Identification of a special cell type as a determinant of the kidney tropism of SARS-CoV-2
Identification of a special cell type as a determinant of the kidney tropism of SARS-CoV-2
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鉴定出一种特殊细胞类型作为 SARS-CoV-2 肾向性的决定因素
DOI：
10.1111/febs.16114
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发表时间：
2021
期刊：
影响因子：
5.4
通讯作者：
Peng Hui
中科院分区：
文献类型：
--
作者：
Lin Hongchun;Ma Xinxin;Xiao Fang;Su Hua;Shi Yaling;Liu Yuntao;Song Lan;Zhang Zhongde;Zhang Chun;Peng Hui
严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 的肾向性已在临床上得到充分验证，通常会导致 2019 冠状病毒病 (COVID-19) 患者出现各种形式的肾损伤。然而，潜在的机制和诊断方法仍有待确定。我们询问了正常人肾脏和患有既往疾病的肾脏的单细胞 RNA 测序 (scRNA-seq) 数据集中病毒相关宿主因子的表达，并通过 COVID-19 患者和健康个体的尿液蛋白质组学验证了结果。我们还使用表达数量性状基因座（eQTL）数据库评估了遗传变异对肾脏易感性的影响。我们发现了一种肾小管细胞亚型，将其命名为 PT-3 细胞，因为它在肾脏中容易受到 SARS-CoV-2 感染。 PT-3细胞富含病毒进入因子以及复制和组装机制，但缺乏抗病毒限制因子。免疫组织化学证实 COVID-19 患者肾脏切片上的 PT-3 细胞标记物 SCL36A2 呈阳性染色。 COVID-19患者的尿液蛋白质组学分析显示，PT-3细胞的标记物显着增加，同时病毒受体血管紧张素转换酶2也升高。我们进一步发现，糖尿病肾病中PT-3细胞的比例增加，但同种异体肾病和狼疮肾病中的PT-3细胞比例减少，这表明这些疾病的肾脏易感性存在差异。我们最终确定了几个调节肾细胞宿主因子表达的 eQTL。 PT-3 细胞可能代表 SARS-CoV-2 肾向性的关键决定因素，PT-3 细胞的检测可用于评估 COVID-19 期间肾脏感染的风险。
The kidney tropism of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has been well‐validated clinically and often leads to various forms of renal damage in coronavirus disease‐2019 (COVID‐19) patients. However, the underlying mechanisms and diagnostic approaches remain to be determined. We interrogated the expression of virus‐related host factors in single‐cell RNA sequencing (scRNA‐seq) datasets of normal human kidneys and kidneys with pre‐existing diseases and validated the results with urinary proteomics of COVID‐19 patients and healthy individuals. We also assessed the effects of genetic variants on kidney susceptibility using expression quantitative trait loci (eQTLs) databases. We identified a subtype of tubular cells, which we named PT‐3 cells, as being vulnerable to SARS‐CoV‐2 infections in the kidneys. PT‐3 cells were enriched in viral entry factors and replication and assembly machinery but lacked antiviral restriction factors. Immunohistochemistry confirmed positive staining of PT‐3 cell marker SCL36A2 on kidney sections from COVID‐19 patients. Urinary proteomic analyses of COVID‐19 patients revealed that markers of PT‐3 cells were significantly increased, along with elevated viral receptor angiotensin‐converting enzyme 2. We further found that the proportion of PT‐3 cells increased in diabetic nephropathy but decreased in kidney allografts and lupus nephropathy, suggesting that kidney susceptibility varied among these diseases. We finally identified several eQTLs that regulate the expression of host factors in kidney cells. PT‐3 cells may represent a key determinant for the kidney tropism of SARS‐CoV‐2, and detection of PT‐3 cells may be used to assess the risk of renal infection during COVID‐19.