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Creating resistance to avian influenza infection through genome editing of the ANP32 gene family

Author

Listed:
  • Alewo Idoko-Akoh

    (University of Edinburgh)

  • Daniel H. Goldhill

    (Imperial College London
    Royal Veterinary College)

  • Carol M. Sheppard

    (Imperial College London)

  • Dagmara Bialy

    (The Pirbright Institute)

  • Jessica L. Quantrill

    (Imperial College London)

  • Ksenia Sukhova

    (Imperial College London)

  • Jonathan C. Brown

    (Imperial College London)

  • Samuel Richardson

    (The Pirbright Institute)

  • Ciara Campbell

    (Imperial College London)

  • Lorna Taylor

    (University of Edinburgh)

  • Adrian Sherman

    (University of Edinburgh)

  • Salik Nazki

    (The Pirbright Institute)

  • Jason S. Long

    (Imperial College London
    National Institute for Biological Standards and Control)

  • Michael A. Skinner

    (Imperial College London)

  • Holly Shelton

    (The Pirbright Institute)

  • Helen M. Sang

    (University of Edinburgh)

  • Wendy S. Barclay

    (Imperial College London)

  • Mike J. McGrew

    (University of Edinburgh)

Abstract

Chickens genetically resistant to avian influenza could prevent future outbreaks. In chickens, influenza A virus (IAV) relies on host protein ANP32A. Here we use CRISPR/Cas9 to generate homozygous gene edited (GE) chickens containing two ANP32A amino acid substitutions that prevent viral polymerase interaction. After IAV challenge, 9/10 edited chickens remain uninfected. Challenge with a higher dose, however, led to breakthrough infections. Breakthrough IAV virus contained IAV polymerase gene mutations that conferred adaptation to the edited chicken ANP32A. Unexpectedly, this virus also replicated in chicken embryos edited to remove the entire ANP32A gene and instead co-opted alternative ANP32 protein family members, chicken ANP32B and ANP32E. Additional genome editing for removal of ANP32B and ANP32E eliminated all viral growth in chicken cells. Our data illustrate a first proof of concept step to generate IAV-resistant chickens and show that multiple genetic modifications will be required to curtail viral escape.

Suggested Citation

  • Alewo Idoko-Akoh & Daniel H. Goldhill & Carol M. Sheppard & Dagmara Bialy & Jessica L. Quantrill & Ksenia Sukhova & Jonathan C. Brown & Samuel Richardson & Ciara Campbell & Lorna Taylor & Adrian Sherm, 2023. "Creating resistance to avian influenza infection through genome editing of the ANP32 gene family," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41476-3
    DOI: 10.1038/s41467-023-41476-3
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    References listed on IDEAS

    as
    1. Maeve Ballantyne & Mark Woodcock & Dadakhalandar Doddamani & Tuanjun Hu & Lorna Taylor & Rachel J. Hawken & Mike J. McGrew, 2021. "Direct allele introgression into pure chicken breeds using Sire Dam Surrogate (SDS) mating," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    2. Aldo R. Camacho-Zarco & Sissy Kalayil & Damien Maurin & Nicola Salvi & Elise Delaforge & Sigrid Milles & Malene Ringkjøbing Jensen & Darren J. Hart & Stephen Cusack & Martin Blackledge, 2020. "Molecular basis of host-adaptation interactions between influenza virus polymerase PB2 subunit and ANP32A," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    3. Benjamin Mänz & Linda Brunotte & Peter Reuther & Martin Schwemmle, 2012. "Adaptive mutations in NEP compensate for defective H5N1 RNA replication in cultured human cells," Nature Communications, Nature, vol. 3(1), pages 1-11, January.
    4. Haitian Fan & Alexander P. Walker & Loïc Carrique & Jeremy R. Keown & Itziar Serna Martin & Dimple Karia & Jane Sharps & Narin Hengrung & Els Pardon & Jan Steyaert & Jonathan M. Grimes & Ervin Fodor, 2019. "Structures of influenza A virus RNA polymerase offer insight into viral genome replication," Nature, Nature, vol. 573(7773), pages 287-290, September.
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    Cited by:

    1. Ecco Staller & Loïc Carrique & Olivia C. Swann & Haitian Fan & Jeremy R. Keown & Carol M. Sheppard & Wendy S. Barclay & Jonathan M. Grimes & Ervin Fodor, 2024. "Structures of H5N1 influenza polymerase with ANP32B reveal mechanisms of genome replication and host adaptation," Nature Communications, Nature, vol. 15(1), pages 1-10, December.

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