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

ABSTRACT

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 < 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.

KEYWORDS:

• SARS-CoV-2
• asthma
• comorbidities
• ACE2
• hub-cDEGs
• drug repurposing

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

All data are derived from publicly available sources, and all links to the data are provided in the materials and methods. Codes were available from the corresponding author on reasonable request.

Author contributions

J.X., R.A.K., A.B., and S.I. conceived the ideas. A.B., J.X., R.A.K., A.H.A., S.I., and R.A.S. designed the study. J.X., R.A.K., H.K.Z., A.F.M., K.F.F., S.I., and A.B. analyzed the data. J.X., R.A.K., H.K.Z., A.G., J.L.A.G., A.F.M., A.H.A., K.F.F., S.I., and A.B. interpreted the data. K.F.F., J.X., R.A.K., H.K.Z., A.F.M., A.H.A., A.G., and J.L.A.G. validated the data. J.X., A.B., K.F.F., and A.H.A. wrote the main manuscript. R.A.K., H.K.Z., A.H.A., K.F.F., and S.I. reviewed and edited the manuscript. All authors read and approved the final version of manuscript.

Ethics approval and consent to participate

The Animal Experiments and Care Committee at University Medical Center Tuebingen (2021–3-7 PN) authorized all animal procedures and experiments to be conducted in accordance with the guiding principles of the institution.

Consent for publication

All of the authors give their consent for publication of the identifiable details of the text.

Supplemental material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/15384101.2024.2340859

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.