Discovery and Genomic Characterization of a 382-Nucleotide Deletion in ORF7b and ORF8 during the Early Evolution of SARS-CoV-2
Discovery and Genomic Characterization of a 382-Nucleotide Deletion in ORF7b and ORF8 during the Early Evolution of SARS-CoV-2
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DOI：
10.1128/mbio.01610-20
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发表时间：
2020-07-01
期刊：
影响因子：
6.4
通讯作者：
Smith, Gavin J. D.
中科院分区：
文献类型：
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作者：
Su, Yvonne C. F.;Anderson, Danielle E.;Smith, Gavin J. D.
迄今为止，已经描述了严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）基因组的有限遗传变化。在这里，我们报道了SARS-CoV-2中382个核苷酸（nt）的缺失，该缺失截断了开放阅读框7b （ORF7b）和ORF8，去除了ORF8转录调控序列（TRS）并消除了ORF8转录。最早的382-nt缺失变异于2020年1月29日在新加坡检测到，该缺失病毒在该国流行，占本研究筛选的SARS-CoV-2样本的23.6%（45/191）。此后，在台湾发现了具有相同缺失的SARS-CoV-2，并在澳大利亚、孟加拉国和西班牙等其他地理位置观察到其他长度从62 nt到345 nt不等的ORF7b/8缺失。sars冠状病毒ORF8的突变或缺失与复制适应度降低和病毒衰减有关。相比之下，SARS-CoV-2 382-nt缺失型病毒在体外的复制适合度明显高于野生型，而在患者病毒载量上没有观察到差异，表明缺失型病毒保留了复制适合度。在SARS-CoV-2感染中观察到对ORF8的强烈抗体反应，这表明ORF8缺失的出现可能是由于免疫驱动的选择，并且在SARS-CoV-2在人类中持续传播期间可能会出现进一步的缺失变体。在2003/2004年SARS流行期间，在SARS- cov的ORF8中观察到许多缺失，最终缺失变体成为主导，导致ORF8是SARS- cov适应人类的进化热点的假设。然而，由于SARS疫情的成功控制，这些缺失对SARS冠状病毒在人类中的流行病学适应性的重要性尚未确定。多种ORF8缺失的SARS-CoV-2毒株的出现，以及对ORF8的强大免疫反应的证据表明，ORF8缺失可能有助于宿主免疫逃避。除了为SARS-CoV-2在适应新的人类宿主时的进化行为提供关键见解外，ORF8缺失变体的出现也可能影响疫苗接种策略。
To date, limited genetic changes in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome have been described. Here, we report a 382-nucleotide (nt) deletion in SARS-CoV-2 that truncates open reading frame 7b (ORF7b) and ORF8, removing the ORF8 transcription regulatory sequence (TRS) and eliminating ORF8 transcription. The earliest 382-nt deletion variant was detected in Singapore on 29 January 2020, with the deletion viruses circulating in the country and accounting for 23.6% (45/191) of SARS-CoV-2 samples screened in this study. SARS-CoV-2 with the same deletion has since been detected in Taiwan, and other ORF7b/8 deletions of various lengths, ranging from 62 nt to 345 nt, have been observed in other geographic locations, including Australia, Bangladesh, and Spain. Mutations or deletions in ORF8 of SARS-CoV have been associated with reduced replicative fitness and virus attenuation. In contrast, the SARS-CoV-2 382-nt deletion viruses showed significantly higher replicative fitness in vitro than the wild type, while no difference was observed in patient viral load, indicating that the deletion variant viruses retained their replicative fitness. A robust antibody response to ORF8 has been observed in SARS-CoV-2 infection, suggesting that the emergence of ORF8 deletions may be due to immune-driven selection and that further deletion variants may emerge during the sustained transmission of SARS-CoV-2 in humans.IMPORTANCE During the SARS epidemic in 2003/2004, a number of deletions were observed in ORF8 of SARS-CoV, and eventually deletion variants became predominant, leading to the hypothesis that ORF8 was an evolutionary hot spot for adaptation of SARS-CoV to humans. However, due to the successful control of the SARS epidemic, the importance of these deletions for the epidemiological fitness of SARS-CoV in humans could not be established. The emergence of multiple SARS-CoV-2 strains with ORF8 deletions, combined with evidence of a robust immune response to ORF8, suggests that the lack of ORF8 may assist with host immune evasion. In addition to providing a key insight into the evolutionary behavior of SARS-CoV-2 as the virus adapts to its new human hosts, the emergence of ORF8 deletion variants may also impact vaccination strategies.