Rapid assembly of SARS-CoV-2 genomes reveals attenuation of the Omicron BA.1 variant through NSP6.
Rapid assembly of SARS-CoV-2 genomes reveals attenuation of the Omicron BA.1 variant through NSP6.
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DOI：
10.1038/s41467-023-37787-0
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发表时间：
2023-04-21
影响因子：
16.6
通讯作者：
Ott, Melanie
中科院分区：
文献类型：
--
作者：
Taha, Taha Y.;Chen, Irene P.;Hayashi, Jennifer M.;Tabata, Takako;Walcott, Keith;Kimmerly, Gabriella R.;Syed, Abdullah M.;Ciling, Alison;Suryawanshi, Rahul K.;Martin, Hannah S.;Bach, Bryan H.;Tsou, Chia-Lin;Montano, Mauricio;Khalid, Mir M.;Sreekumar, Bharath K.;Renuka Kumar, G.;Wyman, Stacia;Doudna, Jennifer A.;Ott, Melanie
尽管SARS-COV-2 OMICRON变体（BA.1）在世界范围内迅速扩散并有效地避免了免疫反应，但其在细胞和动物模型中的病毒适应性降低了这种衰减的确切性质。由于病毒基因组的长度（〜30Kb），基因组具有挑战性。在> 80％的效率上，可以通过一系列自然出现的病毒以及Delta-Omicron，分别在1和3周内生成完全效率的单个连接反应中的完全感染性病毒或非感染的亚基因组复制品。嵌合复制品，我们表明Omicron非结构蛋白6具有严重衰减突变，从而抑制病毒RNA复制并减少脂质液滴消耗。这是pGlue克服了广泛研究SARS-COV-2复制的障碍，并揭示了Omicron衰减的非结构蛋白功能的缺陷。
Omicron Ba.1在感染模型中减弱，尽管这种衰减的确切性质仍然未知，因为产生了复制的病毒基因组是挑战。并表明Omicron NSP6削弱了脂质流动到复制细胞器并减少病毒RNA复制。
Although the SARS-CoV-2 Omicron variant (BA.1) spread rapidly across the world and effectively evaded immune responses, its viral fitness in cell and animal models was reduced. The precise nature of this attenuation remains unknown as generating replication-competent viral genomes is challenging because of the length of the viral genome (~30 kb). Here, we present a plasmid-based viral genome assembly and rescue strategy (pGLUE) that constructs complete infectious viruses or noninfectious subgenomic replicons in a single ligation reaction with >80% efficiency. Fully sequenced replicons and infectious viral stocks can be generated in 1 and 3 weeks, respectively. By testing a series of naturally occurring viruses as well as Delta-Omicron chimeric replicons, we show that Omicron nonstructural protein 6 harbors critical attenuating mutations, which dampen viral RNA replication and reduce lipid droplet consumption. Thus, pGLUE overcomes remaining barriers to broadly study SARS-CoV-2 replication and reveals deficits in nonstructural protein function underlying Omicron attenuation. Omicron BA.1 is attenuated in infection models though the precise nature of this attenuation remains unknown as generating replication-competent viral genomes is challenging. Here the authors present pGLUE, a plasmid-based viral genome assembly and rescue strategy, to systematically characterize Omicron mutations and show that Omicron NSP6 has weakened lipid flow to replication organelles and reduced viral RNA replication.
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DOI：
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发表时间：
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期刊：
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