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      About Skin Pharmacology and Physiology: 2.8 Impact Factor I 5.2 CiteScore I 0.623 Scimago Journal & Country Rank (SJR)

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      Interferon and Toll-Like Receptor 7 Response in COVID-19: Implications of Topical Imiquimod for Prophylaxis and Treatment

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          Abstract

          Background

          The innate immune system is recognized as an essential aspect of COVID-19 pathogenesis. Toll-like receptors (TLRs) are important in inducing antiviral response, triggering downstream production of interferons (IFNs). Certain loss-of-function variants in TLR7 are associated with increased COVID-19 disease severity, and imiquimod (ImiQ) is known to have immunomodulating effects as an agonist of TLR7. Given that topical imiquimod (topImiQ) is indicated for various dermatologic conditions, it is necessary for dermatologists to understand the interplay between innate immunity mechanisms and the potential role of ImiQ in COVID-19, with a particular focus on TLR7.

          Summary

          Our objective was to survey recent peer-reviewed scientific literature in the PubMed database, examine relevant evidence, and elucidate the relationships between IFNs, TLR7, the innate immune system, and topImiQ in the context of COVID-19. Despite limited studies on this topic, current evidence supports the critical role of TLRs in mounting a strong immune response against COVID-19. Of particular interest to dermatologists, topImiQ can result in systemic upregulation of the immune system via activation of TLR7.

          Key Message

          Given the role of TLR7 in the systemic activation of the immune system, ImiQ, as a ligand of the TLR7 receptor, may have potential therapeutic benefit as a topical immunomodulatory treatment for COVID-19.

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          Most cited references97

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          A Novel Coronavirus from Patients with Pneumonia in China, 2019

          Summary In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.)
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            Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19

            Summary Viral pandemics, such as the one caused by SARS-CoV-2, pose an imminent threat to humanity. Because of its recent emergence, there is a paucity of information regarding viral behavior and host response following SARS-CoV-2 infection. Here we offer an in-depth analysis of the transcriptional response to SARS-CoV-2 compared with other respiratory viruses. Cell and animal models of SARS-CoV-2 infection, in addition to transcriptional and serum profiling of COVID-19 patients, consistently revealed a unique and inappropriate inflammatory response. This response is defined by low levels of type I and III interferons juxtaposed to elevated chemokines and high expression of IL-6. We propose that reduced innate antiviral defenses coupled with exuberant inflammatory cytokine production are the defining and driving features of COVID-19.
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              Is Open Access

              Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients

              Coronavirus disease 2019 (COVID-19) is characterized by distinct patterns of disease progression suggesting diverse host immune responses. We performed an integrated immune analysis on a cohort of 50 COVID-19 patients with various disease severity. A unique phenotype was observed in severe and critical patients, consisting of a highly impaired interferon (IFN) type I response (characterized by no IFN-β and low IFN-α production and activity), associated with a persistent blood viral load and an exacerbated inflammatory response. Inflammation was partially driven by the transcriptional factor NF-κB and characterized by increased tumor necrosis factor (TNF)-α and interleukin (IL)-6 production and signaling. These data suggest that type-I IFN deficiency in the blood could be a hallmark of severe COVID-19 and provide a rationale for combined therapeutic approaches.
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                Author and article information

                Journal
                Dermatology
                Dermatology
                DRM
                Dermatology (Basel, Switzerland)
                S. Karger AG (Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com )
                1018-8665
                1421-9832
                31 August 2021
                : 1-10
                Affiliations
                [1] aDepartment of Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA
                [2] bDepartment of Dermatology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
                [3] cArizona College of Osteopathic Medicine, Midwestern University, Glendale, Arizona, USA
                [4] dCollege of Medicine, SUNY Downstate Health Sciences Center, New York, New York, USA
                [5] eSchool of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
                [6] fCollege of Osteopathic Medicine, Rocky Vista University, Parker, Colorado, USA
                [7] gRocky Mountain Regional Veterans Affairs Medical Center, Aurora, Colorado, USA
                Author notes

                Mindy D. Szeto and Jalal Maghfour share first authorship.

                Article
                drm-0001
                10.1159/000518471
                8450856
                34511591
                7b91b4d9-126d-4c20-a180-57d7c3117143
                Copyright © 2021 by S. Karger AG, Basel

                This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.

                History
                : 16 December 2020
                : 13 July 2021
                Page count
                Figures: 1, Tables: 1, References: 66, Pages: 10
                Categories
                Review Article

                Dermatology
                imiquimod,topical imiquimod,toll-like receptors,interferons,covid-19
                Dermatology
                imiquimod, topical imiquimod, toll-like receptors, interferons, covid-19

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