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.

中文翻译：

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分泌的 ORF8 是严重 COVID-19 的致病原因，并且有可能被选定的 NLRP3 抑制剂靶向

COVID-19 是导致血癌患者，尤其是接受免疫抑制治疗的患者发病率和死亡率的重要原因。尽管进行了广泛的研究，但与 SARS-CoV-2 感染相关的、介导重症 COVID-19 患者危及生命的炎性细胞因子反应的特定因素仍未确定。在此，我们证明病毒编码的开放阅读框 8 (ORF8) 蛋白在体外和有症状的 COVID-19 患者中作为糖蛋白大量分泌。^{ORF8 特异性结合 CD14 +}中的 NOD 样受体家族 pyrin 结构域 3 (NLRP3)单核细胞诱导非典型炎症反应，以及当存在第二激活信号时的典型反应。血液中的 ORF8 蛋白水平与急性 SARS-CoV-2 感染患者的严重程度和疾病特异性死亡率相关。此外，在体外，NLRP3 抑制剂 MCC950 很容易抑制 ORF8 诱导的炎性体反应。我们的研究确定了发病机制的主要原因、其潜在机制以及严重 COVID-19 的潜在新疗法。