Li Zhonglin, Yang Ling
Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Front Genet. 2020 Oct 27;11:558557. doi: 10.3389/fgene.2020.558557. eCollection 2020.
BACKGROUND: The coronavirus disease 2019 (COVID-19) has become a worldwide public health crisis. At present, there are no effective antiviral drugs to treat COVID-19. Although some vaccines have been developed, late-stage clinical trials that allow licensure by regulatory agencies are still needed. Previous reports have indicated that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and SARS-CoV are highly homologous and both use angiotensin-converting enzyme 2 (ACE2) as the receptor to enter cells, and SARS-CoV infection reduces the ACE2 expression in the lung. Therefore, the analysis of genes co-expressed with ACE2 in the lung may uncover the underlying mechanism of COVID-19. Finally, we used the Connectivity map (Cmap) database to search for candidate drugs using transcriptome profiles of patients with COVID-19. METHOD: Based on the differentially expressed genes (DEGs), indicated by the expression of RNAs isolated from bronchoalveolar lavage fluid (BALF) cells of patients with COVID-19, we performed functional enrichment analysis and hub gene cluster analysis. Furthermore, we identified genes co-expressed with ACE2 in healthy lung samples and analyzed the significant genes. Additionally, to identify several candidate drugs for the treatment of COVID-19, we queried Cmap using DEGs and genes co-expressed with ACE2. RESULTS AND CONCLUSION: The up-regulated genes in the BALF cells of patients with COVID-19 are related to viral mRNA translation. The down-regulated genes are related to immune response functions. Genes positively correlated with ACE2 are related to immune defense and those negatively correlated are enriched in synaptic transmission functions. The results reflected prosperous viral proliferation and immune dysfunction in patients. Furthermore, ACE2 may not only mediate viral entrance, but also play an important role in immune defense. By using Cmap with transcriptome profiles of patients with COVID-19, we identified candidate drugs for the treatment of COVID-19, such as amantadine and acyclovir.
背景：2019冠状病毒病（COVID-19）已成为全球公共卫生危机。目前，尚无有效的抗病毒药物治疗COVID-19。尽管已研发出一些疫苗，但仍需要进行后期临床试验以获得监管机构的许可。先前的报道表明，严重急性呼吸综合征冠状病毒2（SARS-CoV-2）与SARS-CoV高度同源，二者均以血管紧张素转换酶2（ACE2）作为受体进入细胞，且SARS-CoV感染会降低肺中ACE2的表达。因此，分析肺中与ACE2共表达的基因可能会揭示COVID-19的潜在机制。最后，我们使用连通图（Cmap）数据库，根据COVID-19患者的转录组谱来寻找候选药物。 方法：基于COVID-19患者支气管肺泡灌洗（BALF）细胞中分离的RNA表达所显示的差异表达基因（DEG），我们进行了功能富集分析和枢纽基因聚类分析。此外，我们在健康肺样本中鉴定了与ACE2共表达的基因，并分析了其中的重要基因。另外，为了确定几种治疗COVID-19的候选药物，我们使用DEG和与ACE2共表达的基因查询了Cmap。 结果与结论：COVID-19患者BALF细胞中上调的基因与病毒mRNA翻译有关。下调的基因与免疫反应功能有关。与ACE2呈正相关的基因与免疫防御有关，呈负相关的基因则富集于突触传递功能。这些结果反映出患者体内病毒增殖活跃和免疫功能障碍。此外，ACE2不仅可能介导病毒进入，还在免疫防御中发挥重要作用。通过将Cmap与COVID-19患者的转录组谱相结合，我们确定了治疗COVID-19的候选药物，如金刚烷胺和阿昔洛韦。
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