SARS-CoV-2 ORF3b Is a Potent Interferon Antagonist Whose Activity Is Increased by a Naturally Occurring Elongation Variant
SARS-CoV-2 ORF3b Is a Potent Interferon Antagonist Whose Activity Is Increased by a Naturally Occurring Elongation Variant
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DOI：
10.1016/j.celrep.2020.108185
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发表时间：
2020-09-22
期刊：
影响因子：
8.8
通讯作者：
Sato, Kei
中科院分区：
文献类型：
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作者：
Konno, Yoriyuki;Kimura, Izumi;Sato, Kei
SARS-CoV-2与其致病性更强的对应物SARS-CoV的区别之一是其ORF 3b基因中存在提前终止密码子。在这里，我们表明，SARS-CoV-2 ORF 3b是一种有效的干扰素拮抗剂，抑制I型干扰素的诱导比其SARS-CoV直系同源物更有效。系统发育分析和功能分析表明，SARS-CoV-2相关的蝙蝠和穿山甲病毒也编码截短的ORF 3b基因产物，具有强的抗干扰素活性。此外，对大约17，000个SARS-CoV-2序列的分析鉴定了一种天然变体，其中重建了较长的ORF 3b阅读框架。该变体从两名患有严重疾病的患者中分离，并进一步增加了ORF 3b抑制干扰素诱导的能力。因此，我们的研究结果不仅有助于解释COVID-19患者中干扰素应答差的原因，而且还描述了具有扩展的ORF 3b基因的天然SARS-CoV-2准种的出现，这可能会影响COVID-19的发病机制。
One of the features distinguishing SARS-CoV-2 from its more pathogenic counterpart SARS-CoV is the presence of premature stop codons in its ORF3b gene. Here, we show that SARS-CoV-2 ORF3b is a potent interferon antagonist, suppressing the induction of type I interferon more efficiently than its SARS-CoV ortholog. Phylogenetic analyses and functional assays reveal that SARS-CoV-2-related viruses from bats and pangolins also encode truncated ORF3b gene products with strong anti-interferon activity. Furthermore, analyses of approximately 17,000 SARS-CoV-2 sequences identify a natural variant in which a longer ORF3b reading frame was reconstituted. This variant was isolated from two patients with severe disease and further increased the ability of ORF3b to suppress interferon induction. Thus, our findings not only help to explain the poor interferon response in COVID-19 patients but also describe the emergence of natural SARS-CoV-2 quasispecies with an extended ORF3b gene that may potentially affect COVID-19 pathogenesis.