A unique feature of swine ANP32A provides susceptibility to avian influenza virus infection in pigs
A unique feature of swine ANP32A provides susceptibility to avian influenza virus infection in pigs
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DOI：
10.1371/journal.ppat.1008330
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发表时间：
2020-02-01
期刊：
影响因子：
6.7
通讯作者：
Wang, Xiaojun
中科院分区：
文献类型：
--
作者：
Zhang, Haili;Li, Hongxin;Wang, Xiaojun
流感病毒的复制和转录都由病毒聚合酶复合物催化。大多数禽流感病毒的聚合酶在哺乳动物细胞中的性能较差，这被认为是重要的物种屏障之一。由于猪对禽流感病毒和哺乳动物流感病毒的易感性，猪一直被认为是禽流感病毒种间传播的重要中间宿主。然而，猪流感病毒聚合酶适应的分子基础在很大程度上仍然未知。ANP 32A和ANP 32 B蛋白已被鉴定为在流感病毒复制和宿主范围确定中起重要作用。在本研究中，我们发现猪ANP 32 A（swANP 32 A）与猪ANP 32 B或其他哺乳动物ANP 32 A或B不同，对禽病毒聚合酶显示出更强的支持活性。敲除猪细胞PK 15中的ANP 32A显著降低了禽流感聚合酶活性和病毒感染性，表明swANP 32A在支持禽流感病毒聚合酶方面具有独特的特征。这种物种特异性活性被映射到swANP 32A中的两个关键位点，106 V和156 S。有趣的是，在所有研究的脊椎动物物种中，氨基酸106 V是猪所独有的，当与156 S结合时，在猪中表现出正上位性。106 V和156 S突变到来自其他哺乳动物物种的ANP 32A中发现的标签减弱了swANP 32A与鸡病毒聚合酶之间的相互作用，并降低了聚合酶活性。了解ANP 32蛋白的分子基础可能有助于发现新的抗病毒靶点和设计抗禽流感的基因组编辑pigs.Author summaryThe猪被认为是流感病毒的“混合容器”，因为它可以被人类和禽流感病毒感染。这种病毒的混合可能会产生新的重组菌株，更适合人类或其他哺乳动物。允许猪细胞感染禽流感病毒的允许机制在很大程度上是未知的。在这里，我们揭示了猪细胞蛋白ANP 32A具有独特的106 V/156 S签名，不同于其他哺乳动物的ANP 32A蛋白，使蛋白质能够在进入后步骤强烈结合禽流感聚合酶，并促进禽流感病毒复制。swANP 32A的这种物种特异性106 V/156 S上位性可能决定了猪对禽流感感染的易感性。我们的研究结果提供了新的见解禽IAV鸡和猪之间的种间传播的分子基础。
Both the replication and transcription of the influenza virus are catalyzed by the viral polymerase complex. The polymerases of most avian influenza A viruses have poor performance in mammalian cells, which is considered to be one of the important species barriers. Pigs have been long considered as important intermediate hosts for interspecies transmission of the avian influenza virus, because of their susceptibility to infection with both avian and mammalian influenza viruses. However, the molecular basis of influenza polymerase adaptation in pigs remains largely unknown. ANP32A and ANP32B proteins have been identified as playing fundamental roles in influenza virus replication and host range determination. In this study, we found that swine ANP32A (swANP32A), unlike swine ANP32B or other mammalian ANP32A or B, shows stronger supporting activity to avian viral polymerase. Knockout of ANP32A in pig cells PK15 dramatically reduced avian influenza polymerase activity and viral infectivity, suggesting a unique feature of swANP32A in supporting avian influenza viral polymerase. This species-specific activity is mapped to two key sites, 106V and 156S, in swANP32A. Interestingly, the amino acid 106V is unique to pigs among all the vertebrate species studied, and when combined with 156S, exhibits positive epistasis in pigs. Mutation of 106V and 156S to the signature found in ANP32As from other mammalian species weakened the interaction between swANP32A and chicken viral polymerase, and reduced polymerase activity. Understanding the molecular basis of ANP32 proteins may help to discover new antiviral targets and design avian influenza resistant genome edited pigs.Author summaryThe pig is considered to be a "mixing vessel" for influenza viruses because it can be infected by both human and avian influenza viruses. This mixing of viruses could potentially produce novel recombinant strains that are more adaptable to humans or other mammals. The permissive mechanism that allows pig cells to be infected with avian influenza virus is largely unknown. Here we reveal that the pig cellular protein ANP32A has a unique 106V/156S signature, different from that of ANP32A proteins from other mammals, enabling the protein to bind strongly to avian influenza polymerase at the post-entry step, and promoting avian virus replication. This species-specific 106V/156S epistasis of swANP32A likely determines the susceptibility of pigs to avian influenza infection. Our findings provide novel insights into the molecular basis of interspecies transmission of avian IAV between chickens and pigs.