Viral Mimicry of Interleukin-17A by SARS-CoV-2 ORF8
Xin Wu,
Tian Xia,
Woo-Jin Shin,
Kwang-Min Yu,
Wooram Jung,
Alexandra Herrmann,
Suan-Sin Foo,
Weiqiang Chen,
Pengfei Zhang,
Jong-Soo Lee,
Haryoung Poo,
Suzy A. A. Comhair,
Lara Jehi,
Young Ki Choi,
Armin Ensser,
Jae U. Jung
Affiliations
Xin Wu
Cancer Biology Department, Infection Biology Program, and Global Center for Pathogen and Human Health Research, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
Tian Xia
Cancer Biology Department, Infection Biology Program, and Global Center for Pathogen and Human Health Research, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
Woo-Jin Shin
Cancer Biology Department, Infection Biology Program, and Global Center for Pathogen and Human Health Research, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
Kwang-Min Yu
Center for Study of Emerging and Re-emerging Viruses, Korea Virus Research Institute, Institute for Basic Science (IBS), Daejeon, Republic of Korea
Wooram Jung
Cancer Biology Department, Infection Biology Program, and Global Center for Pathogen and Human Health Research, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
Alexandra Herrmann
Institute for Clinical and Molecular Virology, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany
Suan-Sin Foo
Cancer Biology Department, Infection Biology Program, and Global Center for Pathogen and Human Health Research, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
Weiqiang Chen
Cancer Biology Department, Infection Biology Program, and Global Center for Pathogen and Human Health Research, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
Pengfei Zhang
Cancer Biology Department, Infection Biology Program, and Global Center for Pathogen and Human Health Research, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
Jong-Soo Lee
College of Veterinary Medicine, Chungnam National University, Daejeon, Republic of Korea
Haryoung Poo
Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea
Suzy A. A. Comhair
Respiratory Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
Lara Jehi
Department of Neurology, Epilepsy Center, Cleveland Clinic, Cleveland, Ohio, USA
Young Ki Choi
Center for Study of Emerging and Re-emerging Viruses, Korea Virus Research Institute, Institute for Basic Science (IBS), Daejeon, Republic of Korea
Armin Ensser
Institute for Clinical and Molecular Virology, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany
Jae U. Jung
Cancer Biology Department, Infection Biology Program, and Global Center for Pathogen and Human Health Research, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
ABSTRACT 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 revealed that besides its activation of the hIL-17R pathway, ORF8 upregulated gene expression for fibrosis signaling and coagulation dysregulation. A naturally occurring ORF8 L84S variant that was highly associated with mild COVID-19 showed reduced hIL-17RA binding and attenuated inflammatory responses. This study reveals how SARS-CoV-2 ORF8 by a viral mimicry of the IL-17 cytokine contributes to COVID-19 severe inflammation. IMPORTANCE Patients infected with SARS-CoV-2 variants lacking open reading frame 8 (ORF8) have been associated with milder infection and disease outcome, but the molecular mechanism behind how this viral accessory protein mediates disease pathogenesis is not yet known. In our study, we revealed that secreted ORF8 protein mimics host IL-17 to activate IL-17 receptors A and C (IL-17RA/C) and induces a significantly stronger inflammatory response than host IL-17A, providing molecular insights into the role of ORF8 in COVID-19 pathogenesis and serving as a potential therapeutic target.
