Viral mimicry of Interleukin-17A by SARS-COV-2 ORF8

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. Overall design: After treatment with mock, ORF8, or hIL-17A, human monocytes were isolated from whole blood of male and female donors. Total RNA was isolated with RNeasy Micro Kit (74004) from QIAGEN, and the RNA-seq library was prepared using the KAPA mRNA HyperPrep Kit (KR1352), according to manufacturers' instructions. Sequence reads were obtained using Illumina NovaSeq 6000 as well as the Illumina MiSeq systems with the help of Genomics Core in the Cleveland Clinic Foundation.