Institute of Medical Virology, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.
Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058, Basel, Switzerland.
Nat Commun. 2019 Jul 30;10(1):3396. doi: 10.1038/s41467-019-11388-2.
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.
物种间细胞因子的差异限制了禽流感病毒（IAV）的人畜共患病和人类大流行。IAV 聚合酶 vPol 具有进化位点来克服限制并决定病毒的毒力。在这里，我们确定宿主 ANP32A 是选择的关键驱动因素，并确定了预测病毒进化的宿主特异性 ANP32A 剪接图谱。我们发现，禽类物种差异表达三种 ANP32A 同工型，在促进 vPol 的插入中存在差异。具有较短插入的 ANP32As 与 vPol 相互作用不佳，在支持类似禽类的 IAV 复制方面受到损害，并驱动具有不同动力学的哺乳动物适应性 vPol 序列的选择。通过将选择数据与多物种 ANP32A 剪接变体分析相结合，我们开发了一个数学模型来预测可能驱动（燕子、喜鹊）或维持（鹅、天鹅）哺乳动物适应性 vPol 特征的鸟类物种。支持这些预测，监测数据证实了喜鹊 IAV 中几种哺乳动物适应性 vPol 取代的富集。分析宿主 ANP32A 剪接可以增强对具有大流行潜力的 IAV 的监测和根除工作。
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