Background Both anti-viral and anti-inflammatory bronchial effects are warranted to treat viral infections in asthma. We sought to investigate if imiquimod, a TLR7 agonist, exhibits such dual actions in ex vivo cultured human bronchial epithelial cells (HBECs), targets for SARS-CoV-2 infectivity. Objective To investigate bronchial epithelial effects of imiquimod of potential importance for anti-viral treatment in asthmatic patients. Methods Effects of imiquimod alone were examined in HBECs from healthy (N=4) and asthmatic (N=18) donors. Mimicking SARS-CoV-2 infection, HBECs were stimulated with poly(I:C), a dsRNA analogue, or SARS-CoV-2 spike-protein 1 (SP1; receptor binding) with and without imiquimod treatment. Expression of SARS-CoV-2 receptor (ACE2), pro-inflammatory and anti-viral cytokines were analyzed by RT-qPCR, multiplex ELISA, western blot, and Nanostring and proteomic analyses. Results Imiquimod reduced ACE2 expression at baseline and after poly(I:C) stimulation. Imiquimod also reduced poly(I:C)-induced pro-inflammatory cytokines including IL-1β, IL-6, IL-8, and IL-33. Furthermore, imiquimod increased IFN-β expression, an effect potentiated in presence of poly(I:C) or SP1. Multiplex mRNA analysis verified enrichment in type-I IFN signaling concomitant with suppression of cytokine signaling pathways induced by imiquimod in presence of poly(I:C). Exploratory proteomic analyses revealed potentially protective effects of imiquimod on infections. Conclusion Imiquimod triggers viral resistance mechanisms in HBECs by decreasing ACE2 and increasing IFN-β expression. Additionally, imiquimod improves viral infection tolerance by reducing viral stimulus-induced epithelial cytokines involved in severe COVID-19 infection. Our imiquimod data highlight feasibility of producing pluripotent drugs potentially suited for anti-viral treatment in asthmatic subjects.
【저자키워드】 COVID-19, Asthma, SARS – CoV – 2, anti-viral drug, imiquimod, TLR7 agonist, 【초록키워드】 Treatment, SARS-CoV-2, Tolerance, Asthma, viral infection, ACE2, Cytokines, Anti-inflammatory, feasibility, IL-6, SARS-COV-2 infection, TLR7, cytokine, drug, IFN signaling, viral infections, ELISA, SARS-CoV-2 receptor, Anti-viral, RT-qPCR, infections, Viral, COVID-19 infection, mRNA, qPCR, western blot, IL-33, pathway, IL-8, spike-protein, target, epithelial cells, pro-inflammatory cytokines, donors, multiplex, ACE2 expression, expression, epithelial, mechanism, imiquimod, cytokine signaling, proteomic, protective effect, IL-1β, dsRNA, Analysis, Receptor binding, Viral resistance, Trigger, poly(I:C), triggers, dual, resistance mechanisms, poly(I:C, Ex vivo, Severe COVID-19 Infection, Anti-viral treatment, suppression, IFN-β, treat, pro-inflammatory cytokine, asthmatic, HBECs, pro-inflammatory, Asthmatic patients, anti-viral cytokines, Effect, objective, SP1, highlight, IMPROVE, stimulated, Result, analyzed, examined, involved, healthy, reduced, subjects, reducing, analysis, producing, analyses, exhibit, bronchial epithelial cell, anti-viral cytokine, baseline, HBEC, 【제목키워드】 Asthma, ACE2, Human, response, epithelium, imiquimod, bronchial, decrease,