Multiple Expression Assessments of ACE2 and TMPRSS2 SARS-CoV-2 Entry Molecules in the Urinary Tract and Their Associations with Clinical Manifestations of COVID-19.
Multiple Expression Assessments of ACE2 and TMPRSS2 SARS-CoV-2 Entry Molecules in the Urinary Tract and Their Associations with Clinical Manifestations of COVID-19.
复制标题
尿道中 ACE2 和 TMPRSS2 SARS-CoV-2 进入分子的多重表达评估及其与 COVID-19 临床表现的关联
DOI：
10.2147/idr.s270543
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发表时间：
2020
影响因子：
3.9
通讯作者：
Qin C
中科院分区：
文献类型：
--
作者：
Ren X;Wang S;Chen X;Wei X;Li G;Ren S;Zhang T;Zhang X;Lu Z;You Z;Wang Z;Song N;Qin C
自2019年12月以来，新型冠状病毒严重急性呼吸综合征冠状病毒2（SARS-CoV-2）首先在中国武汉迅速传播，然后在全球范围内传播。根据先前发表的证据，ACE 2和TMPRSS 2都是使SARS-CoV-2能够感染细胞的关键进入分子。同时，促炎细胞因子表达增加，或“细胞因子风暴”，与多器官功能障碍综合征有关，这在危重患者中经常观察到。方法我们研究了ACE 2和TMPRSS 2在人体主要器官，特别是在特定疾病条件下的表达模式。不同物种中ACE 2的多序列比对用于解释动物的易感性。此外，使用单细胞RNA测序（scRNA-seq）评估尿路中ACE 2和细胞因子受体的细胞特异性表达模式。通过使用ACE 2特异性标签的基因集富集分析（GSEA）确定额外的生物相关性。结果ACE 2和TMPRSS 2在泌尿生殖器官中高表达。ACE 2在慢性肾脏疾病和糖尿病肾病患者的肾脏中表达显著增高。在单细胞中，ACE 2主要富集在睾丸和肾近端小管的配子母细胞中。促炎细胞因子的受体，特别是IL 6ST，显着集中在内皮细胞，巨噬细胞，精原干细胞在睾丸和肾内皮细胞，这表明通过自身免疫攻击的替代损伤机制的发生。结论这项研究为SARS-CoV-2的致病机制提供了新的见解，这些机制是在人类睾丸和肾脏中观察到的临床表现的基础。这些观察结果可能会大大促进这种快速传播疾病的有效治疗方法的发展。
Background Since December 2019, the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first spread quickly in Wuhan, China, then globally. From previously published evidence, ACE2 and TMPRSS2, are both pivotal entry molecules that enable cellular infection by SARS-CoV-2. Meanwhile, increased expression of pro-inflammatory cytokines, or a “cytokine storm,” is associated with multiple organ dysfunction syndrome that is often observed in critically ill patients. Methods We investigated the expression pattern of ACE2 and TMPRSS2 in major organs in the human body, especially under specific disease conditions. Multiple sequence alignment of ACE2 in different species was used to explain animal susceptibility. Moreover, the cell-specific expression patterns of ACE2 and cytokine receptors in the urinary tract were assessed using single-cell RNA sequencing (scRNA-seq). Additional biological relevance was determined through Gene Set Enrichment Analysis (GSEA) using an ACE2 specific signature. Results Our results revealed that ACE2 and TMPRSS2 were highly expressed in genitourinary organs. ACE2 was highly and significantly expressed in the kidney among individuals with chronic kidney diseases or diabetic nephropathy. In single cells, ACE2 was primarily enriched in gametocytes in the testis, and renal proximal tubules. The receptors for pro-inflammatory cytokines, especially IL6ST, were remarkably concentrated in endothelial cells, macrophages, and spermatogonial stem cells in the testis, and renal endothelial cells, which suggested the occurrence of alternative damaging mechanisms via autoimmune attacks. Conclusions This study provided new insights into the pathogenicity mechanisms of SARS-CoV-2 that underlie the clinical manifestations observed in the human testis and kidney. These observations might substantially facilitate the development of effective treatments for this rapidly spreading disease.