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, <i>HRAS, IFNG, JUN, CDH1, TLR4, ICAM1</i>, and <i>SCD</i>—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 <i>ICAM1</i> expression in the HDM-stimulated mice group (<i>p</i> &lt; 0.01). This study unveils the common pathogenesis and genetic signature underlying asthma and SARS-CoV-2 infection, delineated by the interaction networks of ACE2-related host factors. These findings provide valuable insights for the design and discovery of drugs aimed at more effective therapeutics within the context of lung disease comorbidities.

血管紧张素转换酶2（Angiotensin-converting enzyme 2, ACE2）被鉴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，该病毒正是当前全球新型冠状病毒肺炎（coronavirus disease 2019, COVID-19）大流行的致病原。本研究旨在通过鉴定哮喘患者体内与SARS-CoV-2感染相关的遗传特征，筛选已获批药物，以阐明潜在治疗策略。本研究通过整合分析开展此项探索，涵盖ACE2受体与COVID-19/哮喘共病相关的常见宿主（共宿主）因子之间的相互作用网络。本次全面分析涵盖共同差异表达基因（common differentially expressed genes, cDEGs）与核心共同差异表达基因（hub-cDEGs）的鉴定、功能注释、相互作用网络构建、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。借助相互作用网络可识别重叠疾病模块与潜在药物靶点。本研究采用计算生物学与分子对接分析手段，以解析功能性药物模块。随后，本研究利用小鼠模型，实验验证了所筛选药物对hub-cDEGs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cDEGs或共宿主因子。其中，7个关键cDEGs及对应蛋白——即HRAS、IFNG、JUN、CDH1、TLR4、ICAM1与SCD——被认定为与ACE2相关的核心宿主因子。对hub-cDEGs的调控网络分析显示，8个排名靠前的转录因子（transcription factors, TFs）蛋白与9个微小RNA（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种排名靠前的可重定位药物分子：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）、尼洛替尼（Nilotinib）、考尼伐坦（Conivaptan）、拉多替尼（Radotinib）与维奈克拉（Venetoclax），可作为哮喘共病患者COVID-19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 < 0.01）。本研究揭示了哮喘与SARS-CoV-2感染共有的发病机制与遗传特征，该特征由ACE2相关宿主因子的相互作用网络所刻画。本研究结果为肺部疾病共病背景下更高效治疗药物的设计与研发提供了重要参考。