An intestinal cell type in zebrafish is the nexus for the SARS-CoV-2 receptor and the Renin-Angiotensin-Aldosterone System that contributes to COVID-19 comorbidities.
An intestinal cell type in zebrafish is the nexus for the SARS-CoV-2 receptor and the Renin-Angiotensin-Aldosterone System that contributes to COVID-19 comorbidities.
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斑马鱼的肠道细胞类型是 SARS-CoV-2 受体和肾素-血管紧张素-醛固酮系统的联系，导致 COVID-19 合并症。
DOI：
10.1101/2020.09.01.278366
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Miller,AdamC
中科院分区：
文献类型：
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作者：
Postlethwait,JohnH;Farnsworth,DylanR;Miller,AdamC
患有高血压、肥胖和糖尿病等基础疾病的人在感染冠状病毒SARS-CoV-2后特别容易出现负面结果。这些COVID-19合并症由肾素-血管紧张素-醛固酮系统（RAAS）加剧，该系统通常通过酶Ace产生的肽血管紧张素II（Ang II）保护血压迅速下降或脱水。Ace paraminase Ace 2降解Ang II，从而抵消其慢性作用。Ace 2也是SARS-CoV-2的受体。Ace、冠状病毒和COVID-19合并症都调节Ace 2，但我们还不知道如何调节。为了利用斑马鱼（Danio rerio）作为疾病模型来了解调节RAAS的机制及其与COVID-19合并症的关系，我们必须首先确定斑马鱼的直系同源物和人类RAAS基因的共同直系同源物，其次，了解这些基因在斑马鱼发育的特定细胞中何时何地表达。为了实现这些目标，我们进行了基因组分析并研究了单细胞转录组。结果表明，大多数人RAAS基因在斑马鱼中有一个直系同源物，有些有两个或更多的共直系同源物。结果进一步确定了斑马鱼幼虫中特定的肠细胞类型作为关键RAAS组分的表达位点，包括Ace，Ace 2，冠状病毒共受体Slc 6a 19以及血管紧张素相关肽裂解酶Anpep和Enpep。结果还确定了表达Ang II受体、爱帕琳和爱帕琳受体基因的特定血管细胞亚型。这些结果确定了特定的基因和细胞类型，以利用斑马鱼作为疾病模型，了解导致COVID-19合并症的机制。概要声明基因组分析确定了导致COVID-19合并症的肾素-血管紧张素-醛固酮系统的斑马鱼直系同源物，单细胞转录组学显示它们在专门的肠道细胞类型中起作用。
People with underlying conditions, including hypertension, obesity, and diabetes, are especially susceptible to negative outcomes after infection with the coronavirus SARS-CoV-2. These COVID-19 comorbidities are exacerbated by the Renin-Angiotensin-Aldosterone System (RAAS), which normally protects from rapidly dropping blood pressure or dehydration via the peptide Angiotensin II (Ang II) produced by the enzyme Ace. The Ace paralog Ace2 degrades Ang II, thus counteracting its chronic effects. Ace2 is also the SARS-CoV-2 receptor.Ace, the coronavirus, and COVID-19 comorbidities all regulateAce2, but we don’t yet understand how. To exploit zebrafish (Danio rerio) as a disease model to understand mechanisms regulating the RAAS and its relationship to COVID-19 comorbidities, we must first identify zebrafish orthologs and co-orthologs of human RAAS genes, and second, understand where and when these genes are expressed in specific cells in zebrafish development. To achieve these goals, we conducted genomic analyses and investigated single cell transcriptomes. Results showed that most human RAAS genes have an ortholog in zebrafish and some have two or more co-orthologs. Results further identified a specific intestinal cell type in zebrafish larvae as the site of expression for key RAAS components, including Ace, Ace2, the coronavirus co-receptor Slc6a19, and the Angiotensin-related peptide cleaving enzymes Anpep and Enpep. Results also identified specific vascular cell subtypes as expressing Ang II receptors,apelin, andapelin receptorgenes. These results identify specific genes and cell types to exploit zebrafish as a disease model for understanding the mechanisms leading to COVID-19 comorbidities.SUMMARY STATEMENTGenomic analyses identify zebrafish orthologs of the Renin-Angiotensin-Aldosterone System that contribute to COVID-19 comorbidities and single-cell transcriptomics show that they act in a specialized intestinal cell type.