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SARS-CoV-2 ORF8 Forms Intracellular Aggregates and Inhibits IFNγ-Induced Antiviral Gene Expression in Human Lung Epithelial Cells.
Front Immunol. 2021; 12:679482.FI

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 (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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Authors+Show Affiliations

Geng H
Center for Intestinal and Liver Inflammation Research, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, United States. Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.
Subramanian S
Center for Intestinal and Liver Inflammation Research, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, United States. Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.
Wu L
Section of Neurosurgery, Department of Surgery, University of Chicago, Chicago, IL, United States.
Bu HF
Center for Intestinal and Liver Inflammation Research, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, United States. Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.
Wang X
Center for Intestinal and Liver Inflammation Research, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, United States. Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.
Du C
Center for Intestinal and Liver Inflammation Research, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, United States. Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.
De Plaen IG
Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States. Division of Neonatology, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, United States.
Tan XD
Center for Intestinal and Liver Inflammation Research, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, United States. Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States. Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States. Research Service, Jesse Brown Veterans Affairs Medical Center, Chicago, IL, United States.

MeSH

COVID-19Gene Expression RegulationHEK293 CellsHumansImmunityInterferon-gammaIntracellular SpaceLungProtein Aggregation, PathologicalRespiratory MucosaSARS-CoV-2Viral Proteins

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

34177923

Citation

Geng, Hua, et al. "SARS-CoV-2 ORF8 Forms Intracellular Aggregates and Inhibits IFNγ-Induced Antiviral Gene Expression in Human Lung Epithelial Cells." Frontiers in Immunology, vol. 12, 2021, p. 679482.
Geng H, Subramanian S, Wu L, et al. SARS-CoV-2 ORF8 Forms Intracellular Aggregates and Inhibits IFNγ-Induced Antiviral Gene Expression in Human Lung Epithelial Cells. Front Immunol. 2021;12:679482.
Geng, H., Subramanian, S., Wu, L., Bu, H. F., Wang, X., Du, C., De Plaen, I. G., & Tan, X. D. (2021). SARS-CoV-2 ORF8 Forms Intracellular Aggregates and Inhibits IFNγ-Induced Antiviral Gene Expression in Human Lung Epithelial Cells. Frontiers in Immunology, 12, 679482. https://doi.org/10.3389/fimmu.2021.679482
Geng H, et al. SARS-CoV-2 ORF8 Forms Intracellular Aggregates and Inhibits IFNγ-Induced Antiviral Gene Expression in Human Lung Epithelial Cells. Front Immunol. 2021;12:679482. PubMed PMID: 34177923.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - SARS-CoV-2 ORF8 Forms Intracellular Aggregates and Inhibits IFNγ-Induced Antiviral Gene Expression in Human Lung Epithelial Cells. AU - Geng,Hua, AU - Subramanian,Saravanan, AU - Wu,Longtao, AU - Bu,Heng-Fu, AU - Wang,Xiao, AU - Du,Chao, AU - De Plaen,Isabelle G, AU - Tan,Xiao-Di, Y1 - 2021/06/09/ PY - 2021/03/11/received PY - 2021/05/17/accepted PY - 2021/6/28/entrez PY - 2021/6/29/pubmed PY - 2021/7/6/medline KW - ORF8 KW - SARS-CoV-2 accessory protein KW - inflammation KW - interferon signaling KW - lung epithelial cells SP - 679482 EP - 679482 JF - Frontiers in immunology JO - Front Immunol VL - 12 N2 - 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. SN - 1664-3224 UR - https://www.unboundmedicine.com/medline/citation/34177923/SARS_CoV_2_ORF8_Forms_Intracellular_Aggregates_and_Inhibits_IFN��_Induced_Antiviral_Gene_Expression_in_Human_Lung_Epithelial_Cells_ DB - PRIME DP - Unbound Medicine ER -