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Species difference in ANP32A underlies influenza A virus polymerase host restriction.

Long, Jason S and Giotis, Efstathios S and Moncorgé, Olivier and Frise, Rebecca and Mistry, Bhakti and James, Joe and Morisson, Mireille and Iqbal, Munir and Vignal, Alain and Skinner, Michael A and Barclay, Wendy S (2016) 'Species difference in ANP32A underlies influenza A virus polymerase host restriction.' Nature, 529 (7584). 101 - 104. ISSN 0028-0836

Species difference in ANP32A underlies influenza A virus polymerase host restriction.pdf - Accepted Version

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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.

Item Type: Article
Uncontrolled Keywords: Cell Line, Animals, Chickens, Dogs, Humans, Cricetulus, Influenza A virus, RNA Replicase, Intracellular Signaling Peptides and Proteins, Avian Proteins, Viral Proteins, Evolution, Molecular, Virus Replication, Species Specificity, Transcription, Genetic, Gene Expression Regulation, Viral, Amino Acid Sequence, Cricetinae, Influenza A Virus, H5N1 Subtype, Gene Knockdown Techniques, Host Specificity, Influenza A Virus, H7N9 Subtype
Divisions: Faculty of Science and Health > Life Sciences, School of
Depositing User: Elements
Date Deposited: 06 Jun 2020 08:33
Last Modified: 06 Jun 2020 09:15

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