The Potential for Respiratory Droplet-Transmissible A/H5N1 Influenza Virus to Evolve in a Mammalian Host

Department of Zoology, University of Cambridge, Cambridge, UK.
Science (Impact Factor: 33.61). 06/2012; 336(6088):1541-7. DOI: 10.1126/science.1222526
Source: PubMed


Avian A/H5N1 influenza viruses pose a pandemic threat. As few as five amino acid substitutions, or four with reassortment, might be sufficient for mammal-to-mammal transmission through respiratory droplets. From surveillance data, we found that two of these substitutions are common in A/H5N1 viruses, and thus, some viruses might require only three additional substitutions to become transmissible via respiratory droplets between mammals. We used a mathematical model of within-host virus evolution to study factors that could increase and decrease the probability of the remaining substitutions evolving after the virus has infected a mammalian host. These factors, combined with the presence of some of these substitutions in circulating strains, make a virus evolving in nature a potentially serious threat. These results highlight critical areas in which more data are needed for assessing, and potentially averting, this threat.

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    • "Public health concerns have mostly centered on the potential of contemporary avian influenza subtype viruses to mutate or reassort with other influenza subtypes to a form that could become transmissible among humans. As a result, multiple studies have been performed to assess the molecular determinants of avian H5, H7 and H9 virus adaptation, pathogenicity and transmissibility in mammalian hosts (Maines et al., 2006; Salomon et al., 2006; Chen et al., 2012; Russell et al., 2012; Herfst et al., 2012; Sorrell et al., 2009). However, relatively less attention has been given to H2 subtype viruses largely due to their sporadic isolation and low pathogenicity in both avian and mammalian species (Pappas et al., 2010; Jones et al., 2014). "
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    ABSTRACT: After their disappearance from the human population in 1968, influenza H2 viruses have continued to circulate in the natural avian reservoir. The isolation of this virus subtype from multiple bird species as well as swine highlights the need to better understand the potential of these viruses to spread and cause disease in humans. Here we analyzed the virulence, transmissibility and receptor-binding preference of two avian influenza H2 viruses (H2N2 and H2N3) and compared them to a swine H2N3 (A/swine/Missouri/2124514/2006 [swMO]), and a human H2N2 (A/England/10/1967 [Eng/67]) virus using the ferret model as a mammalian host. Both avian H2 viruses possessed the capacity to spread efficiently between cohoused ferrets, and the swine (swMO) and human (Eng/67) viruses transmitted to naïve ferrets by respiratory droplets. Further characterization of the swMO hemagglutinin (HA) by x-ray crystallography and glycan microarray array identified receptor-specific adaptive mutations. As influenza virus quasispecies dynamics during transmission have not been well characterized, we sequenced nasal washes collected during transmission studies to better understand experimental adaptation of H2 HA. The avian H2 viruses isolated from ferret nasal washes contained mutations in the HA1, including a Gln226Leu substitution, which is a mutation associated with α2,6 sialic acid (human-like) binding preference. These results suggest that the molecular structure of HA in viruses of the H2 subtype continue to have the potential to adapt to a mammalian host and become transmissible, after acquiring additional genetic markers.
    Virology 03/2015; 477. DOI:10.1016/j.virol.2015.01.002 · 3.32 Impact Factor
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    • "Two of these 4 mutations (N158D and N224K) have lost their glycosylation sequons (Imai et al., 2012). Furthermore, the substitutions of the glycosylation sequon on HA have drifted in and out of the avian virus population over time, which might have been caused by little selective pressure (Russell et al., 2012). In addition, additional glycans in the globular head of HA resulted in substantially attenuated infection in H1N1 virus (Kim et al., 2013; Medina et al., 2013). "
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    ABSTRACT: Cleavage of the hemagglutinin (HA) precursor (HA0) by trypsin, which produces the active HA1 and HA2 complex, is a critical step for activating the avian influenza virus (AIV). However, other tryptic cleavage sites on HA might also cause HA degradation and affect the virulence. Otherwise, HA is modified by glycosylation in the host cell. The conjugated glycans on HA may hinder the antigenic epitopes, and thus prevent the virus from being recognized and attacked by the antibodies. In this study, we observed that glycosylation at the Asn-167 (N167) site on the HA1 of the H6N1 AIV strain A/chicken/Taiwan/2838V/00 (2838V) protected Arg-201 (R201) from tryptic cleavage. The 2838V HA protein became sensitive to tryptic cleavage, whereas the glycans at N167 were removed by N-glycosidase F (PNGase-F). Furthermore, the infectivity of 2838V decreased when pretreated with PNGase-F and trypsin. Our observations suggest that the inaccessibility of the R201 residue of HA1 for tryptic cleavage, which is sterically hindered by glycosylation at N167, is a crucial factor for determining the infectivity of the AIV. Copyright © 2014. Published by Elsevier B.V.
    Virus Research 02/2015; 197:101-107. DOI:10.1016/j.virusres.2014.12.010 · 2.32 Impact Factor
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    • "Transmission from human to human occurs sporadically, usually during care of patients (Ungchusak et al., 2005; Wang et al., 2008; WHO, 2008). But as shown in a ferret model only few mutations of the H5N1 virus are necessary to acquire airborne transmission (Herfst et al., 2012; Imai et al., 2012; Russell et al., 2012) and the segmented genome additionally favours reassortment and the production of a virus that can cause a human pandemic. These findings emphasise the urgent need for improved easy to perform and sensitive diagnostic tests for emergency diagnosis to timely initiate anti-viral therapy. "
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    ABSTRACT: H5-specific monoclonal antibodies may serve as valuable tools for rapid diagnosis of H5N1 avian influenza virus. Therefore, conserved H5-specific sequences of the haemagglutinin (HA) protein were expressed in Pichia pastoris and used for generation of monoclonal antibodies (mAbs). The two mAbs, FD6 and HE4, were strongly reactive against native HA protein and exhibited specificity for subtype H5. By epitope mapping linear epitopes of mAbs were identified that are highly conserved among influenza A virus of subtype H5. Additionally no sequence similarities to homologous regions on HA proteins of other influenza A virus subtypes (i.e. H1, H3, H7, H9) were detected by sequence alignment analysis. Both mAbs did not cross react with native or denatured HA proteins of other influenza A virus subtypes. Furthermore, using ELISA and immunofluorescence test mAb FD6 reacted only to the native H5 protein of recently circulating highly pathogenic H5N1 influenza viruses but not to low pathogenic H5N1 isolates. In conclusion, the use of the two mAbs in non-molecular tests like antigen-capture-ELISA appears promising for detecting influenza A H5N1 virus. Copyright © 2015. Published by Elsevier B.V.
    Virus Research 01/2015; 199. DOI:10.1016/j.virusres.2015.01.006 · 2.32 Impact Factor
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