SARS-CoV-2 ORF8 Forms Intracellular Aggregates and Inhibits IFNγ-Induced Antiviral Gene Expression in Human Lung Epithelial Cells.
SARS-CoV-2 ORF8 Forms Intracellular Aggregates and Inhibits IFNγ-Induced Antiviral Gene Expression in Human Lung Epithelial Cells.
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DOI：
10.3389/fimmu.2021.679482
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发表时间：
2021
影响因子：
7.3
通讯作者：
Tan XD
中科院分区：
文献类型：
--
作者：
Geng H;Subramanian S;Wu L;Bu HF;Wang X;Du C;De Plaen IG;Tan XD
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染导致COVID-19，这是一种涉及严重肺组织损伤的疾病。SARS-CoV-2感染如何导致肺损伤仍然是一个谜。SARS-CoV-2的开放阅读框8（ORF 8）蛋白（ORF 8 SARS-CoV-2）是一种独特的辅助蛋白，但其细胞功能尚不清楚。我们研究了ORF 8 SARS-CoV-2的细胞分布及其在人肺上皮细胞增殖和抗病毒免疫调节中的作用。利用活体成像和免疫荧光染色分析，我们发现异位表达的ORF 8 SARS-CoV-2在肺上皮细胞的胞浆和核区室中形成聚集体。利用计算机生物信息学分析，我们发现ORF 8 SARS-CoV-2在其N-末端残基1-18处具有内在聚集特征。细胞培养没有发现ORF 8 SARS-CoV-2表达对肺上皮细胞增殖和细胞周期进程的任何影响，表明ORF 8 SARS-CoV-2聚集体不影响这些细胞过程。有趣的是，ORF 8 SARS-CoV-2在肺上皮细胞中的异位表达抑制了几种抗病毒分子的基础表达，包括DHX 58，ZBP 1，MX 1和MX 2。此外，ORF 8 SARS-CoV-2的表达减弱了IFNγ对肺上皮细胞中抗病毒分子的诱导作用，但不减弱IFNβ的诱导作用。综上所述，ORF 8 SARS-CoV-2是一种独特的病毒辅助蛋白，在肺上皮细胞中表达时形成聚集体。在基线水平和肺上皮细胞对IFNγ的反应中，它有效地抑制肺细胞抗病毒蛋白的表达，这可能有助于SARS-CoV-2在病毒感染早期逃避宿主的抗病毒先天免疫应答。此外，ORF 8 SARS-CoV-2聚集体的形成似乎与病毒感染无关。因此，研究任何COVID-19患者在从SARS-CoV-2感染中恢复后是否表现出持续的ORF 8 SARS-CoV-2表达将是有趣的。如果是这样的话，ORF 8 SARS-CoV-2长期表达的致病作用及其与COVID后症状的相关性值得将来研究。
Infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a disease that involves significant lung tissue damage. How SARS-CoV-2 infection leads to lung injury remains elusive. The open reading frame 8 (ORF8) protein of SARS-CoV-2 (ORF8SARS-CoV-2) is a unique accessory protein, yet little is known about its cellular function. We examined the cellular distribution of ORF8SARS-CoV-2 and its role in the regulation of human lung epithelial cell proliferation and antiviral immunity. Using live imaging and immunofluorescent staining analyses, we found that ectopically expressed ORF8SARS-CoV-2 forms aggregates in the cytosol and nuclear compartments of lung epithelial cells. Using in silico bioinformatic analysis, we found that ORF8SARS-CoV-2 possesses an intrinsic aggregation characteristic at its N-terminal residues 1-18. Cell culture did not reveal any effects of ORF8SARS-CoV-2 expression on lung epithelial cell proliferation and cell cycle progression, suggesting that ORF8SARS-CoV-2 aggregates do not affect these cellular processes. Interestingly, ectopic expression of ORF8SARS-CoV-2 in lung epithelial cells suppressed basal expression of several antiviral molecules, including DHX58, ZBP1, MX1, and MX2. In addition, expression of ORF8SARS-CoV-2 attenuated the induction of antiviral molecules by IFNγ but not by IFNβ in lung epithelial cells. Taken together, ORF8SARS-CoV-2 is a unique viral accessory protein that forms aggregates when expressing in lung epithelial cells. It potently inhibits the expression of lung cellular anti-viral proteins at baseline and in response to IFNγ in lung epithelial cells, which may facilitate SARS-CoV-2 escape from the host antiviral innate immune response during early viral infection. In addition, it seems that formation of ORF8SARS-CoV-2 aggregate is independent from the viral infection. Thus, it would be interesting to examine whether any COVID-19 patients exhibit persistent ORF8 SARS-CoV-2 expression after recovering from SARS-CoV-2 infection. If so, the pathogenic effect of prolonged ORF8SARS-CoV-2 expression and its association with post-COVID symptoms warrant investigation in the future.
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DOI：
10.1007/978-1-4939-0888-2_10
发表时间：
2014
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Bagga S;Bouchard MJ
通讯作者：
Bouchard MJ
影响因子：
168.9
作者：
Huang, Chaolin;Wang, Yeming;Cao, Bin
通讯作者：
Cao, Bin
DOI：
10.1073/pnas.1519657113
发表时间：
2016-02-23
影响因子：
11.1
作者：
Li, Yize;Banerjee, Shuvojit;Weiss, Susan R.
通讯作者：
Weiss, Susan R.
影响因子：
5.4
作者：
Dove, B;Brooks, G;Hiscox, JA
通讯作者：
Hiscox, JA
DOI：
10.3390/v4112902
发表时间：
2012-11-07
期刊：
Viruses
影响因子：
--
作者：
McBride R;Fielding BC
通讯作者：
Fielding BC