Project description:SARS-CoV-2 infection triggers cytokine-mediated inflammation, leading to a myriad of clinical presentations in COVID19. The SARS-CoV-2 ORF8 is a secreted and rapidly evolving glycoprotein. Patients infected with SARS-CoV-2 ORF8-deleted variants are associated with mild disease outcomes, but the molecular mechanism this behind is unknown. Here, we report that SARS-CoV-2 ORF8 is a viral cytokine that is similar 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 robust inflammatory response. Transcriptome analysis revealed that besides its activation of the hIL-17R pathway, ORF8 upregulated gene expressions for fibrosis signaling and coagulation dysregulation. A naturally occurring ORF8 L84S variant that highly associated with mild COVID-19 showed reduced hIL-17RA binding and attenuated inflammatory responses. This study discovers SARS-CoV-2 ORF8 as a viral mimicry of IL-17 cytokine to contribute COVID-19 severe inflammation.
