{"doi":"10.3389/fimmu.2021.679482","title":"SARS-CoV-2 ORF8 Forms Intracellular Aggregates and Inhibits IFNγ-Induced Antiviral Gene Expression in Human Lung Epithelial Cells","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 IFNγ but not by IFNβ 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 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 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.","journal":"Frontiers in Immunology","year":2021,"id":156958,"datarank":1.83308947000915,"base_score":3.970291913552122,"endowment":3.970291913552122,"self_citation_contribution":0.5955437870328184,"citation_network_contribution":1.2375456829763316,"self_endowment_contribution":0.5955437870328184,"citer_contribution":1.2375456829763316,"corpus_percentile":null,"corpus_rank":null,"citation_count":52,"citer_count":54,"citers_with_citation_signal":43,"citers_with_endowment":43,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9596,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":566126,"name":"Saravanan Subramanian","orcid":"0000-0003-2502-9531","position":1,"is_corresponding":false},{"id":342287,"name":"Longtao Wu","orcid":"0000-0003-3463-4127","position":2,"is_corresponding":false},{"id":663980,"name":"Heng-Fu Bu","orcid":null,"position":3,"is_corresponding":false},{"id":662981,"name":"Xiao Wang","orcid":"0000-0002-5991-7417","position":4,"is_corresponding":false},{"id":662982,"name":"Chao Du","orcid":"0000-0001-8804-1971","position":5,"is_corresponding":false},{"id":505022,"name":"Isabelle G. De Plaen","orcid":"0000-0002-1742-2926","position":6,"is_corresponding":false},{"id":663981,"name":"Xiao-Di Tan","orcid":null,"position":7,"is_corresponding":false},{"id":662980,"name":"Hua Geng","orcid":"0000-0002-0409-2489","position":0,"is_corresponding":true}],"reference_count":55,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:44:17.471040Z","pmid":"34177923","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}