Secreted ORF8 induces monocytic pro-inflammatory cytokines through NLRP3 pathways in patients with severe COVID-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

doi:10.1016/j.isci.2023.106929

Secreted ORF8 induces monocytic pro-inflammatory cytokines through NLRP3 pathways in patients with severe COVID-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

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English (US)
Article number	106929
Journal	iScience
Volume	26
Issue number	6
DOIs	https://doi.org/10.1016/j.isci.2023.106929
State	Published - Jun 16 2023

Keywords

Immunity
Virology

ASJC Scopus subject areas

General

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10.1016/j.isci.2023.106929

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Wu, X., Manske, M. K., Ruan, G. J., Witter, T. L., Nowakowski, K. E., Abeykoon, J. P., Tang, X., Yu, Y., Gwin, K. A., Wu, A., Taupin, V., Bhardwaj, V., Paludo, J., Dasari, S., Dong, H., Ansell, S. M., Badley, A. D., Schellenberg, M. J., & Witzig, T. E. (2023). Secreted ORF8 induces monocytic pro-inflammatory cytokines through NLRP3 pathways in patients with severe COVID-19. iScience, 26(6), Article 106929. https://doi.org/10.1016/j.isci.2023.106929

Wu, X, Manske, MK, Ruan, GJ, Witter, TL, Nowakowski, KE, Abeykoon, JP, Tang, X, Yu, Y, Gwin, KA, Wu, A, Taupin, V, Bhardwaj, V, Paludo, J, Dasari, S , Dong, H , Ansell, SM , Badley, AD , Schellenberg, MJ & Witzig, TE 2023, 'Secreted ORF8 induces monocytic pro-inflammatory cytokines through NLRP3 pathways in patients with severe COVID-19', iScience, vol. 26, no. 6, 106929. https://doi.org/10.1016/j.isci.2023.106929

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title = "Secreted ORF8 induces monocytic pro-inflammatory cytokines through NLRP3 pathways in patients with severe COVID-19",

abstract = "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.",

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author = "Xiaosheng Wu and Manske, {Michelle K.} and Ruan, {Gordon J.} and Witter, {Taylor L.} and Nowakowski, {Kevin E.} and Abeykoon, {Jithma P.} and Xinyi Tang and Yue Yu and Gwin, {Kimberly A.} and Annie Wu and Vanessa Taupin and Vaishali Bhardwaj and Jonas Paludo and Surendra Dasari and Haidong Dong and Ansell, {Stephen M.} and Badley, {Andrew D.} and Schellenberg, {Matthew J.} and Witzig, {Thomas E.}",

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doi = "10.1016/j.isci.2023.106929",

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AU - Wu, Xiaosheng

AU - Manske, Michelle K.

AU - Ruan, Gordon J.

AU - Witter, Taylor L.

AU - Nowakowski, Kevin E.

AU - Abeykoon, Jithma P.

AU - Tang, Xinyi

AU - Yu, Yue

AU - Gwin, Kimberly A.

AU - Wu, Annie

AU - Taupin, Vanessa

AU - Bhardwaj, Vaishali

AU - Paludo, Jonas

AU - Dasari, Surendra

AU - Dong, Haidong

AU - Ansell, Stephen M.

AU - Badley, Andrew D.

AU - Schellenberg, Matthew J.

AU - Witzig, Thomas E.

PY - 2023/6/16

Y1 - 2023/6/16

N2 - 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.

AB - 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.

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Secreted ORF8 induces monocytic pro-inflammatory cytokines through NLRP3 pathways in patients with severe COVID-19

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