Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA.
Nat Med. 2021 Mar;27(3):546-559. doi: 10.1038/s41591-020-01227-z. Epub 2021 Mar 2.
Angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2 and CTSL. Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. Expression programs shared by ACE2TMPRSS2 cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial-macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention.
血管紧张素转换酶 2（ACE2）和辅助蛋白酶（TMPRSS2 和 CTSL）是严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）进入细胞所必需的，它们的表达可能揭示病毒的嗜性和对全身的影响。我们评估了 ACE2、TMPRSS2 和 CTSL 在来自不同组织的 107 个单细胞 RNA 测序研究中的细胞类型特异性表达。ACE2、TMPRSS2 和 CTSL 在鼻腔、气道和肺泡中的呼吸道上皮细胞的特定亚群中共同表达，也在与 2019 年冠状病毒病（COVID-19）传播或病理学相关的其他器官的细胞中表达。我们对 31 项肺单细胞 RNA 测序研究进行了荟萃分析，这些研究涉及来自 228 个人的 377 个鼻腔、气道和肺实质样本中的 1320896 个细胞。这揭示了 ACE2、TMPRSS2 和 CTSL 的表达水平与年龄、性别和吸烟之间的细胞类型特异性关联。进入因子的表达随着年龄的增长而增加，在男性中也是如此，包括气道分泌细胞和肺泡 2 型细胞。在鼻腔、肺和肠道组织中 ACE2TMPRSS2 细胞共享的表达程序包括可能介导病毒进入的基因、关键的免疫功能和上皮-巨噬细胞相互作用，例如涉及白细胞介素 6、白细胞介素 1、肿瘤坏死因子和补体途径的基因。细胞类型特异性表达模式可能有助于 COVID-19 的发病机制，我们的工作强调了潜在的分子途径，以进行治疗干预。
