A natural variant in ANP32B impairs influenza virus replication in human cells.

Ecco Staller,Laury Baillon,Rebecca Frise,Carol M Sheppard,Wendy S Barclay,Thomas P Peacock,Vanessa Sancho-Shimizu

doi:10.1099/jgv.0.001664

Ecco Staller, Laury Baillon + Show 5 more

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https://doi.org/10.1099/jgv.0.001664

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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 Anp32A and Anp32B genes. We note that variant rs182096718 in Anp32B 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.

Highlights

All viruses rely on host factors to support their replication
The Single nucleotide variants (SNV) responsible for a mutant acidic nuclear phosphoproteins of 32 kilodaltons A (ANP32A)-D130N protein is found in a single heterozygous individual out of 3854 in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. This SNV is not described in the much larger gnomAD database, it is cited in the NCBI database dbSNP. rs751239680 (ANP32A-R132Q) is found in a single heterozygous individual out of 10 052 in the African cohort of the gnomAD database, rs772530468 (ANP32A-S158T) is present in a single South Asian male in 23 070 in the gnomAD database, as well as two separate homozygous individuals in the Trans-omics for precision medicine (TOPMed) database [55]
We found that adding increasing amounts of wild-type ANP32B, essentially mimicking the homozygous wild- type genotype, had no effect on FluPol activity compared with FluPol supported by ANP32A alone

Summary

Introduction

All viruses rely on host factors to support their replication. Genetic variation in such proteins can affect susceptibility to infectious disease [1,2,3,4]. Single nucleotide variants (SNV) that redutce susceptibility to virus infection include a P424A substitution in the filovirus endosomal fusion receptor Niemann-PickC1 (NPC1) [6, 7], and a G428A mutation in fucosyltransferase 2 (FUT2) that renders homozygous carriers resistant to norovirus [8, 9]. These variants affect viral entry – no SNVs resulting in defects in replication have far been described. Another important polymorphism in the IFITM3 gene associated with severe influenza is located in the 5′ UTR and leads to transcriptional repression through increased CTCF binding to the promoter [16]

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