A single mutation in Taiwanese H6N1 influenza hemagglutinin switches binding to human‐type receptors

Vries, Robert P. de; Tzarum, N.; Peng, Wenjie; Thompson, Andrew J.; Wickramasinghe, Iresha N. Ambepitiya; Pena, Alba T. Torrents de la; Breemen, Mariëlle J. van; Bouwman, Kim M.; Zhu, Xueyong; McBride, Ryan; Yu, Wenli; Sanders, Rogier W.; Verheije, Monique H.; Wilson, Ian A.; Paulson, James C.

doi:10.15252/emmm.201707726

Cited by 49 publications

(43 citation statements)

References 46 publications

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“…Such N-linked glycans with LacNAc repeats on their antennae have been reported in human and ferret respiratory tissues and in a human airway epithelial cell line (18,25,26). HA mutations that conferred similar human-type receptor specificity were also found for H7N9, H10N8, and H6N1 avian viruses (27)(28)(29). In all cases, the mutations allowed the ␣2-6-sialylated receptor glycan to extend from one RBS and project over the 190 helix in a way that would allow the other branch of the glycan to engage the second RBS of the same trimer.…”

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confidence: 64%

Enhanced Human-Type Receptor Binding by Ferret-Transmissible H5N1 with a K193T Mutation

Peng

Bouwman

McBride

et al. 2018

J Virol

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All human influenza pandemics have originated from avian influenza viruses. Although multiple changes are needed for an avian virus to be able to transmit between humans, binding to human-type receptors is essential. Several research groups have reported mutations in H5N1 viruses that exhibit specificity for human-type receptors and promote respiratory droplet transmission between ferrets. Upon detailed analysis, we have found that these mutants exhibit significant differences in fine receptor specificity compared to human H1N1 and H3N2 and retain avian-type receptor binding. We have recently shown that human influenza viruses preferentially bind to α2-6-sialylated branched N-linked glycans, where the sialic acids on each branch can bind to receptor sites on two protomers of the same hemagglutinin (HA) trimer. In this binding mode, the glycan projects over the 190 helix at the top of the receptor-binding pocket, which in H5N1 would create a stearic clash with lysine at position 193. Thus, we hypothesized that a K193T mutation would improve binding to branched N-linked receptors. Indeed, the addition of the K193T mutation to the H5 HA of a respiratory-droplet-transmissible virus dramatically improves both binding to human trachea epithelial cells and specificity for extended α2-6-sialylated N-linked glycans recognized by human influenza viruses. Infections by avian H5N1 viruses are associated with a high mortality rate in several species, including humans. Fortunately, H5N1 viruses do not transmit between humans because they do not bind to human-type receptors. In 2012, three seminal papers have shown how these viruses can be engineered to transmit between ferrets, the human model for influenza virus infection. Receptor binding, among others, was changed, and the viruses now bind to human-type receptors. Receptor specificity was still markedly different compared to that of human influenza viruses. Here we report an additional mutation in ferret-transmissible H5N1 that increases human-type receptor binding. K193T seems to be a common receptor specificity determinant, as it increases human-type receptor binding in multiple subtypes. The K193T mutation can now be used as a marker during surveillance of emerging viruses to assess potential pandemic risk.

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confidence: 64%

Enhanced Human-Type Receptor Binding by Ferret-Transmissible H5N1 with a K193T Mutation

Peng

Bouwman

McBride

et al. 2018

J Virol

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“…Surprisingly, our study implies that the HBV cross-species barrier is secured by a single-amino-acid change in the virus receptor. Several studies have reported that a single mutation on a virus envelope protein determines species specificity (64,65), but our insight is unique in showing that a single mutation in a host receptor plays a key role in determining the host specificity. It is not known whether all hepadnaviruses (or which hepadnaviruses) use NTCP as their entry receptor.…”

Section: Discussionmentioning

confidence: 89%

A Single Adaptive Mutation in Sodium Taurocholate Cotransporting Polypeptide Induced by Hepadnaviruses Determines Virus Species Specificity

