Involvement of SARS-CoV-2 accessory proteins in immunopathogenesis

IF 1.9 4区 医学 Q4 IMMUNOLOGY
Hayato Ito, Tomokazu Tamura, Lei Wang, Kento Mori, Masumi Tsuda, Rigel Suzuki, Saori Suzuki, Kumiko Yoshimatsu, Shinya Tanaka, Takasuke Fukuhara
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Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the largest single-stranded RNA virus known to date. Its genome contains multiple accessory protein genes that act against host immune responses but are not required for progeny virus production. The functions of the accessory proteins in the viral life cycle have been examined, but their involvement in viral pathogenicity remains unclear. Here, we investigated the roles of the accessory proteins in viral immunopathogenicity. To this end, recombinant SARS-CoV-2 possessing nonsense mutations in the seven accessory protein open reading frames (ORFs) (ORF3a, ORF3b, ORF6, ORF7a, ORF8, ORF9b, and ORF10) was de novo generated using an early pandemic SARS-CoV-2 strain as a backbone. We confirmed that the resultant virus (termed ORF3–10 KO) did not express accessory proteins in infected cells and retained the desired mutations in the viral genome. In cell culture, the ORF3–10 KO virus exhibited similar virus growth kinetics as the parental virus. In hamsters, ORF3–10 KO virus infection resulted in mild weight loss and reduced viral replication in the oral cavity and lung tissue. ORF3–10 KO virus infection led to mild inflammation, indicating that an inability to evade innate immune sensing because of a lack of accessory proteins impairs virus growth in vivo and results in quick elimination from the body. Overall, we showed that SARS-CoV-2 accessory proteins are involved in immunopathogenicity.

SARS-CoV-2 辅助蛋白参与免疫发病机制。
严重急性呼吸系统综合征冠状病毒 2(SARS-CoV-2)是迄今已知的最大的单链 RNA 病毒。它的基因组中含有多种辅助蛋白基因,这些基因能对抗宿主的免疫反应,但并不是产生后代病毒所必需的。人们已经研究了附属蛋白在病毒生命周期中的功能,但它们与病毒致病性的关系仍不清楚。在此,我们研究了附属蛋白在病毒免疫致病性中的作用。为此,我们以早期大流行的 SARS-CoV-2 株系为骨干,从头生成了在七个附属蛋白开放阅读框(ORF)(ORF3a、ORF3b、ORF6、ORF7a、ORF8、ORF9b 和 ORF10)中具有无义突变的重组 SARS-CoV-2 病毒。我们证实,产生的病毒(称为 ORF3-10 KO)在感染细胞中不表达附属蛋白,并在病毒基因组中保留了所需的突变。在细胞培养中,ORF3-10 KO 病毒表现出与亲本病毒相似的病毒生长动力学。仓鼠感染 ORF3-10 KO 病毒后体重轻微下降,口腔和肺组织中的病毒复制减少。ORF3-10 KO病毒感染会导致轻微炎症,这表明由于缺乏附属蛋白而无法躲避先天性免疫感应会影响病毒在体内的生长,并导致病毒被迅速排出体外。总之,我们发现 SARS-CoV-2 辅助蛋白参与了免疫致病性。
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
Microbiology and Immunology
Microbiology and Immunology 医学-免疫学
CiteScore
5.20
自引率
3.80%
发文量
78
审稿时长
1 months
期刊介绍: Microbiology and Immunology is published in association with Japanese Society for Bacteriology, Japanese Society for Virology, and Japanese Society for Host Defense Research. It is peer-reviewed publication that provides insight into the study of microbes and the host immune, biological and physiological responses. Fields covered by Microbiology and Immunology include:Bacteriology|Virology|Immunology|pathogenic infections in human, animals and plants|pathogenicity and virulence factors such as microbial toxins and cell-surface components|factors involved in host defense, inflammation, development of vaccines|antimicrobial agents and drug resistance of microbes|genomics and proteomics.
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