TY - JOUR
T1 - Virulence-Associated Substitution D222G in the Hemagglutinin of 2009 Pandemic Influenza A(H1N1) Virus Affects Receptor Binding
AU - Chutinimitkul, Salin
AU - Herfst, Sander
AU - Steel, John
AU - Lowen, Anice C.
AU - Ye, Jianqiang
AU - van Riel, Debby
AU - Schrauwen, Eefje J. A.
AU - Bestebroer, Theo M.
AU - Koel, Björn
AU - Burke, David F.
AU - Sutherland-Cash, Kyle H.
AU - Whittleston, Chris S.
AU - Russell, Colin A.
AU - Wales, David J.
AU - Smith, Derek J.
AU - Jonges, Marcel
AU - Meijer, Adam
AU - Koopmans, Marion
AU - Rimmelzwaan, Guus F.
AU - Kuiken, Thijs
AU - Osterhaus, Albert D. M. E.
AU - García-Sastre, Adolfo
AU - Perez, Daniel R.
AU - Fouchier, Ron A. M.
PY - 2010
Y1 - 2010
N2 - 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. 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 alpha 2,3- and alpha 2,6-linked sialic acids. Molecular dynamics modeling of the hemagglutinin structure provided an explanation for the retention of alpha 2,6 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
AB - 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. 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 alpha 2,3- and alpha 2,6-linked sialic acids. Molecular dynamics modeling of the hemagglutinin structure provided an explanation for the retention of alpha 2,6 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
U2 - https://doi.org/10.1128/JVI.01136-10
DO - https://doi.org/10.1128/JVI.01136-10
M3 - Article
C2 - 20844044
SN - 0022-538X
VL - 84
SP - 11802
EP - 11813
JO - Journal of Virology
JF - Journal of Virology
IS - 22
ER -