학술논문
Secreted ORF8 induces monocytic pro-inflammatory cytokines through NLRP3 pathways in patients with severe COVID-19
Document Type
article
Author
Xiaosheng Wu; Michelle K. Manske; Gordon J. Ruan; Taylor L. Witter; Kevin E. Nowakowski; Jithma P. Abeykoon; Xinyi Tang; Yue Yu; Kimberly A. Gwin; Annie Wu; Vanessa Taupin; Vaishali Bhardwaj; Jonas Paludo; Surendra Dasari; Haidong Dong; Stephen M. Ansell; Andrew D. Badley; Matthew J. Schellenberg; Thomas E. Witzig
Source
iScience, Vol 26, Iss 6, Pp 106929- (2023)
Subject
Language
English
ISSN
2589-0042
Abstract
Summary: Despite extensive research, the specific factor associated with SARS-CoV-2 infection that mediates the life-threatening inflammatory cytokine response in patients with severe COVID-19 remains unidentified. Herein we demonstrate that the virus-encoded Open Reading Frame 8 (ORF8) protein is abundantly secreted as a glycoprotein in vitro and in symptomatic patients with COVID-19. ORF8 specifically binds to the NOD-like receptor family pyrin domain-containing 3 (NLRP3) in CD14+ monocytes to induce inflammasomal cytokine/chemokine responses including IL1β, IL8, and CCL2. Levels of ORF8 protein in the blood correlate with severity and disease-specific mortality in patients with acute SARS-CoV-2 infection. Furthermore, the ORF8-induced inflammasome response was readily inhibited by the NLRP3 inhibitor MCC950 in vitro. Our study identifies a dominant cause of pathogenesis, its underlying mechanism, and a potential new treatment strategy for severe COVID-19.