1887

Abstract

Viruses require host factors to support their replication, and genetic variation in such factors can affect susceptibility to infectious disease. Influenza virus replication in human cells relies on ANP32 proteins, which are involved in assembly of replication-competent dimeric influenza virus polymerase (FluPol) complexes. Here, we investigate naturally occurring single nucleotide variants (SNV) in the human and genes. We note that variant rs182096718 in is found at a higher frequency than other variants in either gene. This SNV results in a D130A substitution in ANP32B, which is less able to support FluPol activity than wild-type ANP32B and binds FluPol with lower affinity. Interestingly, ANP32B-D130A exerts a dominant negative effect over wild-type ANP32B and interferes with the functionally redundant paralogue ANP32A. FluPol activity and virus replication are attenuated in CRISPR-edited cells expressing wild-type ANP32A and mutant ANP32B-D130A. We propose a model in which the D130A mutation impairs FluPol dimer formation, thus resulting in compromised replication. We suggest that both homozygous and heterozygous carriers of rs182096718 may have some genetic protection against influenza viruses.

Funding
This study was supported by the:
  • biotechnology and biological sciences research council (Award bb/k002456/1)
    • Principle Award Recipient: CarolM. Sheppard
  • ukri future leaders fellowship (Award mr/s032304/1)
    • Principle Award Recipient: VanessaSancho-Shimizu
  • biotechnology and biological sciences research council (Award bb/r013071/1)
    • Principle Award Recipient: ThomasP. Peacock
  • wellcome trust (Award 200187/z/15/z)
    • Principle Award Recipient: RebeccaFrise
  • wellcome trust (Award 209213/z/17/z)
    • Principle Award Recipient: LauryBaillon
  • biotechnology and biological sciences research council (Award bb/k002456/1)
    • Principle Award Recipient: WendyS Barclay
  • wellcome trust (Award 205100)
    • Principle Award Recipient: WendyS Barclay
  • wellcome trust (Award 205100)
    • Principle Award Recipient: CarolM. Sheppard
  • imperial college president's scholarship
    • Principle Award Recipient: EccoStaller
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License. This article was made open access via a Publish and Read agreement between the Microbiology Society and the corresponding author’s institution.
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2021-09-15
2021-12-06
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