Research Institute for Microbial Diseases and Center for Infectious Disease Education and Research, Osaka University, Suita, Osaka, 565-0871, Japan.
TANAKA Kikinzoku Kogyo K.K, Hiratsuka, Kanagawa, 254-0076, Japan.
Sci Rep. 2022 May 16;12(1):8108. doi: 10.1038/s41598-022-12252-y.
A cytokine storm induces acute respiratory distress syndrome, the main cause of death in coronavirus disease 2019 (COVID-19) patients. However, the detailed mechanisms of cytokine induction due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain unclear. To examine the cytokine production in COVID-19, we mimicked the disease in SARS-CoV-2-infected alveoli by adding the lysate of SARS-CoV-2-infected cells to cultured macrophages or induced pluripotent stem cell-derived myeloid cells. The cells secreted interleukin (IL)-6 after the addition of SARS-CoV-2-infected cell lysate. Screening of 25 SARS-CoV-2 protein-expressing plasmids revealed that the N protein-coding plasmid alone induced IL-6 production. The addition of anti-N antibody further enhanced IL-6 production, but the F(ab') fragment did not. Sera from COVID-19 patients also enhanced IL-6 production, and sera from patients with severer disease induced higher levels of IL-6. These results suggest that anti-N antibody promotes IL-6 production in SARS-CoV-2-infected alveoli, leading to the cytokine storm of COVID-19.
细胞因子风暴会引发急性呼吸窘迫综合征，这是 2019 年冠状病毒病（COVID-19）患者死亡的主要原因。然而，导致严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）的细胞因子诱导的详细机制仍不清楚。为了研究 COVID-19 中的细胞因子产生情况，我们通过向培养的巨噬细胞或诱导多能干细胞衍生的髓样细胞中添加 SARS-CoV-2 感染细胞的裂解物来模拟 SARS-CoV-2 感染的肺泡中的疾病。加入 SARS-CoV-2 感染细胞裂解物后，细胞会分泌白细胞介素（IL）-6。对 25 个 SARS-CoV-2 蛋白表达质粒进行筛选后发现，仅 N 蛋白编码质粒可诱导 IL-6 的产生。添加抗 N 抗体进一步增强了 IL-6 的产生，但 F(ab') 片段没有。COVID-19 患者的血清也增强了 IL-6 的产生，且病情更严重的患者诱导产生了更高水平的 IL-6。这些结果表明，抗 N 抗体促进了 SARS-CoV-2 感染肺泡中的 IL-6 产生，导致 COVID-19 的细胞因子风暴。
