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

Domingues, Patricia ORCID; Eletto, Davide; Magnus, Carsten ORCID; Turkington, Hannah L.; Schmutz, Stefan ORCID; Zagordi, Osvaldo; Lenk, Matthias GND; Beer, Martin GND; Stertz, Silke; Hale, Benjamin G. ORCID

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.

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Domingues, Patricia / Eletto, Davide / Magnus, Carsten / et al: Profiling host ANP32A splicing landscapes to predict influenza A virus polymerase adaptation. 2019. Springer Science and Business Media LLC.

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