The HA and NS Genes of Human H5N1 Influenza A Virus Contribute to High Virulence in Ferrets
Highly pathogenic H5N1 influenza A viruses have spread across Asia, Europe, and Africa. More than 500 cases of H5N1 virus infection in humans, with a high lethality rate, have been reported. To understand the molecular basis for the high virulence of H5N1 viruses in mammals, we tested the virulence...
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| Published in | PLoS pathogens Vol. 6; no. 9; p. e1001106 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Public Library of Science
01.09.2010
Public Library of Science (PLoS) |
| Subjects | |
| Online Access | Get full text |
| ISSN | 1553-7374 1553-7366 1553-7374 |
| DOI | 10.1371/journal.ppat.1001106 |
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| Abstract | Highly pathogenic H5N1 influenza A viruses have spread across Asia, Europe, and Africa. More than 500 cases of H5N1 virus infection in humans, with a high lethality rate, have been reported. To understand the molecular basis for the high virulence of H5N1 viruses in mammals, we tested the virulence in ferrets of several H5N1 viruses isolated from humans and found A/Vietnam/UT3062/04 (UT3062) to be the most virulent and A/Vietnam/UT3028/03 (UT3028) to be avirulent in this animal model. We then generated a series of reassortant viruses between the two viruses and assessed their virulence in ferrets. All of the viruses that possessed both the UT3062 hemagglutinin (HA) and nonstructural protein (NS) genes were highly virulent. By contrast, all those possessing the UT3028 HA or NS genes were attenuated in ferrets. These results demonstrate that the HA and NS genes are responsible for the difference in virulence in ferrets between the two viruses. Amino acid differences were identified at position 134 of HA, at positions 200 and 205 of NS1, and at positions 47 and 51 of NS2. We found that the residue at position 134 of HA alters the receptor-binding property of the virus, as measured by viral elution from erythrocytes. Further, both of the residues at positions 200 and 205 of NS1 contributed to enhanced type I interferon (IFN) antagonistic activity. These findings further our understanding of the determinants of pathogenicity of H5N1 viruses in mammals. |
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| AbstractList | Highly pathogenic H5N1 influenza A viruses have spread across Asia, Europe, and Africa. More than 500 cases of H5N1 virus infection in humans, with a high lethality rate, have been reported. To understand the molecular basis for the high virulence of H5N1 viruses in mammals, we tested the virulence in ferrets of several H5N1 viruses isolated from humans and found A/Vietnam/UT3062/04 (UT3062) to be the most virulent and A/Vietnam/UT3028/03 (UT3028) to be avirulent in this animal model. We then generated a series of reassortant viruses between the two viruses and assessed their virulence in ferrets. All of the viruses that possessed both the UT3062 hemagglutinin (HA) and nonstructural protein (NS) genes were highly virulent. By contrast, all those possessing the UT3028 HA or NS genes were attenuated in ferrets. These results demonstrate that the HA and NS genes are responsible for the difference in virulence in ferrets between the two viruses. Amino acid differences were identified at position 134 of HA, at positions 200 and 205 of NS1, and at positions 47 and 51 of NS2. We found that the residue at position 134 of HA alters the receptor-binding property of the virus, as measured by viral elution from erythrocytes. Further, both of the residues at positions 200 and 205 of NS1 contributed to enhanced type I interferon (IFN) antagonistic activity. These findings further our understanding of the determinants of pathogenicity of H5N1 viruses in mammals.Highly pathogenic H5N1 influenza A viruses have spread across Asia, Europe, and Africa. More than 500 cases of H5N1 virus infection in humans, with a high lethality rate, have been reported. To understand the molecular basis for the high virulence of H5N1 viruses in mammals, we tested the virulence in ferrets of several H5N1 viruses isolated from humans and found A/Vietnam/UT3062/04 (UT3062) to be the most virulent and A/Vietnam/UT3028/03 (UT3028) to be avirulent in this animal model. We then generated a series of reassortant viruses between the two viruses and assessed their virulence in ferrets. All of the viruses that