Viral genetic determinants of H5N1 influenza viruses that contribute to cytokine dysregulation.
Human disease caused by highly pathogenic avian influenza (H5N1) is associated with fulminant viral pneumonia and mortality rates in excess of 60%. Cytokine dysregulation is thought to contribute to its pathogenesis. In comparison with human seasonal influenza (H1N1) viruses, clade 1, 2.1, and 2.2 H5N1 viruses induced higher levels of tumor necrosis factor-alpha in primary human macrophages. To understand viral genetic determinants responsible for this hyperinduction of cytokines, we constructed recombinant viruses containing different combinations of genes from high-cytokine (A/Vietnam/1203/04) and low-cytokine (A/WSN/33) phenotype H1N1 viruses and tested their cytokine-inducing phenotype in human macrophages. Our results suggest that the H5N1 polymerase gene segments, and to a lesser extent the NS gene segment, contribute to cytokine hyperinduction in human macrophages and that a putative H5 pandemic virus that may arise through genetic reassortment between H5N1 and one of the current seasonal influenza viruses may have a markedly altered cytokine phenotype.
Mok
Ka Pun
KP
Department of Microbiology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pok Fu Lam, Hong Kong Special Administrative Region, People's Republic of China.
Wong
Charmaine H K
CHK
Department of Microbiology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pok Fu Lam, Hong Kong Special Administrative Region, People's Republic of China.
Cheung
Chung Y
CY
Department of Microbiology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pok Fu Lam, Hong Kong Special Administrative Region, People's Republic of China.
Chan
Michael C
MC
Department of Microbiology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pok Fu Lam, Hong Kong Special Administrative Region, People's Republic of China.
Lee
Suki M Y
SMY
Department of Microbiology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pok Fu Lam, Hong Kong Special Administrative Region, People's Republic of China.
Nicholls
John M
JM
Department of Pathology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pok Fu Lam, Hong Kong Special Administrative Region, People's Republic of China.
Guan
Yi
Y
Department of Microbiology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pok Fu Lam, Hong Kong Special Administrative Region, People's Republic of China.
Peiris
Joseph S M
JSM
Department of Microbiology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pok Fu Lam, Hong Kong Special Administrative Region, People's Republic of China.|HKU-Pasteur Research Centre, Pok Fu Lam, Hong Kong Special Administrative Region, People's Republic of China.
D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism; D015967:Gene Expression Regulation, Viral / Q000502:physiology; D006388:Hemagglutinins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype; D053124:Influenza A Virus, H5N1 Subtype / Q000145:classification / Q000235:genetics*; D007251:Influenza, Human / Q000821:virology; D009439:Neuraminidase / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D014764:Viral Proteins; D014779:Virus Replication
D016207:Cytokines; D006388:Hemagglutinins; D014764:Viral Proteins; D004259:DNA-Directed DNA Polymerase; D009439:Neuraminidase
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