biostudies-literatureWu XHHS | National Institutes of HealthBayerisches Staatsministerium für Bildung und Kultus, Wissenschaft und KunstThe institute for Basic science, KoreaNIDCR NIH HHSKRIBB, KoreaNIAID NIH HHSNCI NIH HHSe0040222https://www.ebi.ac.uk/biostudies/studies/S-EPMC9040823biostudies-literatureUnknown13(2)Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection triggers cytokine-mediated inflammation, leading to a myriad of clinical presentations in COVID-19. The SARS-CoV-2 open reading frame 8 (ORF8) is a secreted and rapidly evolving glycoprotein. Patients infected with SARS-CoV-2 variants with ORF8 deleted are associated with mild disease outcomes, but the molecular mechanism behind this is unknown. Here, we report that SARS-CoV-2 ORF8 is a viral cytokine that is similar to but distinct from interleukin 17A (IL-17A) as it induces stronger and broader human IL-17 receptor (hIL-17R) signaling than IL-17A. ORF8 primarily targeted blood monocytes and induced the heterodimerization of hIL-17RA and hIL-17RC, triggering a robust inflammatory response. Transcriptome analysis revealmBioViral Mimicry of Interleukin-17A by SARS-CoV-2 ORF8.PMC9040823BMBF SenseCoV2 01KI20172ADE027888R35 CA200422R01 DE028521R01 AI140705R01 AI140718R01 CA251275AI152190CA200422K99 DE028573DE023926AI140705KGM9942011IBS-R801-D1R00 DE028573CA251275R01 AI152190AI140705S1R21 DE027888AI140718DE028521R01 DE023926DFG Fokus COVID-19 EN423/7-1K99DE028573Poo HHerrmann AXia TShin WJJehi LZhang PLee JSJung WChoi YKJung JUEnsser AFoo SSChen WComhair SAAYu KMWu XfalseViral Mimicry of Interleukin-17A by SARS-CoV-2 ORF8.Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection triggers cytokine-mediated inflammation, leading to a myriad of clinical presentations in COVID-19. The SARS-CoV-2 open reading frame 8 (ORF8) is a secreted and rapidly evolving glycoprotein. Patients infected with SARS-CoV-2 variants with ORF8 deleted are associated with mild disease outcomes, but the molecular mechanism behind this is unknown. Here, we report that SARS-CoV-2 ORF8 is a viral cytokine that is similar to but distinct from interleukin 17A (IL-17A) as it induces stronger and broader human IL-17 receptor (hIL-17R) signaling than IL-17A. ORF8 primarily targeted blood monocytes and induced the heterodimerization of hIL-17RA and hIL-17RC, triggering a robust inflammatory response. Transcriptome analysis reveal2022-01-01T00:00:00Z2022 Apr2026-06-07T03:18:42.813Z2025-04-20T03:08:12.831ZS-EPMC90408233534378610.1128/mbio.00402-22