Wang Julia Y, Zhang Wei, Roehrl Victor B, Roehrl Michael W, Roehrl Michael H
Curandis, New York, USA.
Department of Gastroenterology, Affiliated Hospital of Guizhou Medical University, Guizhou, China.
bioRxiv. 2021 Apr 6:2021.04.05.438500. doi: 10.1101/2021.04.05.438500.
To understand how COVID-19 may induce autoimmune diseases, we have been compiling an atlas of COVID-autoantigens (autoAgs). Using dermatan sulfate (DS) affinity enrichment of autoantigenic proteins extracted from HS-Sultan lymphoblasts, we identified 362 DS-affinity proteins, of which at least 201 (56%) are confirmed autoAgs. Comparison with available multi-omic COVID data shows that 315 (87%) of the 362 proteins are affected in SARS-CoV-2 infection via altered expression, interaction with viral components, or modification by phosphorylation or ubiquitination, at least 186 (59%) of which are known autoAgs. These proteins are associated with gene expression, mRNA processing, mRNA splicing, translation, protein folding, vesicles, and chromosome organization. Numerous nuclear autoAgs were identified, including both classical ANAs and ENAs of systemic autoimmune diseases and unique autoAgs involved in the DNA replication fork, mitotic cell cycle, or telomerase maintenance. We also identified many uncommon autoAgs involved in nucleic acid and peptide biosynthesis and nucleocytoplasmic transport, such as aminoacyl-tRNA synthetases. In addition, this study found autoAgs that potentially interact with multiple SARS-CoV-2 Nsp and Orf components, including CCT/TriC chaperonin, insulin degrading enzyme, platelet-activating factor acetylhydrolase, and the ezrin-moesin-radixin family. Furthermore, B-cell-specific IgM-associated ER complex (including MBZ1, BiP, heat shock proteins, and protein disulfide-isomerases) is enriched by DS-affinity and up-regulated in B-cells of COVID-19 patients, and a similar IgH-associated ER complex was also identified in autoreactive pre-B1 cells in our previous study, which suggests a role of autoreactive B1 cells in COVID-19 that merits further investigation. In summary, this study demonstrates that virally infected cells are characterized by alterations of proteins with propensity to become autoAgs, thereby providing a possible explanation for infection-induced autoimmunity. The COVID autoantigen-ome provides a valuable molecular resource and map for investigation of COVID-related autoimmune sequelae and considerations for vaccine design.
为了解新冠病毒（COVID-19）如何诱发自身免疫性疾病，我们一直在编制一份新冠自身抗原（autoAgs）图谱。利用硫酸皮肤素（DS）亲和富集从HS-Sultan淋巴母细胞中提取的自身抗原性蛋白质，我们鉴定出362种DS亲和蛋白，其中至少201种（56%）为已确认的自身抗原。与现有的多组学新冠数据比较显示，362种蛋白质中的315种（87%）在SARS-CoV-2感染中通过表达改变、与病毒成分相互作用或磷酸化或泛素化修饰而受到影响，其中至少186种（59%）为已知的自身抗原。这些蛋白质与基因表达、mRNA加工、mRNA剪接、翻译、蛋白质折叠、囊泡和染色体组织相关。鉴定出了许多核自身抗原，包括系统性自身免疫性疾病的经典抗核抗体（ANAs）和可提取核抗原（ENAs）以及参与DNA复制叉、有丝分裂细胞周期或端粒酶维持的独特自身抗原。我们还鉴定出许多参与核酸和肽生物合成以及核质运输的不常见自身抗原，如氨酰-tRNA合成酶。此外，本研究发现了可能与多种SARS-CoV-2 Nsp和Orf成分相互作用的自身抗原，包括CCT/TriC伴侣蛋白、胰岛素降解酶、血小板活化因子乙酰水解酶和埃兹蛋白-莫伊辛-根蛋白家族。此外，B细胞特异性IgM相关内质网复合体（包括MBZ1、BiP、热休克蛋白和蛋白质二硫键异构酶）通过DS亲和富集，在COVID-19患者的B细胞中上调，并且在我们之前的研究中，在自身反应性前B1细胞中也鉴定出了类似的IgH相关内质网复合体，这表明自身反应性B1细胞在COVID-19中发挥作用，值得进一步研究。总之，本研究表明，病毒感染细胞的特征是具有成为自身抗原倾向的蛋白质发生改变，从而为感染诱导的自身免疫提供了一种可能的解释。新冠自身抗原组为研究新冠相关自身免疫后遗症和疫苗设计考量提供了宝贵的分子资源和图谱。
