Thompson Elizabeth A, Cascino Katherine, Ordonez Alvaro A, Zhou Weiqiang, Vaghasia Ajay, Hamacher-Brady Anne, Brady Nathan R, Sun Im-Hong, Wang Rulin, Rosenberg Avi Z, Delannoy Michael, Rothman Richard, Fenstermacher Katherine, Sauer Lauren, Shaw-Saliba Kathyrn, Bloch Evan M, Redd Andrew D, Tobian Aaron Ar, Horton Maureen, Smith Kellie, Pekosz Andrew, D'Alessio Franco R, Yegnasubramanian Srinivasan, Ji Hongkai, Cox Andrea L, Powell Jonathan D
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.
medRxiv. 2020 Oct 5:2020.09.10.20186064. doi: 10.1101/2020.09.10.20186064.
It remains unclear why some patients infected with SARS-CoV-2 readily resolve infection while others develop severe disease. To address this question, we employed a novel assay to interrogate immune-metabolic programs of T cells and myeloid cells in severe and recovered COVID-19 patients. Using this approach, we identified a unique population of T cells expressing high H3K27me3 and the mitochondrial membrane protein voltage-dependent anion channel (VDAC), which were expanded in acutely ill COVID-19 patients and distinct from T cells found in patients infected with hepatitis c or influenza and in recovered COVID-19. Increased VDAC was associated with gene programs linked to mitochondrial dysfunction and apoptosis. High-resolution fluorescence and electron microscopy imaging of the cells revealed dysmorphic mitochondria and release of cytochrome into the cytoplasm, indicative of apoptosis activation. The percentage of these cells was markedly increased in elderly patients and correlated with lymphopenia. Importantly, T cell apoptosis could be inhibited by targeting the oligomerization of VDAC or blocking caspase activity. In addition to these T cell findings, we also observed a robust population of Hexokinase II polymorphonuclear-myeloid derived suppressor cells (PMN-MDSC), exclusively found in the acutely ill COVID-19 patients and not the other viral diseases. Finally, we revealed a unique population of monocytic MDSC (M-MDSC) expressing high levels of carnitine palmitoyltransferase 1a (CPT1a) and VDAC. The metabolic phenotype of these cells was not only highly specific to COVID-19 patients but the presence of these cells was able to distinguish severe from mild disease. Overall, the identification of these novel metabolic phenotypes not only provides insight into the dysfunctional immune response in acutely ill COVID-19 patients but also provide a means to predict and track disease severity as well as an opportunity to design and evaluate novel metabolic therapeutic regimens.
目前尚不清楚为何有些感染了SARS-CoV-2的患者能轻易康复，而另一些患者却会发展为重症疾病。为了解决这个问题，我们采用了一种新的检测方法来探究重症和康复期COVID-19患者中T细胞和髓系细胞的免疫代谢程序。通过这种方法，我们鉴定出了一群独特的T细胞，它们表达高水平的H3K27me3和线粒体膜蛋白电压依赖性阴离子通道（VDAC），这些细胞在急性病COVID-19患者中扩增，且与丙型肝炎或流感感染患者以及康复期COVID-19患者体内的T细胞不同。VDAC增加与线粒体功能障碍和凋亡相关的基因程序有关。对这些细胞进行高分辨率荧光和电子显微镜成像显示线粒体形态异常，细胞色素释放到细胞质中，这表明凋亡被激活。这些细胞的百分比在老年患者中显著增加，且与淋巴细胞减少相关。重要的是，通过靶向VDAC的寡聚化或阻断半胱天冬酶活性，可以抑制T细胞凋亡。除了这些T细胞发现外，我们还观察到了一群强大的己糖激酶II多形核髓系来源抑制细胞（PMN-MDSC），仅在急性病COVID-19患者中发现，而在其他病毒性疾病中未发现。最后，我们发现了一群独特的单核细胞MDSC（M-MDSC），它们表达高水平的肉碱棕榈酰转移酶1a（CPT1a）和VDAC。这些细胞的代谢表型不仅对COVID-19患者具有高度特异性，而且这些细胞的存在能够区分重症和轻症疾病。总体而言，这些新代谢表型的鉴定不仅为深入了解急性病COVID-19患者的功能失调免疫反应提供了思路，还提供了预测和跟踪疾病严重程度的方法，以及设计和评估新型代谢治疗方案的机会。
