit. "
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    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.
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