tetano
Editor, Senior Moderator
J Virol. 2010 Sep 15. [Epub ahead of print]
Virulence-associated substitution D222G in hemagglutinin of 2009 pandemic influenza A(H1N1) virus affects receptor binding.
Chutinimitkul S, Herfst S, Steel J, Lowen AC, Ye J, van Riel D, Schrauwen EJ, Bestebroer TM, Koel B, Burke DF, Sutherland-Cash KH, Whittleston CS, Russell CA, Wales DJ, Smith DJ, Jonges M, Meijer A, Koopmans M, Rimmelzwaan GF, Kuiken T, Osterhaus AD, Garcia-Sastre A, Perez DR, Fouchier RA.
National Influenza Center and Department of Virology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Microbiology, Mount Sinai School of Medicine, New York, USA; Department of Veterinary Medicine, University of Maryland, College Park, Maryland, USA; Department of Zoology, University of Cambridge, Downing Street, Cambridge, CB2 3EJ, UK; University Chemical Laboratories, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK; National Institute for Public Health and the Environment, Laboratory for Infectious Diseases and Screening, Bilthoven, The Netherlands; Department of Medicine, Division of Infectious Diseases, Mount Sinai School of Medicine, New York, USA; Global Health and Emerging Pathogens Institute, Mount Sinai School of Medicine, New York, USA; Fogarty International Center, National Institutes of Health, Bethesda, Maryland, USA.
Abstract
The clinical impact of the 2009 pandemic influenza A(H1N1) virus (pdmH1N1) has been relatively low. However, amino acid substitution D222G in the hemagglutinin of pdmH1N1 has been associated with cases of severe disease and fatalities. Here, D222G was introduced in a prototype pdmH1N1 by reverse genetics, and the effect on virus receptor binding, replication, antigenic properties, and pathogenesis and transmission in animal models was investigated. pdmH1N1 with D222G caused ocular disease in mice without further indications of enhanced virulence in mice and ferrets. pdmH1N1 with D222G retained transmissibility via aerosols or respiratory droplets in ferrets and guinea pigs. The virus displayed changes in attachment to human respiratory tissues in vitro, in particular increased binding to macrophages and type II pneumocytes in the alveoli and to tracheal and bronchial submucosal glands. Virus attachment studies further indicated that pdmH1N1 with D222G acquired dual receptor specificity for complex α2,3- and α2,6-linked sialic acids. Molecular dynamics modeling of the hemagglutinin structure provided an explanation for the retention of α2,6 binding. Altered receptor specificity of the virus with D222G thus affected interaction with cells of the human lower respiratory tract, possibly explaining the observed association with enhanced disease in humans.
PMID: 20844044 [PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/20844044
Virulence-associated substitution D222G in hemagglutinin of 2009 pandemic influenza A(H1N1) virus affects receptor binding.
Chutinimitkul S, Herfst S, Steel J, Lowen AC, Ye J, van Riel D, Schrauwen EJ, Bestebroer TM, Koel B, Burke DF, Sutherland-Cash KH, Whittleston CS, Russell CA, Wales DJ, Smith DJ, Jonges M, Meijer A, Koopmans M, Rimmelzwaan GF, Kuiken T, Osterhaus AD, Garcia-Sastre A, Perez DR, Fouchier RA.
National Influenza Center and Department of Virology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Microbiology, Mount Sinai School of Medicine, New York, USA; Department of Veterinary Medicine, University of Maryland, College Park, Maryland, USA; Department of Zoology, University of Cambridge, Downing Street, Cambridge, CB2 3EJ, UK; University Chemical Laboratories, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK; National Institute for Public Health and the Environment, Laboratory for Infectious Diseases and Screening, Bilthoven, The Netherlands; Department of Medicine, Division of Infectious Diseases, Mount Sinai School of Medicine, New York, USA; Global Health and Emerging Pathogens Institute, Mount Sinai School of Medicine, New York, USA; Fogarty International Center, National Institutes of Health, Bethesda, Maryland, USA.
Abstract
The clinical impact of the 2009 pandemic influenza A(H1N1) virus (pdmH1N1) has been relatively low. However, amino acid substitution D222G in the hemagglutinin of pdmH1N1 has been associated with cases of severe disease and fatalities. Here, D222G was introduced in a prototype pdmH1N1 by reverse genetics, and the effect on virus receptor binding, replication, antigenic properties, and pathogenesis and transmission in animal models was investigated. pdmH1N1 with D222G caused ocular disease in mice without further indications of enhanced virulence in mice and ferrets. pdmH1N1 with D222G retained transmissibility via aerosols or respiratory droplets in ferrets and guinea pigs. The virus displayed changes in attachment to human respiratory tissues in vitro, in particular increased binding to macrophages and type II pneumocytes in the alveoli and to tracheal and bronchial submucosal glands. Virus attachment studies further indicated that pdmH1N1 with D222G acquired dual receptor specificity for complex α2,3- and α2,6-linked sialic acids. Molecular dynamics modeling of the hemagglutinin structure provided an explanation for the retention of α2,6 binding. Altered receptor specificity of the virus with D222G thus affected interaction with cells of the human lower respiratory tract, possibly explaining the observed association with enhanced disease in humans.
PMID: 20844044 [PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/20844044