Human TRA2A determines influenza A virus host adaptation by regulating viral mRNA splicing
Human TRA2A determines influenza A virus host adaptation by regulating viral mRNA splicing
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人类TRA2A通过调节病毒mRNA剪接决定甲型流感病毒宿主适应
DOI：
10.1126/sciadv.aaz5764
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发表时间：
2020-06-01
期刊：
影响因子：
13.6
通讯作者：
Zhou, Hongbo
中科院分区：
文献类型：
--
作者：
Zhu, Yinxing;Wang, Ruifang;Zhou, Hongbo
人类宿主因子TRA2A在禽流感病毒的跨物种传播中发挥着重要作用。几种甲型禽流感病毒（IAV）已经适应了包括人类在内的哺乳动物物种。迄今为止，实现这些宿主转变的机制仍未完全了解。在这里，我们发现宿主因子人 TRA2A (huTRA2A) 抑制禽类 IAV 复制，但通过改变病毒信使 RNA (mRNA) 剪接的调节而有利于人类 IAV 复制。 huTRA2A 通过与代表性禽类 YS/H5N1 的 M mRNA 或代表性人 PR8/H1N1 病毒的 NS mRNA 中的内含子剪接沉默基序结合来抑制 mRNA 剪接，从而对人和禽病毒的体外和体内复制产生完全相反的影响。我们还证实，M-334 位点和 NS-234/236 位点对于 TRA2A 结合、mRNA 剪接、病毒复制和致病性至关重要。我们的研究结果揭示了禽流感病毒适应人类宿主的潜在机制，并提出了保护公众健康的合理策略。
The human host factor TRA2A plays an important role in cross-species transmission of avian influenza virus. Several avian influenza A viruses (IAVs) have adapted to mammalian species, including humans. To date, the mechanisms enabling these host shifts remain incompletely understood. Here, we show that a host factor, human TRA2A (huTRA2A), inhibits avian IAV replication, but benefits human IAV replication by altered regulation of viral messenger RNA (mRNA) splicing. huTRA2A depresses mRNA splicing by binding to the intronic splicing silencer motif in the M mRNA of representative avian YS/H5N1 or in the NS mRNA of representative human PR8/H1N1 virus, leading to completely opposite effects on replication of the human and avian viruses in vitro and in vivo. We also confirm that the M-334 site and NS-234/236 sites are critical for TRA2A binding, mRNA splicing, viral replication, and pathogenicity. Our results reveal the underlying mechanisms of adaptation of avian influenza virus to human hosts, and suggest rational strategies to protect public health.