Imiquimod Boosts Interferon Response, and Decreases ACE2 and Pro-Inflammatory Response of Human Bronchial Epithelium in Asthma.

Juan José Nieto-Fontarigo,Lena Uller,Mandy Menzel,Sofia Tillgren,Morten Hvidtfeldt,Celeste Porsbjerg,Asger Sverrild,Sangeetha Ramu,Samuel Cerps,Adam Frederik Sander

doi:10.3389/fimmu.2021.743890

Abstract

BackgroundBoth 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.ObjectiveTo investigate bronchial epithelial effects of imiquimod of potential importance for anti-viral treatment in asthmatic patients.MethodsEffects 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.ResultsImiquimod 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.ConclusionImiquimod 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.

Highlights

Asthma is a chronic inflammatory disease affecting more than 300 million people worldwide [1]
The first epidemiologic studies could not find an association of asthma with an increase risk to suffer from COVID-19, novel data from large cohorts evidenced a higher prevalence of asthma in patients with COVID-19 compared to the general population [6]
Treatment with imiquimod for 24 hours resulted in a clear decrease of Angiotensin Converting Enzyme II (ACE2) expression (P

Summary

Introduction

Asthma is a chronic inflammatory disease affecting more than 300 million people worldwide [1]. In December 2019, a novel coronavirus disease, named coronavirus disease-19 (COVID-19), emerged in the Hubei province of China [4]. This disease is caused by severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) [5]. There is still a need for new drug opportunities to treat SARS-CoV-2 infection, especially in patients with a high risk to develop a severe sickness such as asthmatic subjects. 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

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Discussion

Conclusion