Mammalian ANP32A and ANP32B Proteins Drive Differential Polymerase Adaptations in Avian Influenza Virus.
Mammalian ANP32A and ANP32B Proteins Drive Differential Polymerase Adaptations in Avian Influenza Virus.
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DOI：
10.1128/jvi.00213-23
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发表时间：
2023-05-31
影响因子：
5.4
通讯作者：
Barclay, Wendy S.
中科院分区：
文献类型：
--
作者：
Peacock, Thomas P.;Sheppard, Carol M.;Lister, Margaret G.;Staller, Ecco;Frise, Rebecca;Swann, Olivia C.;Goldhill, Daniel H.;Long, Jason S.;Barclay, Wendy S.
关键词：
作为流感聚合酶辅助因子的ANP32蛋白在鸟类和哺乳动物之间有所不同。据报道，在哺乳动物中，ANP32A和ANP32B在支持流感聚合酶活性方面发挥着重要但冗余的作用。众所周知的哺乳动物适应性PB2-E627K使流感聚合酶能够使用哺乳动物ANP32蛋白。然而，一些适应哺乳动物的流感病毒没有这种替代。在这里，我们发现PB2的另一种适应性，Q591R和D701N，也允许流感聚合酶使用哺乳动物的ANP32蛋白，而其他PB2突变，G158E， T271A和D740N，也增加了禽流感ANP32蛋白存在下的聚合酶活性。此外，PB2-E627K强烈倾向于使用哺乳动物ANP32B蛋白，而D701N则没有这种偏好。因此，PB2-E627K适应出现在具有强前病毒ANP32B蛋白的物种中，如人类和小鼠，而D701N更常见于猪、狗和马的分离物中，其中ANP32A蛋白是首选的辅助因子。通过实验进化方法，我们发现含有禽类聚合酶的病毒在人类细胞中的传代驱动PB2-E627K的获得，但在缺乏ANP32B的情况下则不会。最后，我们发现ANP32B对PB2-E627K的强前病毒支持映射到ANP32B的低复杂性酸性区域（LCAR）尾部。流感病毒自然存在于野生水禽体内。然而，流感病毒的高突变率使它们能够迅速和频繁地适应新的宿主，包括哺乳动物。在这些人畜共患跳跃中成功的病毒构成了大流行威胁，因此病毒能够充分适应，有效地在人与人之间传播。流感病毒聚合酶是病毒复制的核心，限制聚合酶活性是物种跳跃的主要障碍。ANP32蛋白对流感聚合酶活性至关重要。在这项研究中，我们描述了禽流感病毒如何以几种不同的方式适应使用哺乳动物ANP32蛋白。我们进一步表明，哺乳动物ANP32蛋白之间的差异可以选择不同的适应性变化，并负责哺乳动物适应流感聚合酶中出现的一些典型突变。这些不同的适应性突变可能决定流感病毒的相对人畜共患潜力，从而有助于评估其大流行风险。
ANP32 proteins, which act as influenza polymerase cofactors, vary between birds and mammals. In mammals, ANP32A and ANP32B have been reported to serve essential but redundant roles to support influenza polymerase activity. The well-known mammalian adaptation PB2-E627K enables influenza polymerase to use mammalian ANP32 proteins. However, some mammalian-adapted influenza viruses do not harbor this substitution. Here, we show that alternative PB2 adaptations, Q591R and D701N, also allow influenza polymerase to use mammalian ANP32 proteins, whereas other PB2 mutations, G158E, T271A, and D740N, increase polymerase activity in the presence of avian ANP32 proteins as well. Furthermore, PB2-E627K strongly favors use of mammalian ANP32B proteins, whereas D701N shows no such bias. Accordingly, PB2-E627K adaptation emerges in species with strong pro-viral ANP32B proteins, such as humans and mice, while D701N is more commonly seen in isolates from swine, dogs, and horses, where ANP32A proteins are the preferred cofactor. Using an experimental evolution approach, we show that the passage of viruses containing avian polymerases in human cells drove acquisition of PB2-E627K, but not in the absence of ANP32B. Finally, we show that the strong pro-viral support of ANP32B for PB2-E627K maps to the low-complexity acidic region (LCAR) tail of ANP32B. IMPORTANCE Influenza viruses naturally reside in wild aquatic birds. However, the high mutation rate of influenza viruses allows them to rapidly and frequently adapt to new hosts, including mammals. Viruses that succeed in these zoonotic jumps pose a pandemic threat whereby the virus adapts sufficiently to efficiently transmit human-to-human. The influenza virus polymerase is central to viral replication and restriction of polymerase activity is a major barrier to species jumps. ANP32 proteins are essential for influenza polymerase activity. In this study, we describe how avian influenza viruses can adapt in several different ways to use mammalian ANP32 proteins. We further show that differences between mammalian ANP32 proteins can select different adaptive changes and are responsible for some of the typical mutations that arise in mammalian-adapted influenza polymerases. These different adaptive mutations may determine the relative zoonotic potential of influenza viruses and thus help assess their pandemic risk.
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