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SARS-CoV-2 ORF8 Forms Intracellular Aggregates and Inhibits IFN-Induced Antiviral Gene Expression in Human Lung Epithelial Cells Open Access (recommended)

Geng H, Subramanian S, Wu LT, Bu HF, Wang X, Du C, De Plaen IG, Tan XD. SARS-CoV-2 ORF8 Forms Intracellular Aggregates and Inhibits IFN gamma-Induced Antiviral Gene Expression in Human Lung Epithelial Cells. Frontiers in Immunology. 2021;12:11.

Descriptions

Resource type(s)
Article
Keyword
SARS-CoV-2 accessory protein
ORF8
lung epithelial cells
interferon signaling
inflammation
Rights
Attribution 4.0 International

Creator
Geng, Hua
Subramanian, Saravanan
Wu, Longtao
Bu, Heng-Fu
Wang, Xiao
Duan, Chao
De Plaen, Isabelle G.
Tan, Xiao-Di
Abstract
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 (ORF8(SARS-CoV-2)) is a unique accessory protein, yet little is known about its cellular function. We examined the cellular distribution of ORF8(SARS-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 ORF8(SARS-CoV-2) forms aggregates in the cytosol and nuclear compartments of lung epithelial cells. Using in silico bioinformatic analysis, we found that ORF8(SARS-CoV-2) possesses an intrinsic aggregation characteristic at its N-terminal residues 1-18. Cell culture did not reveal any effects of ORF8(SARS-CoV-2) expression on lung epithelial cell proliferation and cell cycle progression, suggesting that ORF8(SARS-CoV-2) aggregates do not affect these cellular processes. Interestingly, ectopic expression of ORF8(SARS-CoV-2) in lung epithelial cells suppressed basal expression of several antiviral molecules, including DHX58, ZBP1, MX1, and MX2. In addition, expression of ORF8(SARS-CoV-2) attenuated the induction of antiviral molecules by IFN gamma but not by IFN beta in lung epithelial cells. Taken together, ORF8(SARS-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 IFN gamma 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 ORF8(SARS-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 ORF8(SARS-CoV-2) expression and its association with post-COVID symptoms warrant investigation in the future.
Related URL
Publisher
FRONTIERS MEDIA SA
Date Created
2021-06-09
Original Identifier
(PMID) 34177923
Grants and funding
COVID-19 Exploratory Springboard Award from the Stanley Manne Children's Research Institute; Ann & Robert H. Lurie Children's Hospital of Chicago; US National Institutes of Health (NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01GM117628, R01GM122406, R01DK123826]; US Department of Veterans Affairs Merit Review AwardUS Department of Veterans Affairs [I01BX001690]; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01DK116568]
DOI
10.3389/fimmu.2021.679482

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