Letter | Published:

Species difference in ANP32A underlies influenza A virus polymerase host restriction

Nature volume 529, pages 101104 (07 January 2016) | Download Citation

Abstract

Influenza pandemics occur unpredictably when zoonotic influenza viruses with novel antigenicity acquire the ability to transmit amongst humans1. 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 cells2. Mutants of the heterotrimeric viral polymerase components, particularly PB2 protein, are selected during mammalian adaptation, but their mode of action is unknown3,4,5,6. 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.

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ArrayExpress

Data deposits

The microarray data have been submitted to The European Bioinformatics Institute (EBI) (http://www.ebi.ac.uk) ArrayExpress under accession number E-MTAB-3643.

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Acknowledgements

We thank G. Maertens, J. Stech, R. Fouchier, A. Cauldwell, G. Roche, J. McCauley, D. Huntley, A. Vaughan, V. Nair and H. Shelton for provision of reagents, advice and discussions. This work was funded by BBSRC sLoLa BB/K002465/1 “Developing Rapid Responses to Emerging Virus Infections of Poultry (DDREVIP)” which funds J.S.L. and E.S.G., B.M. was funded by a Wellcome Trust studentship. R.F. and O.M. were funded by a Wellcome Trust Programme Grant (087039/Z/08/Z). O.M. was funded by MRC (G0600006). M.I. was funded by a BBSRC Avian Diseases Programme Grant (BBS/E/I/00001708).

Author information

Affiliations

  1. Section of Virology, Department of Medicine, Imperial College London, St Mary’s Campus, London W2 1PG, UK

    • Jason S. Long
    • , Efstathios S. Giotis
    • , Rebecca Frise
    • , Bhakti Mistry
    • , Joe James
    • , Michael A. Skinner
    •  & Wendy S. Barclay
  2. Centre d’études d’agents Pathogènes et Biotechnologies pour la Santé (CPBS), FRE 3689, CNRS-UM, 34293 Montpellier, France

    • Olivier Moncorgé
  3. Avian Viral Diseases Programme, The Pirbright Institute, Ash Road, Pirbright, Woking GU24 0NF, UK

    • Joe James
    •  & Munir Iqbal
  4. UMR INRA/Génétique Physiologie et Systèmes d'Elevage, INRA, 31326 Castanet-Tolosan, France

    • Mireille Morisson
    •  & Alain Vignal

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Contributions

J.S.L. designed and performed the experiments and wrote the manuscript. E.S.G. performed microarrays and analysed data. O.M. generated plasmids for polymerase assays and wrote the manuscript. R.F., E.S.G. and B.M. performed qRT–PCR analysis. J.J. generated plasmids for polymerase assays. M.I. supplied UDL/08 reverse genetics system. A.V. and M.M. supplied radiation hybrid clones. M.A.S. analysed data, designed microarray experiments and wrote the manuscript. W.S.B. designed experiments and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Wendy S. Barclay.

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DOI

https://doi.org/10.1038/nature16474

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