title: Species difference in ANP32A underlies influenza A virus polymerase host restriction.
abstract: Influenza pandemics occur unpredictably when zoonotic influenza viruses with novel antigenicity acquire the ability to transmit amongst humans. Host range breaches are limited by incompatibilities between avian virus components and the human host. Barriers include receptor preference, virion stability and poor activity of the avian virus RNA-dependent RNA polymerase in human cells. Mutants of the heterotrimeric viral polymerase components, particularly PB2 protein, are selected during mammalian adaptation, but their mode of action is unknown. We show that a species-specific difference in host protein ANP32A accounts for the suboptimal function of avian virus polymerase in mammalian cells. Avian ANP32A possesses an additional 33 amino acids between the leucine-rich repeats and carboxy-terminal low-complexity acidic region domains. In mammalian cells, avian ANP32A rescued the suboptimal function of avian virus polymerase to levels similar to mammalian-adapted polymerase. Deletion of the avian-specific sequence from chicken ANP32A abrogated this activity, whereas its insertion into human ANP32A, or closely related ANP32B, supported avian virus polymerase function. Substitutions, such as PB2(E627K), were rapidly selected upon infection of humans with avian H5N1 or H7N9 influenza viruses, adapting the viral polymerase for the shorter mammalian ANP32A. Thus ANP32A represents an essential host partner co-opted to support influenza virus replication and is a candidate host target for novel antivirals.
authors.affiliation: Section of Virology, Department of Medicine, Imperial College London, St Mary's Campus, London W2 1PG, UK.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Long
authors.affiliation: Section of Virology, Department of Medicine, Imperial College London, St Mary's Campus, London W2 1PG, UK.
authors.forename: Efstathios S
authors.initials: ES
authors.lastname: Giotis
authors.affiliation: Centre d'études d'agents Pathogènes et Biotechnologies pour la Santé (CPBS), FRE 3689, CNRS-UM, 34293 Montpellier, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Moncorgé
authors.affiliation: Section of Virology, Department of Medicine, Imperial College London, St Mary's Campus, London W2 1PG, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Frise
authors.affiliation: Section of Virology, Department of Medicine, Imperial College London, St Mary's Campus, London W2 1PG, UK.
authors.forename: Bhakti
authors.initials: B
authors.lastname: Mistry
authors.affiliation: Section of Virology, Department of Medicine, Imperial College London, St Mary's Campus, London W2 1PG, UK.|Avian Viral Diseases Programme, The Pirbright Institute, Ash Road, Pirbright, Woking GU24 0NF, UK.
authors.forename: Joe
authors.initials: J
authors.lastname: James
authors.affiliation: UMR INRA/Génétique Physiologie et Systèmes d'Elevage, INRA, 31326 Castanet-Tolosan, France.
authors.forename: Mireille
authors.initials: M
authors.lastname: Morisson
authors.affiliation: Avian Viral Diseases Programme, The Pirbright Institute, Ash Road, Pirbright, Woking GU24 0NF, UK.
authors.forename: Munir
authors.initials: M
authors.lastname: Iqbal
authors.affiliation: UMR INRA/Génétique Physiologie et Systèmes d'Elevage, INRA, 31326 Castanet-Tolosan, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Vignal
authors.affiliation: Section of Virology, Department of Medicine, Imperial College London, St Mary's Campus, London W2 1PG, UK.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Skinner
authors.affiliation: Section of Virology, Department of Medicine, Imperial College London, St Mary's Campus, London W2 1PG, UK.
authors.forename: Wendy S
authors.initials: WS
authors.lastname: Barclay
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D030161:Avian Proteins / Q000737:chemistry* / Q000172:deficiency / Q000378:metabolism*; D002460:Cell Line; D002645:Chickens / Q000821:virology; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D019143:Evolution, Molecular; D015967:Gene Expression Regulation, Viral; D055785:Gene Knockdown Techniques; D058507:Host Specificity; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000201:enzymology / Q000235:genetics / Q000502:physiology; D064766:Influenza A Virus, H7N9 Subtype / Q000201:enzymology / Q000235:genetics / Q000502:physiology; D009980:Influenza A virus / Q000201:enzymology* / Q000235:genetics / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000172:deficiency / Q000378:metabolism*; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D012324:RNA-Dependent RNA Polymerase / Q000235:genetics / Q000378:metabolism*; D013045:Species Specificity; D014158:Transcription, Genetic; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication
chemical_list: C087425:ANP32A protein, human; D030161:Avian Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C057027:PB2 protein, Influenzavirus A; D016601:RNA-Binding Proteins; D014764:Viral Proteins; D012324:RNA-Dependent RNA Polymerase