Enhanced virulence of influenza A viruses with the haemagglutinin of the 1918 pandemic virus.
The 'Spanish' influenza pandemic of 1918-19 was the most devastating outbreak of infectious disease in recorded history. At least 20 million people died from their illness, which was characterized by an unusually severe and rapid clinical course. The complete sequencing of several genes of the 1918 influenza virus has made it possible to study the functions of the proteins encoded by these genes in viruses generated by reverse genetics, a technique that permits the generation of infectious viruses entirely from cloned complementary DNA. Thus, to identify properties of the 1918 pandemic influenza A strain that might be related to its extraordinary virulence, viruses were produced containing the viral haemagglutinin (HA) and neuraminidase (NA) genes of the 1918 strain. The HA of this strain supports the pathogenicity of a mouse-adapted virus in this animal. Here we demonstrate that the HA of the 1918 virus confers enhanced pathogenicity in mice to recent human viruses that are otherwise non-pathogenic in this host. Moreover, these highly virulent recombinant viruses expressing the 1918 viral HA could infect the entire lung and induce high levels of macrophage-derived chemokines and cytokines, which resulted in infiltration of inflammatory cells and severe haemorrhage, hallmarks of the illness produced during the original pandemic.
Department of Pathobiological Sciences, University of Wisconsin, Madison, Wisconsin 53706, USA.
Darwyn
D
Kobasa
Ayato
A
Takada
Kyoko
K
Shinya
Masato
M
Hatta
Peter
P
Halfmann
Steven
S
Theriault
Hiroshi
H
Suzuki
Hidekazu
H
Nishimura
Keiko
K
Mitamura
Norio
N
Sugaya
Taichi
T
Usui
Takeomi
T
Murata
Yasuko
Y
Maeda
Shinji
S
Watanabe
M
M
Suresh
Takashi
T
Suzuki
Yasuo
Y
Suzuki
Heinz
H
Feldmann
Yoshihiro
Y
Kawaoka
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D001667:Binding, Competitive; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D004285:Dogs; D005814:Genes, Viral / Q000235:genetics; D005818:Genetic Engineering; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006470:Hemorrhage / Q000150:complications / Q000473:pathology / Q000821:virology; D006801:Humans; D007106:Immune Sera / Q000276:immunology; D007223:Infant; D009980:Influenza A virus / Q000235:genetics* / Q000276:immunology / Q000472:pathogenicity*; D007251:Influenza, Human / Q000150:complications / Q000453:epidemiology* / Q000473:pathology / Q000821:virology*; D008168:Lung / Q000473:pathology / Q000821:virology; D051379:Mice; D008875:Middle Aged; D009439:Neuraminidase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009500:Neutralization Tests; D011995:Recombination, Genetic / Q000235:genetics; D013997:Time Factors; D014774:Virulence / Q000235:genetics; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*
D000914:Antibodies, Viral; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007106:Immune Sera; D037521:Virulence Factors; D009439:Neuraminidase