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

Patricia Domingues, Davide Eletto, Carsten Magnus, Hannah L. Turkington, Stefan Schmutz, Osvaldo Zagordi, Matthias Lenk, Martin Beer, Silke Stertz and Benjamin G. Hale ()
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Patricia Domingues: University of Zurich
Davide Eletto: University of Zurich
Carsten Magnus: University of Zurich
Hannah L. Turkington: University of Zurich
Stefan Schmutz: University of Zurich
Osvaldo Zagordi: University of Zurich
Matthias Lenk: Federal Research Institute for Animal Health
Martin Beer: Federal Research Institute for Animal Health
Silke Stertz: University of Zurich
Benjamin G. Hale: University of Zurich

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11388-2

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