Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA.
HKU-Pasteur Research Pole, School of Public Health, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong (HKU), Hong Kong.
Science. 2020 Sep 4;369(6508):1210-1220. doi: 10.1126/science.abc6261. Epub 2020 Aug 11.
Coronavirus disease 2019 (COVID-19) represents a global crisis, yet major knowledge gaps remain about human immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We analyzed immune responses in 76 COVID-19 patients and 69 healthy individuals from Hong Kong and Atlanta, Georgia, United States. In the peripheral blood mononuclear cells (PBMCs) of COVID-19 patients, we observed reduced expression of human leukocyte antigen class DR (HLA-DR) and proinflammatory cytokines by myeloid cells as well as impaired mammalian target of rapamycin (mTOR) signaling and interferon-α (IFN-α) production by plasmacytoid dendritic cells. By contrast, we detected enhanced plasma levels of inflammatory mediators-including EN-RAGE, TNFSF14, and oncostatin M-which correlated with disease severity and increased bacterial products in plasma. Single-cell transcriptomics revealed a lack of type I IFNs, reduced HLA-DR in the myeloid cells of patients with severe COVID-19, and transient expression of IFN-stimulated genes. This was consistent with bulk PBMC transcriptomics and transient, low IFN-α levels in plasma during infection. These results reveal mechanisms and potential therapeutic targets for COVID-19.
2019 年冠状病毒病（COVID-19）代表了一场全球性危机，但人类对严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）的免疫仍存在重大知识空白。我们分析了来自中国香港和美国佐治亚州亚特兰大的 76 名 COVID-19 患者和 69 名健康个体的免疫反应。在 COVID-19 患者的外周血单核细胞（PBMC）中，我们观察到髓样细胞 HLA-DR（人类白细胞抗原 DR）和促炎细胞因子的表达减少，以及浆细胞样树突状细胞的哺乳动物雷帕霉素靶蛋白（mTOR）信号和干扰素-α（IFN-α）产生受损。相比之下，我们检测到促炎介质的血浆水平升高-包括 EN-RAGE、TNFSF14 和肿瘤坏死因子超家族成员 14-其与疾病严重程度和血浆中增加的细菌产物相关。单细胞转录组学揭示了缺乏 I 型干扰素，严重 COVID-19 患者髓样细胞中 HLA-DR 减少，以及 IFN 刺激基因的瞬时表达。这与 PBMC 转录组学一致，并且在感染过程中 IFN-α 水平短暂且较低。这些结果揭示了 COVID-19 的机制和潜在治疗靶点。
