Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan.
Laboratory of Immunochemistry, World Premier International Immunology Frontier Research Centre, Osaka University, Osaka, 565-0871, Japan.
Int Immunol. 2023 Jan 21;35(1):43-52. doi: 10.1093/intimm/dxac044.
Many patients with severe COVID-19 suffer from pneumonia and the elucidation of the mechanisms underlying the development of this severe condition is important. The in vivo function of the ORF8 protein secreted by SARS-CoV-2 is not well understood. Here, we analyzed the function of ORF8 protein by generating ORF8-knockout SARS-CoV-2 and found that the lung inflammation observed in wild-type SARS-CoV-2-infected hamsters was decreased in ORF8-knockout SARS-CoV-2-infected hamsters. Administration of recombinant ORF8 protein to hamsters also induced lymphocyte infiltration into the lungs. Similar pro-inflammatory cytokine production was observed in primary human monocytes treated with recombinant ORF8 protein. Furthermore, we demonstrated that the serum ORF8 protein levels are well-correlated with clinical markers of inflammation. These results demonstrated that the ORF8 protein is a SARS-CoV-2 viral cytokine involved in the immune dysregulation observed in COVID-19 patients, and that the ORF8 protein could be a novel therapeutic target in severe COVID-19 patients.
许多患有严重 COVID-19 的患者患有肺炎，阐明这种严重疾病发展的机制非常重要。SARS-CoV-2 分泌的 ORF8 蛋白的体内功能尚未得到很好的理解。在这里，我们通过生成 ORF8 敲除 SARS-CoV-2 来分析 ORF8 蛋白的功能，发现 ORF8 敲除 SARS-CoV-2 感染的仓鼠中观察到的肺部炎症减少。向仓鼠施用重组 ORF8 蛋白也诱导了淋巴细胞浸润肺部。用重组 ORF8 蛋白处理的原代人单核细胞中也观察到类似的促炎细胞因子产生。此外，我们证明了血清 ORF8 蛋白水平与 COVID-19 患者炎症的临床标志物密切相关。这些结果表明，ORF8 蛋白是一种 SARS-CoV-2 病毒细胞因子，参与 COVID-19 患者中观察到的免疫失调，并且 ORF8 蛋白可能是严重 COVID-19 患者的新的治疗靶标。
