PMID- 35343786
OWN - NLM
STAT- MEDLINE
DCOM- 20220428
LR  - 20240214
IS  - 2150-7511 (Electronic)
VI  - 13
IP  - 2
DP  - 2022 Apr 26
TI  - Viral Mimicry of Interleukin-17A by SARS-CoV-2 ORF8.
PG  - e0040222
LID - 10.1128/mbio.00402-22 [doi]
LID - e00402-22
AB  - 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.
FAU - Wu, Xin
AU  - Wu X
AD  - Cancer Biology Department, Infection Biology Program, and Global Center for 
      Pathogen and Human Health Research, Lerner Research Institute, Cleveland 
      Clinicgrid.254293.bgrid.239578.2, Cleveland, Ohio, USA.
FAU - Xia, Tian
AU  - Xia T
AD  - Cancer Biology Department, Infection Biology Program, and Global Center for 
      Pathogen and Human Health Research, Lerner Research Institute, Cleveland 
      Clinicgrid.254293.bgrid.239578.2, Cleveland, Ohio, USA.
FAU - Shin, Woo-Jin
AU  - Shin WJ
AD  - Cancer Biology Department, Infection Biology Program, and Global Center for 
      Pathogen and Human Health Research, Lerner Research Institute, Cleveland 
      Clinicgrid.254293.bgrid.239578.2, Cleveland, Ohio, USA.
AD  - Cleveland Clinicgrid.254293.bgrid.239578.2 Florida Research & Innovation Center, 
      Port St. Lucie, Florida, USA.
FAU - Yu, Kwang-Min
AU  - Yu KM
AD  - Center for Study of Emerging and Re-emerging Viruses, Korea Virus Research 
      Institute, Institute for Basic Science (IBS), Daejeon, Republic of Korea.
FAU - Jung, Wooram
AU  - Jung W
AD  - Cancer Biology Department, Infection Biology Program, and Global Center for 
      Pathogen and Human Health Research, Lerner Research Institute, Cleveland 
      Clinicgrid.254293.bgrid.239578.2, Cleveland, Ohio, USA.
FAU - Herrmann, Alexandra
AU  - Herrmann A
AD  - Institute for Clinical and Molecular Virology, University Hospital Erlangen, 
      Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany.
FAU - Foo, Suan-Sin
AU  - Foo SS
AD  - Cancer Biology Department, Infection Biology Program, and Global Center for 
      Pathogen and Human Health Research, Lerner Research Institute, Cleveland 
      Clinicgrid.254293.bgrid.239578.2, Cleveland, Ohio, USA.
FAU - Chen, Weiqiang
AU  - Chen W
AUID- ORCID: 0000-0002-8840-1823
AD  - Cancer Biology Department, Infection Biology Program, and Global Center for 
      Pathogen and Human Health Research, Lerner Research Institute, Cleveland 
      Clinicgrid.254293.bgrid.239578.2, Cleveland, Ohio, USA.
FAU - Zhang, Pengfei
AU  - Zhang P
AD  - Cancer Biology Department, Infection Biology Program, and Global Center for 
      Pathogen and Human Health Research, Lerner Research Institute, Cleveland 
      Clinicgrid.254293.bgrid.239578.2, Cleveland, Ohio, USA.
FAU - Lee, Jong-Soo
AU  - Lee JS
AD  - College of Veterinary Medicine, Chungnam National Universitygrid.254230.2, 
      Daejeon, Republic of Korea.
FAU - Poo, Haryoung
AU  - Poo H
AD  - Infectious Disease Research Center, Korea Research Institute of Bioscience and 
      Biotechnology, Daejeon, Republic of Korea.
FAU - Comhair, Suzy A A
AU  - Comhair SAA
AD  - Respiratory Institute, Lerner Research Institute, Cleveland 
      Clinicgrid.254293.bgrid.239578.2, Cleveland, Ohio, USA.
FAU - Jehi, Lara
AU  - Jehi L
AD  - Department of Neurology, Epilepsy Center, Cleveland 
      Clinicgrid.254293.bgrid.239578.2, Cleveland, Ohio, USA.
FAU - Choi, Young Ki
AU  - Choi YK
AUID- ORCID: 0000-0002-0872-0147
AD  - Center for Study of Emerging and Re-emerging Viruses, Korea Virus Research 
      Institute, Institute for Basic Science (IBS), Daejeon, Republic of Korea.
FAU - Ensser, Armin
AU  - Ensser A
AUID- ORCID: 0000-0001-8873-3863
AD  - Institute for Clinical and Molecular Virology, University Hospital Erlangen, 
      Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany.
FAU - Jung, Jae U
AU  - Jung JU
AUID- ORCID: 0000-0003-4559-8774
AD  - Cancer Biology Department, Infection Biology Program, and Global Center for 
      Pathogen and Human Health Research, Lerner Research Institute, Cleveland 
      Clinicgrid.254293.bgrid.239578.2, Cleveland, Ohio, USA.
LA  - eng
GR  - R21 DE027888/DE/NIDCR NIH HHS/United States
GR  - R01 AI140718/AI/NIAID NIH HHS/United States
GR  - R01 AI140705/AI/NIAID NIH HHS/United States
GR  - R35 CA200422/CA/NCI NIH HHS/United States
GR  - R00 DE028573/DE/NIDCR NIH HHS/United States
GR  - R01 DE023926/DE/NIDCR NIH HHS/United States
GR  - R01 CA251275/CA/NCI NIH HHS/United States
GR  - R01 AI152190/AI/NIAID NIH HHS/United States
GR  - R01 DE028521/DE/NIDCR NIH HHS/United States
GR  - K99 DE028573/DE/NIDCR NIH HHS/United States
PT  - Journal Article
DEP - 20220328
PL  - United States
TA  - mBio
JT  - mBio
JID - 101519231
RN  - 0 (IL17A protein, human)
RN  - 0 (Interleukin-17)
RN  - 0 (Viral Proteins)
RN  - SARS-CoV-2 variants
SB  - IM
MH  - *COVID-19
MH  - Humans
MH  - Inflammation/genetics
MH  - Interleukin-17/genetics
MH  - Open Reading Frames
MH  - *SARS-CoV-2/genetics
MH  - Viral Proteins/metabolism
PMC - PMC9040823
OTO - NOTNLM
OT  - COVID-19
OT  - inflammation
OT  - viral IL-17
COIS- The authors declare no conflict of interest.
EDAT- 2022/03/29 06:00
MHDA- 2022/04/29 06:00
PMCR- 2022/03/28
CRDT- 2022/03/28 12:15
PHST- 2022/03/29 06:00 [pubmed]
PHST- 2022/04/29 06:00 [medline]
PHST- 2022/03/28 12:15 [entrez]
PHST- 2022/03/28 00:00 [pmc-release]
AID - 00402-22 [pii]
AID - mbio.00402-22 [pii]
AID - 10.1128/mbio.00402-22 [doi]
PST - ppublish
SO  - mBio. 2022 Apr 26;13(2):e0040222. doi: 10.1128/mbio.00402-22. Epub 2022 Mar 28.