Takeuchi

Fukano

Iwamoto

et al. 2019

J Virol

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Hepatitis B virus (HBV) and its hepadnavirus relatives infect a wide range of vertebrates, from fish to human. Hepadnaviruses and their hosts have a long history of acquiring adaptive mutations. However, there are no reports providing direct molecular evidence for such a coevolutionary “arms race” between hepadnaviruses and their hosts. Here, we present evidence suggesting that the adaptive evolution of the sodium taurocholate cotransporting polypeptide (NTCP), an HBV receptor, has been influenced by virus infection. Evolutionary analysis of the NTCP-encoding genes from 20 mammals showed that most NTCP residues are highly conserved among species, exhibiting evolution under negative selection (dN/dS ratio [ratio of nonsynonymous to synonymous evolutionary changes] of <1); this observation implies that the evolution of NTCP is restricted by maintaining its original protein function. However, 0.7% of NTCP amino acid residues exhibit rapid evolution under positive selection (dN/dS ratio of >1). Notably, a substitution at amino acid (aa) 158, a positively selected residue, converting the human NTCP to a monkey-type sequence abrogated the capacity to support HBV infection; conversely, a substitution at this residue converting the monkey Ntcp to the human sequence was sufficient to confer HBV susceptibility. Together, these observations suggested a close association of the aa 158 positive selection with the pressure by virus infection. Moreover, the aa 158 sequence determined attachment of the HBV envelope protein to the host cell, demonstrating the mechanism whereby HBV infection would create positive selection at this NTCP residue. In summary, we provide the first evidence in agreement with the function of hepadnavirus as a driver for inducing adaptive mutation in host receptor. IMPORTANCE HBV and its hepadnavirus relatives infect a wide range of vertebrates, with a long infectious history (hundreds of millions of years). Such a long history generally allows adaptive mutations in hosts to escape from infection while simultaneously allowing adaptive mutations in viruses to overcome host barriers. However, there is no published molecular evidence for such a coevolutionary arms race between hepadnaviruses and hosts. In the present study, we performed coevolutionary phylogenetic analysis between hepadnaviruses and the sodium taurocholate cotransporting polypeptide (NTCP), an HBV receptor, combined with virological experimental assays for investigating the biological significance of NTCP sequence variation. Our data provide the first molecular evidence supporting that HBV-related hepadnaviruses drive adaptive evolution in the NTCP sequence, including a mechanistic explanation of how NTCP mutations determine host viral susceptibility. Our novel insights enhance our understanding of how hepadnaviruses evolved with their hosts, permitting the acquisition of strong species specificity.

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“…Zoonotic IAV strains adapt to transmission among human hosts initially through changes in receptor specificity, increased HA stability, replication-enhancing polymerase mutations, and, subsequently, through antigenic drift within the HA head and addition of head-domain glycans. While research in many of these areas has matured significantly during the last decade, particularly with respect to receptor specificity switching (Chen et al, 2012;de Vries et al, 2017ade Vries et al, , 2017bSrinivasan et al, 2013;Tzarum et al, 2017;Yamada et al, 2006), details of IAV glycosylation and evolutionary or adaptive changes to the HA glycome remain poorly understood. This is in-part due to substantial technical challenges, meaning many studies employ non-sitespecific or poorly quantitative techniques to interpret glycosylation patterns, while more advanced methods have proved labor-intensive and extremely low-throughput, revealing only limited insights.…”

Section: Discussionmentioning

confidence: 99%

Human Influenza Virus Hemagglutinins Contain Conserved Oligomannose N-Linked Glycans Allowing Potent Neutralization by Lectins

Thompson

Cao

et al. 2020

Cell Host & Microbe

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A single mutation in Taiwanese H6N1 influenza hemagglutinin switches binding to human‐type receptors

Cited by 49 publications

References 46 publications

Enhanced Human-Type Receptor Binding by Ferret-Transmissible H5N1 with a K193T Mutation

Enhanced Human-Type Receptor Binding by Ferret-Transmissible H5N1 with a K193T Mutation

A Single Adaptive Mutation in Sodium Taurocholate Cotransporting Polypeptide Induced by Hepadnaviruses Determines Virus Species Specificity

Human Influenza Virus Hemagglutinins Contain Conserved Oligomannose N-Linked Glycans Allowing Potent Neutralization by Lectins

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