possessed both the UT3062 hemagglutinin (HA) and nonstructural protein (NS) genes were highly virulent. By contrast, all those possessing the UT3028 HA or NS genes were attenuated in ferrets. These results demonstrate that the HA and NS genes are responsible for the difference in virulence in ferrets between the two viruses. Amino acid differences were identified at position 134 of HA, at positions 200 and 205 of NS1, and at positions 47 and 51 of NS2. We found that the residue at position 134 of HA alters the receptor-binding property of the virus, as measured by viral elution from erythrocytes. Further, both of the residues at positions 200 and 205 of NS1 contributed to enhanced type I interferon (IFN) antagonistic activity. These findings further our understanding of the determinants of pathogenicity of H5N1 viruses in mammals. Highly pathogenic H5N1 influenza A viruses have spread across Asia, Europe, and Africa. More than 500 cases of H5N1 virus infection in humans, with a high lethality rate, have been reported. To understand the molecular basis for the high virulence of H5N1 viruses in mammals, we tested the virulence in ferrets of several H5N1 viruses isolated from humans and found A/Vietnam/UT3062/04 (UT3062) to be the most virulent and A/Vietnam/UT3028/03 (UT3028) to be avirulent in this animal model. We then generated a series of reassortant viruses between the two viruses and assessed their virulence in ferrets. All of the viruses that possessed both the UT3062 hemagglutinin (HA) and nonstructural protein (NS) genes were highly virulent. By contrast, all those possessing the UT3028 HA or NS genes were attenuated in ferrets. These results demonstrate that the HA and NS genes are responsible for the difference in virulence in ferrets between the two viruses. Amino acid differences were identified at position 134 of HA, at positions 200 and 205 of NS1, and at positions 47 and 51 of NS2. We found that the residue at position 134 of HA alters the receptor-binding property of the virus, as measured by viral elution from erythrocytes. Further, both of the residues at positions 200 and 205 of NS1 contributed to enhanced type I interferon (IFN) antagonistic activity. These findings further our understanding of the determinants of pathogenicity of H5N1 viruses in mammals. Highly pathogenic H5N1 influenza A viruses have caused more than 500 human infections with approximately 60% lethality in 15 countries and continue to pose a pandemic threat. The recent worldwide spread of pandemic H1N1 influenza A viruses raises the concern of reassortment between the H5N1 viruses and other influenza viruses. However, the molecular determinants for high virulence of the H5N1 viruses in mammals are not fully understood. We, therefore, investigated their virulence in a ferret model, which is a widely accepted animal model for assessing human influenza virus replication. We identified an amino acid in hemagglutinin and four amino acids in nonstructural proteins that are associated with high virulence of a human H5N1 virus, A/Vietnam/UT3062/04. We also found that the amino acid in hemagglutinin changes its receptor-binding property and the amino acids in nonstructural protein 1 affect its interferon antagonistic ability. These findings provide insight into the pathogenesis of H5N1 viruses in mammals. Highly pathogenic H5N1 influenza A viruses have spread across Asia, Europe, and Africa. More than 500 cases of H5N1 virus infection in humans, with a high lethality rate, have been reported. To understand the molecular basis for the high virulence of H5N1 viruses in mammals, we tested the virulence in ferrets of several H5N1 viruses isolated from humans and found A/Vietnam/UT3062/04 (UT3062) to be the most virulent and A/Vietnam/UT3028/03 (UT3028) to be avirulent in this animal model. We then generated a series of reassortant viruses between the two viruses and assessed their virulence in ferrets. All of the viruses that possessed both the UT3062 hemagglutinin (HA) and nonstructural protein (NS) genes were highly virulent. By contrast, all those possessing the UT3028 HA or NS genes were attenuated in ferrets. These results demonstrate that the HA and NS genes are responsible for the difference in virulence in ferrets between the two viruses. Amino acid differences were identified at position 134 of HA, at positions 200 and 205 of NS1, and at positions 47 and 51 of NS2. We found that the residue at position 134 of HA