title: Cellular response to influenza virus infection: a potential role for autophagy in CXCL10 and interferon-alpha induction.
abstract: Historically, influenza pandemics have arisen from avian influenza viruses. Avian influenza viruses H5N1 and H9N2 are potential pandemic candidates. Infection of humans with the highly pathogenic avian influenza H5N1 virus is associated with a mortality in excess of 60%, which has been attributed to dysregulation of the cytokine system. Human macrophages and epithelial cells infected with some genotypes of H5N1 and H9N2 viruses express markedly elevated cytokine and chemokine levels when compared with seasonal influenza A subtype H1N1 virus. The mechanisms underlying this cytokine and chemokine hyperinduction are not fully elucidated. In the present study, we demonstrate that autophagy, a tightly regulated homeostatic process for self-digestion of unwanted cellular subcomponents, plays a role in cytokine induction. Autophagy is induced to a greater extent by H9N2/G1, in association with cytokine hyperinduction, compared with H1N1 and the novel pandemic swine-origin influenza A/H1N1 viruses. Using 3-methyladenine to inhibit autophagy and small interfering RNA to silence the autophagy gene, Atg5, we further show that autophagic responses play a role in influenza virus-induced CXCL10 and interferon-alpha expression in primary human blood macrophages. Our results provide new insights into the pathogenic mechanisms of avian influenza viruses.
authors.affiliation: Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Anna Hing-Yee
authors.initials: AH
authors.lastname: Law
authors.forename: Davy Chun-Wai
authors.initials: DC
authors.lastname: Lee
authors.forename: Kwok-Yung
authors.initials: KY
authors.lastname: Yuen
authors.forename: Malik
authors.initials: M
authors.lastname: Peiris
authors.forename: Allan Sik-Yin
authors.initials: AS
authors.lastname: Lau
mesh_terms: D000818:Animals; D001343:Autophagy / Q000276:immunology*; D000071187:Autophagy-Related Protein 5; D054357:Chemokine CXCL10 / Q000096:biosynthesis*; D004285:Dogs; D055785:Gene Knockdown Techniques; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology; D053124:Influenza A Virus, H5N1 Subtype / Q000276:immunology; D053127:Influenza A Virus, H9N2 Subtype / Q000276:immunology; D009980:Influenza A virus / Q000276:immunology*; D007251:Influenza, Human / Q000276:immunology* / Q000821:virology*; D016898:Interferon-alpha / Q000096:biosynthesis*; D008869:Microtubule-Associated Proteins / Q000276:immunology; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000821:virology; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: C502778:ATG5 protein, human; D000071187:Autophagy-Related Protein 5; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D016898:Interferon-alpha; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering
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