Profiling host ANP32A splicing landscapes to predict influenza A virus polymerase adaptation

Nature Communications
Patricia DominguesBenjamin G Hale

Abstract

Species' differences in cellular factors limit avian influenza A virus (IAV) zoonoses and human pandemics. The IAV polymerase, vPol, harbors evolutionary sites to overcome restriction and determines virulence. Here, we establish host ANP32A as a critical driver of selection, and identify host-specific ANP32A splicing landscapes that predict viral evolution. We find that avian species differentially express three ANP32A isoforms diverging in a vPol-promoting insert. ANP32As with shorter inserts interact poorly with vPol, are compromised in supporting avian-like IAV replication, and drive selection of mammalian-adaptive vPol sequences with distinct kinetics. By integrating selection data with multi-species ANP32A splice variant profiling, we develop a mathematical model to predict avian species potentially driving (swallow, magpie) or maintaining (goose, swan) mammalian-adaptive vPol signatures. Supporting these predictions, surveillance data confirm enrichment of several mammalian-adaptive vPol substitutions in magpie IAVs. Profiling host ANP32A splicing could enhance surveillance and eradication efforts against IAVs with pandemic potential.

References

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Citations

Apr 4, 2021·Viruses·Joe McKellarCaroline Goujon
Apr 22, 2021·The Journal of Experimental Medicine·Caroline LanzSilke Stertz
May 14, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Young Hyun ParkJae Yong Han
Sep 30, 2020·Cold Spring Harbor Perspectives in Medicine·Ecco Staller, Wendy S Barclay

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Methods Mentioned

BETA
transfection
PCR
transfections
reverse transcription-PCR

Software Mentioned

stats
BEAST2
TreeAnnotator
R
Bowtie2
LoFreq
R package DescTools
MiSeq
vPol
deSolve

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