Abstract
The coronavirus disease 2019 (COVID-19) outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affects almost everyone in the world in many ways. We previously predicted antivirals (atazanavir, remdesivir and lopinavir/ritonavir) and non-antiviral drugs (tiotropium and rapamycin) that may inhibit the replication complex of SARS-CoV-2 using our molecular transformer–drug target interaction (MT–DTI) deep-learning-based drug–target affinity prediction model. In this study, we dissected molecular pathways upregulated in SARS-CoV-2-infected normal human bronchial epithelial (NHBE) cells by analyzing an RNA-seq data set with various bioinformatics approaches, such as gene ontology, protein–protein interaction-based network and gene set enrichment analyses. The results indicated that the SARS-CoV-2 infection strongly activates TNF and NFκB-signaling pathways through significant upregulation of the TNF, IL1B, IL6, IL8, NFKB1, NFKB2 and RELB genes. In addition to these pathways, lung fibrosis, keratinization/cornification, rheumatoid arthritis, and negative regulation of interferon-gamma production pathways were also significantly upregulated. We observed that these pathologic features of SARS-CoV-2 are similar to those observed in patients with chronic obstructive pulmonary disease (COPD). Intriguingly, tiotropium, as predicted by MT–DTI, is currently used as a therapeutic intervention in COPD patients. Treatment with tiotropium has been shown to improve pulmonary function by alleviating airway inflammation. Accordingly, a literature search summarized that tiotropium reduced expressions of IL1B, IL6, IL8, RELA, NFKB1 and TNF in vitro or in vivo, and many of them have been known to be deregulated in COPD patients. These results suggest that COVID-19 is similar to an acute mode of COPD caused by the SARS-CoV-2 infection, and therefore tiotropium may be effective for COVID-19 patients.
Highlights
The coronavirus disease (COVID-19) outbreak caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1] has become a pandemic like the 1918 influenza pandemic [2], which was the most severe pandemic in recent history
SARS-CoV-2-infected normal human bronchial epithelialinfection (NHBE)interferes cells cultured in bronchial epithelial pathways in host cells, we reanalyzed RNA-seq data sets (GSE147507) performed in SARS-CoV-2growth media supplemented with BEGM SingleQuots [24]
The results showed that ADRB2, nuclear factor kappa B subunit 2 (NFKB2), NFKB inhibitor alpha (NFKBIA), TNF alpha induced protein 3 (TNFAIP3), RELBsuppressor proto-oncogene (RELB), tumor necrosis factor (TNF) and intercellular adhesion molecule 1 (ICAM1) were the that ADRB2, NFKB2, NFKBIA, TNFAIP3, RELB, TNF and ICAM1 were the most highly mostconnected highly connected thatregulate may regulate signaling pathways through
Summary
The coronavirus disease (COVID-19) outbreak caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1] has become a pandemic like the 1918 influenza pandemic [2], which was the most severe pandemic in recent history. Patients die mostly from severe multiple organ dysfunction, acute respiratory distress syndrome (ARDS), heart failure and renal failure, with uncontrolled immunological signatures [4]. Viruses 2020, 12, 776 proinflammatory genes may lead to a phenomenon called cytokine storm [5] which has been proposed to be diagnosed in a severe COVID-19 patient subgroup. SARS-CoV-2 manipulates host defense systems, leading to overexpression of proinflammatory cytokines such as interleukin 6 (IL-6), interleukin 1B (IL-1B) and tumor necrosis factor (TNF) [6]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
