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

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 Sherman, Salik Nazki, Jason S. Long, Michael A. Skinner, Holly Shelton, Helen M. Sang (), Wendy S. Barclay () and Mike J. McGrew ()
Additional contact information
Alewo Idoko-Akoh: University of Edinburgh
Daniel H. Goldhill: Imperial College London
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
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

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41476-3

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