Wong Chee Hong, Ngan Chew Yee, Goldfeder Rachel L, Idol Jennifer, Kuhlberg Chris, Maurya Rahul, Kelly Kevin, Omerza Gregory, Renzette Nicholas, De Abreu Francine, Li Lei, Browne Frederick A, Liu Edison T, Wei Chia-Lin
The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032 USA.
Griffin Hospital, Derby, CT 06418 USA.
Commun Med (Lond). 2021 Sep 22;1:33. doi: 10.1038/s43856-021-00034-y. eCollection 2021.
It is estimated that up to 80% of infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are asymptomatic and asymptomatic patients can still effectively transmit the virus and cause disease. While much of the effort has been placed on decoding single nucleotide variation in SARS-CoV-2 genomes, considerably less is known about their transcript variation and any correlation with clinical severity in human hosts, as defined here by the presence or absence of symptoms.
To assess viral genomic signatures of disease severity, we conducted a systematic characterization of SARS-CoV-2 transcripts and genetic variants in 81 clinical specimens collected from symptomatic and asymptomatic individuals using multi-scale transcriptomic analyses including amplicon-seq, short-read metatranscriptome and long-read Iso-seq.
Here we show a highly coordinated and consistent pattern of sgRNA expression from individuals with robust SARS-CoV-2 symptomatic infection and their expression is significantly repressed in the asymptomatic infections. We also observe widespread inter- and intra-patient variants in viral RNAs, known as quasispecies frequently found in many RNA viruses. We identify unique sets of deletions preferentially found primarily in symptomatic individuals, with many likely to confer changes in SARS-CoV-2 virulence and host responses. Moreover, these frequently occurring structural variants in SARS-CoV-2 genomes serve as a mechanism to further induce SARS-CoV-2 proteome complexity.
Our results indicate that differential sgRNA expression and structural mutational burden are highly correlated with the clinical severity of SARS-CoV-2 infection. Longitudinally monitoring sgRNA expression and structural diversity could further guide treatment responses, testing strategies, and vaccine development.
据估计，严重急性呼吸综合征冠状病毒2（SARS-CoV-2）引起的感染中，高达80%是无症状的，无症状患者仍可有效传播病毒并导致疾病。虽然大部分努力都集中在解码SARS-CoV-2基因组中的单核苷酸变异上，但对于其转录本变异以及与人类宿主临床严重程度的任何相关性（在此定义为有无症状），人们了解得要少得多。
为了评估疾病严重程度的病毒基因组特征，我们使用多尺度转录组分析，包括扩增子测序、短读长宏转录组和长读长Iso-seq，对从有症状和无症状个体收集的81份临床标本中的SARS-CoV-2转录本和基因变异进行了系统表征。
在这里，我们展示了来自有强烈SARS-CoV-2症状性感染个体的sgRNA表达高度协调且一致的模式，而其表达在无症状感染中受到显著抑制。我们还观察到病毒RNA中存在广泛的患者间和患者内变异，即许多RNA病毒中常见的准种。我们确定了一组独特的缺失，主要优先在有症状个体中发现，其中许多可能导致SARS-CoV-2毒力和宿主反应的变化。此外，SARS-CoV-2基因组中这些频繁出现的结构变异是进一步诱导SARS-CoV-2蛋白质组复杂性的一种机制。
我们的结果表明，sgRNA表达差异和结构突变负担与SARS-CoV-2感染的临床严重程度高度相关。纵向监测sgRNA表达和结构多样性可进一步指导治疗反应、检测策略和疫苗开发。
