Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Cell Rep. 2021 Mar 16;34(11):108863. doi: 10.1016/j.celrep.2021.108863. Epub 2021 Feb 26.
It is unclear why some SARS-CoV-2 patients readily resolve infection while others develop severe disease. By interrogating metabolic programs of immune cells in severe and recovered coronavirus disease 2019 (COVID-19) patients compared with other viral infections, we identify a unique population of T cells. These T cells express increased Voltage-Dependent Anion Channel 1 (VDAC1), accompanied by gene programs and functional characteristics linked to mitochondrial dysfunction and apoptosis. The percentage of these cells increases in elderly patients and correlates with lymphopenia. Importantly, T cell apoptosis is inhibited in vitro by targeting the oligomerization of VDAC1 or blocking caspase activity. We also observe an expansion of myeloid-derived suppressor cells with unique metabolic phenotypes specific to COVID-19, and their presence distinguishes severe from mild disease. Overall, the identification of these metabolic phenotypes provides insight into the dysfunctional immune response in acutely ill COVID-19 patients and provides a means to predict and track disease severity and/or design metabolic therapeutic regimens.
目前尚不清楚为什么有些 SARS-CoV-2 患者能够轻易清除感染，而有些患者则会发展为重症。通过比较严重和康复的 2019 年冠状病毒病（COVID-19）患者与其他病毒感染患者的免疫细胞代谢程序，我们鉴定出了一类独特的 T 细胞亚群。这些 T 细胞表达高水平的电压依赖性阴离子通道 1（VDAC1），同时伴有与线粒体功能障碍和细胞凋亡相关的基因程序和功能特征。这些细胞在老年患者中的比例增加，并与淋巴细胞减少症相关。重要的是，通过靶向 VDAC1 寡聚化或阻断半胱天冬酶活性，可在体外抑制 T 细胞凋亡。我们还观察到 COVID-19 患者中存在具有独特代谢表型的髓系来源抑制细胞的扩增，其存在可将重症与轻症区分开来。总的来说，这些代谢表型的鉴定为急性 COVID-19 患者免疫功能障碍的反应机制提供了新的认识，并为预测和跟踪疾病严重程度以及/或设计代谢治疗方案提供了新的方法。
