Imiquimod suppresses respiratory syncytial virus (RSV) replication via PKA pathway and reduces RSV induced-inflammation and viral load in mice lungs

Abstract

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract disease and bronchiolitis in children, as well as an important cause of morbidity and mortality in elderly and immunocompromised individuals. However, there is no safe and efficacious RSV vaccine or antiviral treatment. Toll Like Receptors (TLR) are important molecular mediators linking innate and adaptive immunity, and their stimulation by cognate agonists has been explored as antiviral agents. Imiquimod is known as a TLR7 agonist, but additionally acts as an antagonist for adenosine receptors. In this study, we demonstrate that imiquimod, but not resiquimod, has direct anti-RSV activity via PKA pathway in HEp-2 and A549 cells, independently of an innate response. Imiquimod restricts RSV infection after viral entry into the host cell, interfering with viral RNA and protein synthesis. Probably as a consequence of these anti-RSV properties, imiquimod displays cytokine modulating activity in RSV infected epithelial cells. Moreover, in a murine model of RSV infection, imiquimod treatment improves the course of acute disease, evidenced by decreased weight loss, reduced RSV lung titers, and attenuated airway inflammation. Consequently, imiquimod represents a promising therapeutic alternative against RSV infection and may inform the development of novel therapeutic targets to control RSV pathogenesis.

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

“…Imiquimod-induced attenuation of the pro-inflammatory cytokines IL-6 and TNF-α, the neutrophilic chemokine IL-8, or different TH-type cytokines including IL-4, IFN-β, or IL-17, has been previously shown in airway epithelial cells or mouse models of RSV and Influenza A virus infections ( 37 , 38 ). Of note, Salinas et al.…”

“…Of note, Salinas et al. suggested the interference of imiquimod with viral macromolecular synthesis as one potential mechanism of imiquimod-dependent down-regulation of pro-inflammatory cytokines after RSV infection ( 38 ). This possibility is in line with our exploratory proteomic analysis on the direct effect of imiquimod on HBECs; our data revealed a possible protective effect of imiquimod on viral infections through down-modulation of proteins implicated in viral mRNA and protein synthesis, including several ribosomal proteins.…”

“…Imiquimod is a TLR7 agonist clinically approved as topical treatment of viral and tumoral skin conditions. Imiquimod may activate the production of type-I and III interferons as well as the NF-κB pathway ( 36 ), although results vary ( 37 , 38 ) and effects on human airway epithelium seem unexplored. Imiquimod has been considered as treatment for allergic diseases like asthma due to its inhibition of allergic type 2 inflammation and favoring of type 1 responses ( 39 , 40 ).…”

A TLR7 antagonist restricts interferon-dependent and -independent immunopathology in a mouse model of severe influenza

“…However, influenza virus infection in C57BL/6 does not lead to the massive CS observed in 129 mice ( Davidson et al, 2014 ) and therefore could not be used as a model of severe flu in our experiments. Prophylactic or early use of TLR7 agonists is efficient against flu ( To et al, 2019 ; Wu et al, 2007 ) and respiratory syncytial virus ( Salinas et al, 2020 ), as induction of IFN-I before infection efficiently blunts viral replication at its onset ( Davidson et al, 2016 ). While such prophylaxis for uninfected people is clinically unrealistic, we show that administration of the TLR7 antagonist IRS661 4 d after infection cuts down the otherwise prolonged production of IFN-I, inflammatory cytokines, and chemokines.…”

Screening and pharmacodynamic evaluation of the antirespiratory syncytial virus activity of steroidal pyridine compounds in vitro and in vivo

“…Hep‐2 cells in log growth phase were inoculated at 1 × 10 4 per well into 96‐well plates and incubated for 24 h. A series of compounds were added to the cells and 20 µl MTT was added to each well after 48 h and the amount of OD 490 nm value was determined. The 50% cytotoxic concentration (CC 50 ) is the concentration of compounds required to reduce cell viability by 50% 14 …”