alters the receptor-binding property of the virus, as measured by viral elution from erythrocytes. Further, both of the residues at positions 200 and 205 of NS1 contributed to enhanced type I interferon (IFN) antagonistic activity. These findings further our understanding of the determinants of pathogenicity of H5N1 viruses in mammals. Highly pathogenic H5N1 influenza A viruses have caused more than 500 human infections with approximately 60% lethality in 15 countries and continue to pose a pandemic threat. The recent worldwide spread of pandemic H1N1 influenza A viruses raises the concern of reassortment between the H5N1 viruses and other influenza viruses. However, the molecular determinants for high virulence of the H5N1 viruses in mammals are not fully understood. We, therefore, investigated their virulence in a ferret model, which is a widely accepted animal model for assessing human influenza virus replication. We identified an amino acid in hemagglutinin and four amino acids in nonstructural proteins that are associated with high virulence of a human H5N1 virus, A/Vietnam/UT3062/04. We also found that the amino acid in hemagglutinin changes its receptor-binding property and the amino acids in nonstructural protein 1 affect its interferon antagonistic ability. These findings provide insight into the pathogenesis of H5N1 viruses in mammals. Highly pathogenic H5N1 influenza A viruses have spread across Asia, Europe, and Africa. More than 500 cases of H5N1 virus infection in humans, with a high lethality rate, have been reported. To understand the molecular basis for the high virulence of H5N1 viruses in mammals, we tested the virulence in ferrets of several H5N1 viruses isolated from humans and found A/Vietnam/UT3062/04 (UT3062) to be the most virulent and A/Vietnam/UT3028/03 (UT3028) to be avirulent in this animal model. We then generated a series of reassortant viruses between the two viruses and assessed their virulence in ferrets. All of the viruses that possessed both the UT3062 hemagglutinin (HA) and nonstructural protein (NS) genes were highly virulent. By contrast, all those possessing the UT3028 HA or NS genes were attenuated in ferrets. These results demonstrate that the HA and NS genes are responsible for the difference in virulence in ferrets between the two viruses. Amino acid differences were identified at position 134 of HA, at positions 200 and 205 of NS1, and at positions 47 and 51 of NS2. We found that the residue at position 134 of HA alters the receptor-binding property of the virus, as measured by viral elution from erythrocytes. Further, both of the residues at positions 200 and 205 of NS1 contributed to enhanced type I interferon (IFN) antagonistic activity. These findings further our understanding of the determinants of pathogenicity of H5N1 viruses in mammals. Highly pathogenic H5N1 influenza A viruses have spread across Asia, Europe, and Africa. More than 500 cases of H5N1 virus infection in humans, with a high lethality rate, have been reported. To understand the molecular basis for the high virulence of H5N1 viruses in mammals, we tested the virulence in ferrets of several H5N1 viruses isolated from humans and found A/Vietnam/UT3062/04 (UT3062) to be the most virulent and A/Vietnam/UT3028/03 (UT3028) to be avirulent in this animal model. We then generated a series of reassortant viruses between the two viruses and assessed their virulence in ferrets. All of the viruses that possessed both the UT3062 hemagglutinin (HA) and nonstructural protein (NS) genes were highly virulent. By contrast, all those possessing the UT3028 HA or NS genes were attenuated in ferrets. These results demonstrate that the HA and NS genes are responsible for the difference in virulence in ferrets between the two viruses. Amino acid differences were identified at position 134 of HA, at positions 200 and 205 of NS1, and at positions 47 and 51 of NS2. We found that the residue at position 134 of HA alters the receptor-binding property of the virus, as measured by viral elution from erythrocytes. Further, both of the residues at positions 200 and 205 of NS1 contributed to enhanced type I interferon (IFN) antagonistic activity. These findings further our understanding of the determinants of pathogenicity of H5N1 viruses in mammals. |
| Audience | Academic |
