Virulence-associated substitution D222G in the hemagglutinin of 2009 pandemic influenza A(H1N1) virus affects receptor binding.
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 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.
Chutinimitkul
Salin
S
Department of Virology, Erasmus Medical Center Rotterdam, Rotterdam, Netherlands.
Herfst
Sander
S
Steel
John
J
Lowen
Anice C
AC
Ye
Jianqiang
J
van Riel
Debby
D
Schrauwen
Eefje J A
EJ
Bestebroer
Theo M
TM
Koel
Björn
B
Burke
David F
DF
Sutherland-Cash
Kyle H
KH
Whittleston
Chris S
CS
Russell
Colin A
CA
Wales
David J
DJ
Smith
Derek J
DJ
Jonges
Marcel
M
Meijer
Adam
A
Koopmans
Marion
M
Rimmelzwaan
Guus F
GF
Kuiken
Thijs
T
Osterhaus
Albert D M E
AD
García-Sastre
Adolfo
A
Perez
Daniel R
DR
Fouchier
Ron A M
RA
D020816:Amino Acid Motifs; D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D005289:Ferrets; D006168:Guinea Pigs; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology*; D007251:Influenza, Human / Q000453:epidemiology / Q000378:metabolism* / Q000635:transmission / Q000821:virology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D019158:N-Acetylneuraminic Acid / Q000737:chemistry / Q000378:metabolism; D058873:Pandemics; D011991:Receptors, Virus / Q000737:chemistry / Q000378:metabolism*; D014422:Turkeys; D014774:Virulence; D053585:Virus Attachment
D019267:Hemagglutinin Glycoproteins, Influenza Virus; D011991:Receptors, Virus; D019158:N-Acetylneuraminic Acid