<br>SARS-CoV-2 感染期间缺陷病毒基因组的生成和功能分析,bioRxiv - Microbiology

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SARS-CoV-2 感染期间缺陷病毒基因组的生成和功能分析
bioRxiv - Microbiology Pub Date : 2022-09-23 , DOI: 10.1101/2022.09.22.509123
Terry Zhou ₁ , Nora J Gilliam _{1,

2,

3} , Sizhen Li ₄ , Simone Spaudau ₁ , Raven M Osborn _{1,

3} , Christopher S Anderson ₅ , Thomas J Mariani ₆ , Juilee Thakar _{1,

7,

8} , Stephen Dewhurst ₁ , David H Mathews ₉ , Liang Huang ₄ , Yan Sun ₁

Affiliation

Department of Immunology and Microbiology, University of Rochester Medical Center, Rochester, NY 14642.
Medical Scientist Training Program, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642.
Translational Biomedical Sciences PhD Program, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642.
School of Electrical Engineering & Computer Science, Oregon State University, Corvallis, OR 97331.
Division of Neonatology, Department of Pediatrics, University of Rochester Medical Center, Rochester, NY, USA.
Department of Pediatrics and Center for Children's Health Research, University of Rochester.
Department of Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642.
Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642.
Department of Biochemistry & Biophysics and Center for RNA Biology, University of Rochester Medical Center, Rochester, NY 14642.

在许多 RNA 病毒中，缺陷病毒基因组 (DVG) 已被确定为影响抗病毒免疫反应和病毒发病机制的主要因素。然而，DVG 在 SARS-CoV-2 感染中的产生和功能尚不清楚。在这项研究中，我们阐明了 SARS-CoV-2 中 DVG 的产生及其与宿主抗病毒免疫反应的关系。我们从 COVID-19 患者体外感染和尸检肺组织的 RNA-seq 数据集中观察到 DVG 无处不在。确定了 DVG 重组的四个基因组热点，并建议 RNA 二级结构介导 DVG 形成。从功能上讲，批量和单细胞 RNA 序列分析表明 SARS-CoV-2 DVG 受到 IFN 刺激。我们进一步将我们的标准应用于已发表的队列研究的 NGS 数据集，并观察到有症状患者的 DVG 数量和频率显着高于无症状患者。最后，我们在一名因 COVID-19 入院后长达 140 天的免疫抑制患者中观察到异常高的 DVG 频率，这首次表明 DVG 与 SARS-CoV-2 持续病毒感染之间存在关联。总之，我们的研究结果强烈表明 DVG 在调节宿主 IFN 反应和症状发展中发挥着关键作用，呼吁进一步研究 DVG 的产生机制以及 DVG 在 SARS-CoV-2 感染期间如何调节宿主反应和感染结果。

"点击查看英文标题和摘要"

Generation and functional analysis of defective viral genomes during SARS-CoV-2 infection

Defective viral genomes (DVGs) have been identified in many RNA viruses as a major factor influencing antiviral immune response and viral pathogenesis. However, the generation and function of DVGs in SARS-CoV-2 infection are less known. In this study, we elucidated DVG generation in SARS-CoV-2 and its relationship with host antiviral immune response. We observed DVGs ubiquitously from RNA-seq datasets of in vitro infections and autopsy lung tissues of COVID-19 patients. Four genomic hotspots were identified for DVG recombination and RNA secondary structures were suggested to mediate DVG formation. Functionally, bulk and single cell RNA-seq analysis indicated the IFN stimulation of SARS-CoV-2 DVGs. We further applied our criteria to the NGS dataset from a published cohort study and observed significantly higher DVG amount and frequency in symptomatic patients than that in asymptomatic patients. Finally, we observed unusually high DVG frequency in one immunosuppressive patient up to 140 days after admitted to hospital due to COVID-19, first-time suggesting an association between DVGs and persistent viral infections in SARS-CoV-2. Together, our findings strongly suggest a critical role of DVGs in modulating host IFN responses and symptom development, calling for further inquiry into the mechanisms of DVG generation and how DVGs modulate host responses and infection outcome during SARS-CoV-2 infection.

更新日期：2022-09-24

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