| Author | Nidom, Chairul A. Shimojima, Masayuki Kakugawa, Satoshi Muramoto, Yukiko Iwatsuki-Horimoto, Kiyoko Goto, Hideo Takahashi, Kei Kiso, Maki Takano, Ryo Imai, Hirotaka Noda, Takeshi Kawaoka, Yoshihiro Sakabe, Saori Sakai-Tagawa, Yuko Omori, Yasuyuki Ito, Mutsumi Shinya, Kyoko Le, Mai thi Quynh Yamada, Shinya Horimoto, Taisuke Murakami, Shin |
| AuthorAffiliation | 3 The International Center for Medical Research and Treatment, Kobe University, Kobe, Japan 4 National Institute of Hygiene and Epidemiology, Hanoi, Vietnam Mount Sinai School of Medicine, United States of America 1 Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan 5 Avian Influenza Laboratory, Tropical Disease Centre, Airlangga University, Surabaya, Indonesia 6 Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, The University of Tokyo, Tokyo, Japan 7 School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America 2 ERATO Infection-induced Host Responses Project, Saitama, Japan |
| AuthorAffiliation_xml | – name: 2 ERATO Infection-induced Host Responses Project, Saitama, Japan – name: 7 School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America – name: Mount Sinai School of Medicine, United States of America – name: 3 The International Center for Medical Research and Treatment, Kobe University, Kobe, Japan – name: 5 Avian Influenza Laboratory, Tropical Disease Centre, Airlangga University, Surabaya, Indonesia – name: 6 Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, The University of Tokyo, Tokyo, Japan – name: 1 Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan – name: 4 National Institute of Hygiene and Epidemiology, Hanoi, Vietnam |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/20862325$$D View this record in MEDLINE/PubMed |
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| Copyright | COPYRIGHT 2010 Public Library of Science Imai et al. 2010 2010 Imai et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Imai H, Shinya K, Takano R, Kiso M, Muramoto Y, et al. (2010) The HA and NS Genes of Human H5N1 Influenza A Virus Contribute to High Virulence in Ferrets. PLoS Pathog 6(9): e1001106. doi:10.1371/journal.ppat.1001106 |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1 Conceived and designed the experiments: HI YM SM SY YK. Performed the experiments: HI KS RT MK YM SS MI KT YO TN MS SK HG KIH TH. Analyzed the data: HI KS YK. Contributed reagents/materials/analysis tools: HI SS MI MtQL CAN YST. Wrote the paper: HI KS YK. |
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| Snippet | Highly pathogenic H5N1 influenza A viruses have spread across Asia, Europe, and Africa. More than 500 cases of H5N1 virus infection in humans, with a high... Highly pathogenic H5N1 influenza A viruses have spread across Asia, Europe, and Africa. More than 500 cases of H5N1 virus infection in humans, with a high... |
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| SubjectTerms | Amino acids Animal models Animals Avian flu Avian influenza viruses Cells, Cultured Diseases Dogs Erythrocytes Experiments Ferrets Genes Genetic aspects Grants Hemagglutinin Glycoproteins, Influenza Virus - genetics Hemagglutinin Glycoproteins, Influenza Virus - metabolism Hemagglutinins Humans Infection Infections Infectious Diseases Infectious Diseases/Viral Infections Influenza A Influenza A virus Influenza A Virus, H5N1 Subtype - isolation & purification Influenza A Virus, H5N1 Subtype - pathogenicity Influenza virus Influenza, Human - genetics Influenza, Human - pathology Influenza, Human - virology Interferon Interferons - metabolism Kidney - cytology Kidney - metabolism Kidney - virology Lethality Lung - cytology Lung - metabolism Lung - virology Male Microbiology Microbiology/Immunity to Infections Mink Mortality Mustela Mutation - genetics Nonstructural proteins Orthomyxoviridae Infections - genetics Orthomyxoviridae Infections - pathology Orthomyxoviridae Infections - virology Pandemics Pathogenicity Pathogens Pathology Replication Respiratory Medicine/Respiratory Infections Viral Nonstructural Proteins - genetics Viral Nonstructural Proteins - metabolism Virology Virology/Animal Models of Infection Virology/Effects of Virus Infection on Host Gene Expression Virology/Emerging Viral Diseases Virology/Host Antiviral Responses Virology/Virulence Factors and Mechanisms Virulence Virulence (Microbiology) Virulence - physiology Viruses |
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| Title | The HA and NS Genes of Human H5N1 Influenza A Virus Contribute to High Virulence in Ferrets |
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