Discovery of common molecular signatures and drug repurposing for COVID-19/Asthma comorbidity: ACE2 and multi-partite networks

Angiotensin-converting enzyme 2 (ACE2) is identified as the functional receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the ongoing global coronavirus disease-2019 (COVID-19) pandemic. This study aimed to elucidate potential therapeutic avenues by scrutinizing approved drugs through the identification of the genetic signature associated with SARS-CoV-2 infection in individuals with asthma. This exploration was conducted through an integrated analysis, encompassing interaction networks between the ACE2 receptor and common host (co-host) factors implicated in COVID-19/asthma comorbidity. The comprehensive analysis involved the identification of common differentially expressed genes (cDEGs) and hub-cDEGs, functional annotations, interaction networks, gene set variation analysis (GSVA), gene set enrichment analysis (GSEA), and module construction. Interaction networks were used to identify overlapping disease modules and potential drug targets. Computational biology and molecular docking analyzes were utilized to discern functional drug modules. Subsequently, the impact of the identified drugs on the expression of hub-cDEGs was experimentally validated using a mouse model. A total of 153 cDEGs or co-host factors associated with ACE2 were identified in the COVID-19 and asthma comorbidity. Among these, seven significant cDEGs and proteins – namely, HRAS, IFNG, JUN, CDH1, TLR4, ICAM1, and SCD—were recognized as pivotal host factors linked to ACE2. Regulatory network analysis of hub-cDEGs revealed eight top-ranked transcription factors (TFs) proteins and nine microRNAs as key regulatory factors operating at the transcriptional and post-transcriptional levels, respectively. Molecular docking simulations led to the proposal of 10 top-ranked repurposable drug molecules (Rapamycin, Ivermectin, Everolimus, Quercetin, Estradiol, Entrectinib, Nilotinib, Conivaptan, Radotinib, and Venetoclax) as potential treatment options for COVID-19 in individuals with comorbid asthma. Validation analysis demonstrated that Rapamycin effectively inhibited ICAM1 expression in the HDM-stimulated mice group (p血管紧张素转换酶2（Angiotensin-converting enzyme 2, ACE2）被确定为严重急性呼吸综合征冠状病毒2（severe acute respiratory syndrome coronavirus 2, SARS-CoV-2）的功能性受体，而该病毒正是当前全球新型冠状病毒肺炎（coronavirus disease 2019, COVID-19）大流行的病原体。本研究旨在通过分析哮喘患者体内与SARS-CoV-2感染相关的遗传特征，筛选已获批药物，以阐明潜在的治疗策略。本研究采用整合分析策略，涵盖ACE2受体与COVID-19/哮喘共病相关的常见宿主（共宿主，co-host）因子间的相互作用网络。该综合分析包括鉴定共同差异表达基因（common differentially expressed genes, cDEGs）及核心共同差异表达基因（hub-cDEGs）、功能注释、相互作用网络分析、基因集变异分析（gene set variation analysis, GSVA）、基因集富集分析（gene set enrichment analysis, GSEA）以及模块构建。研究借助相互作用网络鉴定重叠疾病模块与潜在药物靶点。结合计算生物学与分子对接分析，以识别功能性药物模块。随后，本研究利用小鼠模型实验验证了所筛选药物对核心共同差异表达基因表达的影响。在COVID-19与哮喘共病样本中，共鉴定出153个与ACE2相关的共同差异表达基因或共宿主因子。其中，HRAS、IFNG、JUN、CDH1、TLR4、ICAM1及SCD这7个关键共同差异表达基因及其编码蛋白，被认定为与ACE2关联的核心宿主因子。对核心共同差异表达基因的调控网络分析显示，8个顶级转录因子（transcription factors, TFs）蛋白与9个microRNA分别为转录水平与转录后水平的关键调控因子。分子对接模拟筛选出10种排名靠前的可药物重定位候选药物分子：雷帕霉素（Rapamycin）、伊维菌素（Ivermectin）、依维莫司（Everolimus）、槲皮素（Quercetin）、雌二醇（Estradiol）、恩曲替尼（Entrectinib）、尼罗替尼（Nilotinib）、考尼伐坦（Conivaptan）、拉多替尼（Radotinib）与维奈克拉（Venetoclax），可作为哮喘合并COVID-19患者的潜在治疗方案。验证分析结果显示，在屋尘螨（House Dust Mite, HDM）刺激的小鼠模型组中，雷帕霉素可有效抑制ICAM1的表达（p