title: Highly pathogenic avian influenza H5N1 virus delays apoptotic responses via activation of STAT3.
abstract: Highly pathogenic avian influenza (HPAI) H5N1 virus continues to pose pandemic threat, but there is a lack of understanding of its pathogenesis. We compared the apoptotic responses triggered by HPAI H5N1 and low pathogenic H1N1 viruses using physiologically relevant respiratory epithelial cells. We demonstrated that H5N1 viruses delayed apoptosis in primary human bronchial and alveolar epithelial cells (AECs) compared to H1N1 virus. Both caspase-8 and -9 were activated by H5N1 and H1N1 viruses in AECs, while H5N1 differentially up-regulated TRAIL. H5N1-induced apoptosis was reduced by TRAIL receptor silencing. More importantly, STAT3 knock-down increased apoptosis by H5N1 infection suggesting that H5N1 virus delays apoptosis through activation of STAT3. Taken together, we demonstrate that STAT3 is involved in H5N1-delayed apoptosis compared to H1N1. Since delay in apoptosis prolongs the duration of virus replication and production of pro-inflammatory cytokines and TRAIL from H5N1-infected cells, which contribute to orchestrate cytokine storm and tissue damage, our results suggest that STAT3 may play a previously unsuspected role in H5N1 pathogenesis.
authors.affiliation: Centre of Influenza Research and School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Kenrie P Y
authors.initials: KP
authors.lastname: Hui
authors.affiliation: Centre of Influenza Research and School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Hung Sing
authors.initials: HS
authors.lastname: Li
authors.affiliation: Centre of Influenza Research and School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Man Chun
authors.initials: MC
authors.lastname: Cheung
authors.affiliation: Centre of Influenza Research and School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.|Department of Paediatrics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Renee W Y
authors.initials: RW
authors.lastname: Chan
authors.affiliation: Centre of Influenza Research and School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Kit M
authors.initials: KM
authors.lastname: Yuen
authors.affiliation: Centre of Influenza Research and School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.|The HKU-Pasteur Research Pole, School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Chris K P
authors.initials: CK
authors.lastname: Mok
authors.affiliation: Department of Pathology, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China.
authors.forename: John M
authors.initials: JM
authors.lastname: Nicholls
authors.affiliation: Centre of Influenza Research and School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: J S Malik
authors.initials: JS
authors.lastname: Peiris
authors.affiliation: Centre of Influenza Research and School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Michael C W
authors.initials: MC
authors.lastname: Chan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001717:Birds; D001980:Bronchi / Q000378:metabolism / Q000821:virology; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004285:Dogs; D004847:Epithelial Cells / Q000378:metabolism / Q000821:virology; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000821:virology; D053118:Influenza A Virus, H1N1 Subtype / Q000472:pathogenicity; D053124:Influenza A Virus, H5N1 Subtype / Q000472:pathogenicity*; D005585:Influenza in Birds / Q000378:metabolism*; D007251:Influenza, Human / Q000378:metabolism / Q000821:virology; D061985:Madin Darby Canine Kidney Cells; D009976:Orthomyxoviridae Infections; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D014779:Virus Replication / Q000502:physiology
chemical_list: D016207:Cytokines; D050796:STAT3 Transcription Factor; D053181:Caspase 8; D053453:Caspase 9