{"doi":"10.4049/jimmunol.2300110","title":"SARS-CoV-2 ORF8 Mediates Signals in Macrophages and Monocytes through MyD88 Independently of the IL-17 Receptor","abstract":"SARS-CoV-2 has caused an estimated 7 million deaths worldwide to date. A secreted SARS-CoV-2 accessory protein, known as open reading frame 8 (ORF8), elicits inflammatory pulmonary cytokine responses and is associated with disease severity in COVID-19 patients. Recent reports proposed that ORF8 mediates downstream signals in macrophages and monocytes through the IL-17 receptor complex (IL-17RA, IL-17RC). However, generally IL-17 signals are found to be restricted to the nonhematopoietic compartment, thought to be due to rate-limiting expression of IL-17RC. Accordingly, we revisited the capacity of IL-17 and ORF8 to induce cytokine gene expression in mouse and human macrophages and monocytes. In SARS-CoV-2-infected human and mouse lungs, IL17RC mRNA was undetectable in monocyte/macrophage populations. In cultured mouse and human monocytes and macrophages, ORF8 but not IL-17 led to elevated expression of target cytokines. ORF8-induced signaling was fully preserved in the presence of anti-IL-17RA/RC neutralizing Abs and in Il17ra-/- cells. ORF8 signaling was also operative in Il1r1-/- bone marrow-derived macrophages. However, the TLR/IL-1R family adaptor MyD88, which is dispensable for IL-17R signaling, was required for ORF8 activity yet MyD88 is not required for IL-17 signaling. Thus, we conclude that ORF8 transduces inflammatory signaling in monocytes and macrophages via MyD88 independently of the IL-17R.","journal":"The Journal of Immunology","year":2023,"id":342759,"datarank":0.40620753016533157,"base_score":2.70805020110221,"endowment":2.70805020110221,"self_citation_contribution":0.40620753016533157,"citation_network_contribution":0.0,"self_endowment_contribution":0.40620753016533157,"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":0.9568,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":642499,"name":"Karsen E. Shoger","orcid":"0000-0002-1894-7361","position":1,"is_corresponding":false},{"id":923776,"name":"Mst Shamima Khatun","orcid":"0009-0004-3889-0720","position":2,"is_corresponding":false},{"id":12817,"name":"Mrinal K. Sarkar","orcid":"0000-0001-8505-4259","position":3,"is_corresponding":false},{"id":37703,"name":"Ipsita Dey","orcid":"0000-0002-0538-124X","position":4,"is_corresponding":false},{"id":641122,"name":"Tiffany C. Taylor","orcid":"0000-0002-4971-3728","position":5,"is_corresponding":false},{"id":1079749,"name":"Rylee N. Cisney","orcid":"0000-0002-8206-2955","position":6,"is_corresponding":false},{"id":1079750,"name":"S. Arunkumar","orcid":"0000-0002-1397-9399","position":7,"is_corresponding":false},{"id":12829,"name":"Jóhann E. Guðjónsson","orcid":"0000-0002-0080-0812","position":8,"is_corresponding":false},{"id":246970,"name":"Jay K. Kolls","orcid":"0000-0001-5151-6304","position":9,"is_corresponding":false},{"id":573677,"name":"Rachel A. Gottschalk","orcid":"0000-0002-5248-8816","position":10,"is_corresponding":false},{"id":37710,"name":"Sarah L. Gaffen","orcid":"0000-0001-8511-2041","position":11,"is_corresponding":false},{"id":620694,"name":"Nicole O. Ponde","orcid":"0000-0003-2704-0451","position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:11:17.288563Z","pmid":"37265402","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":[]}