{"doi":"10.1101/2021.12.02.470978","title":"Secreted ORF8 is a pathogenic cause of severe COVID-19 and is potentially targetable with select NLRP3 inhibitors","abstract":"ABSTRACT COVID-19 is a significant cause of morbidity and mortality in blood cancer patients, especially those on immunosuppressive therapy. Despite extensive research, the specific factor associated with SARS-CoV-2 infection that mediates the life-threatening inflammatory cytokine response in patients with severe COVID-19 remains unidentified. Herein we demonstrate that the virus-encoded Open Reading Frame 8 (ORF8) protein is abundantly secreted as a glycoprotein in vitro and in symptomatic patients with COVID-19. ORF8 specifically binds to the NOD-like receptor family pyrin domain-containing 3 (NLRP3) in CD14 + monocytes to induce a non-canonical inflammasomal response, and a canonical response when the second activation signal is present. Levels of ORF8 protein in the blood correlate with severity and disease-specific mortality in patients with acute SARS-CoV-2 infection. Furthermore, the ORF8-induced inflammasome response was readily inhibited by the NLRP3 inhibitor MCC950 in vitro . Our study identifies a dominant cause of pathogenesis, its underlying mechanism, and a potential new treatment for severe COVID-19. Key points Secreted glycoprotein ORF8 induces monocytic pro-inflammatory cytokines involving the activation of the NLPR3 inflammasome pathway. ORF8 is prognostically present in the blood of symptomatic patients with covid-19 and is targetable with NLRP3 inhibitor MCC-950.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":213916,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9617,"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":486943,"name":"Michelle K. Manske","orcid":"0000-0002-4084-8351","position":1,"is_corresponding":false},{"id":806592,"name":"Gordon Ruan","orcid":"0000-0002-6969-9169","position":2,"is_corresponding":false},{"id":806593,"name":"Taylor L. Witter","orcid":"0000-0003-3096-3011","position":3,"is_corresponding":false},{"id":807330,"name":"Kevin E. Nowakowski","orcid":null,"position":4,"is_corresponding":false},{"id":233827,"name":"Jithma P. Abeykoon","orcid":"0000-0003-3939-6252","position":5,"is_corresponding":false},{"id":273486,"name":"Xinyi Tang","orcid":"0000-0002-1889-4562","position":6,"is_corresponding":false},{"id":806594,"name":"Yue Yu","orcid":"0000-0003-0505-7084","position":7,"is_corresponding":false},{"id":807331,"name":"Kimberly Gwin","orcid":null,"position":8,"is_corresponding":false},{"id":227508,"name":"Annie A. Wu","orcid":"0000-0002-0730-298X","position":9,"is_corresponding":false},{"id":466741,"name":"Vanessa Taupin","orcid":null,"position":10,"is_corresponding":false},{"id":785975,"name":"Vaishali Bhardwaj","orcid":"0000-0002-2880-0187","position":11,"is_corresponding":false},{"id":694880,"name":"Jonas Paludo","orcid":"0000-0002-7350-5531","position":12,"is_corresponding":false},{"id":235319,"name":"Surendra Dasari","orcid":"0000-0002-7972-3556","position":13,"is_corresponding":false},{"id":230198,"name":"Haidong Dong","orcid":"0000-0002-5782-2983","position":14,"is_corresponding":false},{"id":262228,"name":"Stephen M. Ansell","orcid":"0000-0003-1244-6758","position":15,"is_corresponding":false},{"id":302354,"name":"Andrew D. Badley","orcid":"0000-0001-7796-7680","position":16,"is_corresponding":false},{"id":225574,"name":"Matthew J. Schellenberg","orcid":"0000-0001-7036-5943","position":17,"is_corresponding":false},{"id":11125,"name":"Thomas E. Witzig","orcid":"0000-0002-4215-6500","position":18,"is_corresponding":false},{"id":643091,"name":"Xiaosheng Wu","orcid":"0000-0001-8043-2177","position":0,"is_corresponding":true}],"reference_count":34,"raw_metadata":null,"created_at":"2026-07-18T23:52:41.672172Z","pmid":null,"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":[]}