Secreted ORF8 induces monocytic pro-inflammatory cytokines through NLRP3 pathways in patients with severe COVID-19
Abstrak
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.
Topik & Kata Kunci
Penulis (19)
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
Akses Cepat
- Tahun Terbit
- 2023
- Sumber Database
- DOAJ
- DOI
- 10.1016/j.isci.2023.106929
- Akses
- Open Access ✓