Secreted ORF8 is a pathogenic cause of severe Covid-19 and potentially targetable with select NLRP3 inhibitors

Wu, X.; Manske, M. K.; Ruan, G.; Nowakowski, K. E.; Abeykoon, J. P.; Tang, X.; Yu, Y.; Witter, T. L.; Taupin, V.; Paludo, J.; Ansell, S. M.; Badley, A. D.; Schellenberg, M.; Witzig, T. E.

doi:10.1101/2021.12.02.470978

bioRxiv · 10.1101/2021.12.02.470978

Secreted ORF8 is a pathogenic cause of severe Covid-19 and potentially targetable with select NLRP3 inhibitors

Wu, X.·Manske, M. K.·Ruan, G.·Nowakowski, K. E.·Abeykoon, J. P.·Tang, X.·Yu, Y.·Witter, T. L.·Taupin, V.·Paludo, J.·Ansell, S. M.·Badley, A. D.·Schellenberg, M.·Witzig, T. E.

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Abstract

COVID-19 is a significant cause of morbidity and mortality in blood cancer patients, especially those on immunosuppressive therapy. 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 a non-canonical inflammasomal response, and a canonical response when the second activation signal is present. 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 for severe COVID-19. Key pointsO_LISecreted glycoprotein ORF8 induces monocytic pro-inflammatory cytokines involving the activation of the NLPR3 inflammasome pathway. C_LIO_LIORF8 is prognostically present in the blood of symptomatic patients with covid-19 and is targetable with NLRP3 inhibitor MCC-950. C_LI

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Wu, X., Manske, M. K., Ruan, G., Nowakowski, K. E., Abeykoon, J. P., Tang, X., Yu, Y., Witter, T. L., Taupin, V., Paludo, J., Ansell, S. M., Badley, A. D., Schellenberg, M., Witzig, T. E.. 2021-12-03. Secreted ORF8 is a pathogenic cause of severe Covid-19 and potentially targetable with select NLRP3 inhibitors. https://doi.org/10.1101/2021.12.02.470978

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