Introduction: COVID-19 is caused by a new strain of coronavirus called SARS-coronavirus-2 (SARS-CoV-2), which is a positive sense single strand RNA virus. In humans, it binds to angiotensin converting enzyme 2 (ACE2) with the help a structural protein on its surface called the S-spike. Further, cleavage of the viral spike protein (S) by the proteases like transmembrane serine protease 2 (TMPRSS2) or Cathepsin L (CTSL) is essential to effectuate host cell membrane fusion and virus infectivity. COVID-19 poses intriguing issues with imperative relevance to clinicians. The pathogenesis of GI symptoms, diabetes-associated mortality, and disease recurrence in COVID-19 are of particular relevance because they cannot be sufficiently explained from the existing knowledge of the viral diseases. Tissue specific variations of SARS-CoV-2 cell entry related receptors expression in healthy individuals can help in understanding the pathophysiological basis the aforementioned collection of symptoms. Materials and Methods: The data were downloaded from the Human Protein Atlas available at (https://www.proteinatlas.org/humanproteome/sars-cov-2) and the tissue specific expressions (both mRNA and protein) of ACE2 and TMPRSS2 as yielded from the studies with RNA sequencing and immunohistochemistry (IHC) were analyzed as a function of the various components of the digestive tract. A digestive system specific functional enrichment map of ACE2 gene was created using g:profiler (https://biit.cs.ut.ee/gprofiler/gost) utility and the data were visualized using Cytoscape software, version 3.7.2 (https://cytoscape.org/). Results: The correlated expression (transcriptomic and proteomic) of ACE2 (to which SARS-CoV-2 binds through the S-spike) was found to be enriched in the lower gastrointestinal tract (GIT) (highest in small intestine, followed by colon and rectum), and was undetectable in the upper GIT components: mouth cavity (tongue, oral mucosa, and salivary glands), esophagus, and stomach. High expression of ACE2 was noted in the glandular cells as well as in the enterocytes in the lining epithelium (including brush border epithelium). Among other digestive system organs, Gall bladder (GB) showed high expression of ACE2 in glandular cells, while any protein expression was undetectable in liver and pancreas. TMPRSS2 was found enhanced in GIT and exocrine glands of pancreas, and co-localized with ACE2 in enterocytes. Conclusions: Based on the findings of this study and supportive evidence from the literature we propose that a SARS-CoV-2 binding with ACE2 mediates dysregulation of the sodium dependent nutrient transporters and hence may be a plausible basis for the digestive symptoms in COVID-19 patients. ACE2 mediated dysregulation of sodium dependent glucose transporter (SGLT1 or SLC5A1) in the intestinal epithelium also links it to the pathogenesis of diabetes mellitus which can be a possible reason for the associated mortality in COVID-19 patients with diabetes. High expression of ACE2 in mucosal cells of the intestine and GB make these organs potential sites for the virus entry and replication. Continued replication of the virus at these ACE2 enriched sites may be a basis for the disease recurrence reported in some, thought to be cured, patients.

中文翻译：

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胃肠道组织中SARS-CoV-2相关因子ACE2和TMPRSS2的表达与COVID-19患者消化系统症状，糖尿病相关的死亡率和疾病复发的发病机制的相关性

简介：COVID-19是由一种称为SARS-冠状病毒2（SARS-CoV-2）的新型冠状病毒引起的，这是一种正向单链RNA病毒。在人类中，它借助表面上称为S-spike的结构蛋白与血管紧张素转化酶2（ACE2）结合。此外，诸如跨膜丝氨酸蛋白酶2（TMPRSS2）或组织蛋白酶L（CTSL）之类的蛋白酶对病毒刺突蛋白（S）的切割对于实现宿主细胞膜融合和病毒感染性至关重要。COVID-19提出了与临床医生势在必行的有趣问题。GI症状的发病机制，与糖尿病相关的死亡率以及COVID-19中的疾病复发特别相关，因为无法从病毒性疾病的现有知识中充分解释它们。健康个体中SARS-CoV-2细胞进入相关受体表达的组织特异性变异可以帮助理解上述症状的病理生理基础。材料和方法：数据从可在（https://www.proteinatlas.org/humanproteome/sars-cov-2）上获得的人蛋白质图谱下载，ACE2和TMPRSS2的组织特异性表达（mRNA和蛋白质）分别为通过RNA测序和免疫组化（IHC）研究获得的结果根据消化道各种成分进行了分析。使用g：profiler（https://biit.cs.ut.ee/gprofiler/gost）实用程序创建了ACE2基因的消化系统特定功能富集图，并使用Cytoscape软件3.7.2版（https： //cytoscape.org/）。结果：发现ACE2（SARS-CoV-2通过S-spike与之结合）的相关表达（转录组和蛋白质组学）在下胃肠道（GIT）中富集（在小肠中最高，其次是结肠和直肠）。 ，并且在上部GIT组件中无法检测到：口腔（舌，口腔粘膜和唾液腺），食道和胃。ACE2在腺细胞以及衬里上皮（包括刷状缘上皮）的肠上皮细胞中均高表达。在其他消化系统器官中，胆囊（GB）在腺细胞中显示ACE2高表达，而在肝脏和胰腺中均未检测到任何蛋白质表达。发现TMPRSS2在胰腺的GIT和外分泌腺中增强，并与ACE2在肠上皮细胞中共定位。结论：基于这项研究的发现和文献的支持证据，我们提出SARS-CoV-2与ACE2的结合可介导钠依赖性营养转运蛋白的失调，因此可能是COVID-19患者消化系统症状的合理依据。ACE2介导的肠上皮中钠依赖性葡萄糖转运蛋白（SGLT1或SLC5A1）的失调也将其与糖尿病的发病机制相关，这可能是导致COVID-19糖尿病患者相关死亡的可能原因。ACE2在肠和GB粘膜细胞中的高表达使这些器官成为病毒进入和复制的潜在位点。病毒在这些富含ACE2的位点继续复制可能是某些患者（据认为已治愈）报告的疾病复发的基础。