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1.
Cell ; 153(7): 1475-85, 2013 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-23746829

RESUMO

Of the factors governing human-to-human transmission of the highly pathogenic avian-adapted H5N1 virus, the most critical is the acquisition of mutations on the viral hemagglutinin (HA) to "quantitatively switch" its binding from avian to human glycan receptors. Here, we describe a structural framework that outlines a necessary set of H5 HA receptor-binding site (RBS) features required for the H5 HA to quantitatively switch its preference to human receptors. We show here that the same RBS HA mutations that lead to aerosol transmission of A/Vietnam/1203/04 and A/Indonesia/5/05 viruses, when introduced in currently circulating H5N1, do not lead to a quantitative switch in receptor preference. We demonstrate that HAs from circulating clades require as few as a single base pair mutation to quantitatively switch their binding to human receptors. The mutations identified by this study can be used to monitor the emergence of strains having human-to-human transmission potential.


Assuntos
Glicoproteínas de Hemaglutininação de Vírus da Influenza/química , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Virus da Influenza A Subtipo H5N1/química , Influenza Aviária/virologia , Influenza Humana/transmissão , Influenza Humana/virologia , Sequência de Aminoácidos , Animais , Aves , Evolução Molecular , Glicoproteínas de Hemaglutininação de Vírus da Influenza/metabolismo , Especificidade de Hospedeiro , Humanos , Virus da Influenza A Subtipo H5N1/patogenicidade , Virus da Influenza A Subtipo H5N1/fisiologia , Influenza Humana/epidemiologia , Modelos Moleculares , Dados de Sequência Molecular , Mutação , Ácido N-Acetilneuramínico/metabolismo , Filogenia , Receptores Virais/química , Receptores Virais/metabolismo , Alinhamento de Sequência
2.
Cell ; 153(7): 1486-93, 2013 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-23746830

RESUMO

The advent of H7N9 in early 2013 is of concern for a number of reasons, including its capability to infect humans, the lack of clarity in the etiology of infection, and because the human population does not have pre-existing immunity to the H7 subtype. Earlier sequence analyses of H7N9 hemagglutinin (HA) point to amino acid changes that predicted human receptor binding and impinge on the antigenic characteristics of the HA. Here, we report that the H7N9 HA shows limited binding to human receptors; however, should a single amino acid mutation occur, this would result in structural changes within the receptor binding site that allow for extensive binding to human receptors present in the upper respiratory tract. Furthermore, a subset of the H7N9 HA sequences demarcating coevolving amino acids appears to be in the antigenic regions of H7, which, in turn, could impact effectiveness of the current WHO-recommended prepandemic H7 vaccines.


Assuntos
Glicoproteínas de Hemaglutininação de Vírus da Influenza/metabolismo , Vírus da Influenza A/classificação , Vírus da Influenza A/fisiologia , Influenza Humana/virologia , Receptores Virais/metabolismo , Sequência de Aminoácidos , Glicoproteínas de Hemaglutininação de Vírus da Influenza/química , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Especificidade de Hospedeiro , Humanos , Vírus da Influenza A/química , Vírus da Influenza A/genética , Vacinas contra Influenza/imunologia , Modelos Moleculares , Dados de Sequência Molecular , Mutação , Filogenia , Polissacarídeos/metabolismo , Receptores Virais/química , Traqueia/virologia
3.
Sci Rep ; 6: 21428, 2016 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-26888262

RESUMO

An influenza H3N8 virus, carrying mammalian adaptation mutations, was isolated from New England harbor seals in 2011. We sought to assess the risk of its human transmissibility using two complementary approaches. First, we tested the binding of recombinant hemagglutinin (HA) proteins of seal H3N8 and human-adapted H3N2 viruses to respiratory tissues of humans and ferrets. For human tissues, we observed strong tendency of the seal H3 to bind to lung alveoli, which was in direct contrast to the human-adapted H3 that bound mainly to the trachea. This staining pattern was also consistent in ferrets, the primary animal model for human influenza pathogenesis. Second, we compared the binding of the recombinant HAs to a library of 610 glycans. In contrast to the human H3, which bound almost exclusively to α-2,6 sialylated glycans, the seal H3 bound preferentially to α-2,3 sialylated glycans. Additionally, the seal H3N8 virus replicated in human lung carcinoma cells. Our data suggest that the seal H3N8 virus has retained its avian-like receptor binding specificity, but could potentially establish infection in human lungs.


Assuntos
Glicoproteínas de Hemaglutininação de Vírus da Influenza/metabolismo , Vírus da Influenza A Subtipo H3N8/fisiologia , Tropismo Viral/fisiologia , Replicação Viral/fisiologia , Animais , Linhagem Celular Tumoral , Embrião de Galinha , Cães , Humanos , Células Madin Darby de Rim Canino , Especificidade da Espécie
4.
Sci Rep ; 3: 1822, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23661027

RESUMO

The 2009 swine-origin H1N1 influenza, though antigenically novel to the population at the time, was antigenically similar to the 1918 H1N1 pandemic influenza, and consequently was considered to be "archived" in the swine species before reemerging in humans. Given that the H3N2 is another subtype that currently circulates in the human population and is high on WHO pandemic preparedness list, we assessed the likelihood of reemergence of H3N2 from a non-human host. Using HA sequence features relevant to immune recognition, receptor binding and transmission we have identified several recent H3 strains in avian and swine that present hallmarks of a reemerging virus. IgG polyclonal raised in rabbit with recent seasonal vaccine H3 fail to recognize these swine H3 strains suggesting that existing vaccines may not be effective in protecting against these strains. Vaccine strategies can mitigate risks associated with a potential H3N2 pandemic in humans.


Assuntos
Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Vírus da Influenza A Subtipo H3N2/imunologia , Influenza Aviária/imunologia , Influenza Humana/imunologia , Infecções por Orthomyxoviridae/veterinária , Doenças dos Suínos/imunologia , Sequência de Aminoácidos , Animais , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Aves , Reações Cruzadas/imunologia , Saúde Global/estatística & dados numéricos , Glicoproteínas de Hemaglutininação de Vírus da Influenza/química , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Humanos , Vírus da Influenza A Subtipo H3N2/classificação , Vírus da Influenza A Subtipo H3N2/genética , Influenza Aviária/epidemiologia , Influenza Humana/epidemiologia , Modelos Moleculares , Dados de Sequência Molecular , Conformação Proteica , Alinhamento de Sequência , Suínos , Doenças dos Suínos/epidemiologia
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