Long-term serial passaging of SARS-CoV-2 reveals signatures of convergent evolution.

IF 3.8 2区 医学 Q2 VIROLOGY
Journal of Virology Pub Date : 2025-07-22 Epub Date: 2025-06-09 DOI:10.1128/jvi.00363-25
Charles S P Foster, Gregory J Walker, Tyra Jean, Maureen Wong, Levent Brassil, Sonia R Isaacs, Yonghui Lyu, Stuart Turville, Anthony Kelleher, William D Rawlinson
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引用次数: 0

Abstract

Understanding viral evolutionary dynamics is crucial to pandemic responses, prediction of virus adaptation over time, and virus surveillance for public health strategies. Whole-genome sequencing (WGS) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has enabled fine-grained studies of virus evolution in the human population. Serial passaging in vitro offers a complementary controlled environment to investigate the emergence and persistence of genetic variants that may confer selective advantage. In this study, nine virus lineages, including four "variants of concern" and three former "variants under investigation," were sampled over ≥33 serial passages (range 33-100) in Vero E6 cells. WGS was used to examine virus evolutionary dynamics and identify key mutations with implications for fitness and/or transmissibility. Viruses accumulated mutations regularly during serial passaging. Many low-frequency variants were lost, but others became fixed, suggesting either in vitro benefits or at least a lack of deleterious effect. Mutations arose convergently both across passage lines and when compared with contemporaneous SARS-CoV-2 clinical sequences. These mutations included some that are hypothesized to drive lineage success through host immune evasion (e.g., S:A67V, S:H655Y). The appearance of these mutations in vitro suggested key mutations can arise convergently even in the absence of a multicellular host immune response through mechanisms other than immune-driven mutation. Such mutations may provide other benefits to the viruses in vitro, or arise stochastically. Our quantitative investigation into SARS-CoV-2 evolutionary dynamics spans the greatest number of serial passages to date and will inform measures to reduce the effects of SARS-CoV-2 infection on the human population.IMPORTANCEThe ongoing evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a challenge for long-term public health efforts to minimize the effects of coronavirus disease 2019. Whole-genome sequencing of outbreak cases has enabled global contact tracing efforts and the identification of mutations of concern within the virus' genome. However, complementary approaches are necessary to inform our understanding of virus evolution and clinical outcomes. Here, we charted the evolution of the virus within a controlled cell culture environment, focusing on nine different virus lineages. Our approach demonstrates how SARS-CoV-2 continues to evolve readily in vitro, with changes mirroring those seen in outbreak cases globally. Findings of the study are important for (i) investigating the mechanisms of how mutations arise, (ii) predicting the future evolutionary trajectory of SARS-CoV-2, and (iii) informing treatment and prevention design.

SARS-CoV-2的长期连续传代显示趋同进化特征。
了解病毒进化动力学对于大流行应对、预测病毒随时间的适应以及为公共卫生战略监测病毒至关重要。严重急性呼吸综合征冠状病毒2 (SARS-CoV-2)的全基因组测序(WGS)使人们能够对病毒在人群中的进化进行细致的研究。体外连续传代为研究可能具有选择优势的遗传变异的出现和持续提供了一个互补的受控环境。在这项研究中,九种病毒谱系,包括四种“关注变体”和三种以前的“正在调查的变体”,在Vero E6细胞中进行了≥33次连续传代(范围33-100)取样。WGS用于检查病毒的进化动力学,并确定对适合度和/或传播性有影响的关键突变。病毒在连续传代过程中有规律地积累突变。许多低频变异消失了,但其他变异却固定了,这表明要么在体外有益,要么至少没有有害影响。突变在传代系之间以及与同期SARS-CoV-2临床序列比较时都是趋同出现的。这些突变包括一些被假设通过宿主免疫逃避驱动谱系成功的突变(例如,S:A67V, S:H655Y)。这些突变在体外的出现表明,即使在没有多细胞宿主免疫应答的情况下,关键突变也可以通过免疫驱动突变以外的机制聚合产生。这种突变可能在体外为病毒提供其他好处,或者随机出现。我们对SARS-CoV-2进化动态的定量调查跨越了迄今为止最多的连续传代,并将为减少SARS-CoV-2感染对人类的影响提供措施。严重急性呼吸综合征冠状病毒2 (SARS-CoV-2)的持续演变仍然是减少2019冠状病毒病影响的长期公共卫生努力面临的挑战。暴发病例的全基因组测序使全球接触者追踪工作得以开展,并确定了病毒基因组中令人关注的突变。然而,补充方法是必要的,以告知我们对病毒进化和临床结果的理解。在这里,我们绘制了病毒在受控细胞培养环境中的进化图,重点关注了九种不同的病毒谱系。我们的方法证明了SARS-CoV-2如何在体外继续迅速进化,其变化反映了在全球爆发病例中看到的变化。该研究的发现对于(i)调查突变如何产生的机制,(ii)预测SARS-CoV-2的未来进化轨迹,以及(iii)为治疗和预防设计提供信息非常重要。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Virology
Journal of Virology 医学-病毒学
CiteScore
10.10
自引率
7.40%
发文量
906
审稿时长
1 months
期刊介绍: Journal of Virology (JVI) explores the nature of the viruses of animals, archaea, bacteria, fungi, plants, and protozoa. We welcome papers on virion structure and assembly, viral genome replication and regulation of gene expression, genetic diversity and evolution, virus-cell interactions, cellular responses to infection, transformation and oncogenesis, gene delivery, viral pathogenesis and immunity, and vaccines and antiviral agents.
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