Corticosteroid suppression of antiviral immunity increases bacterial loads and mucus production in COPD exacerbations

Abstract

Inhaled corticosteroids (ICS) have limited efficacy in reducing chronic obstructive pulmonary disease (COPD) exacerbations and increase pneumonia risk, through unknown mechanisms. Rhinoviruses precipitate most exacerbations and increase susceptibility to secondary bacterial infections. Here, we show that the ICS fluticasone propionate (FP) impairs innate and acquired antiviral immune responses leading to delayed virus clearance and previously unrecognised adverse effects of enhanced mucus, impaired antimicrobial peptide secretion and increased pulmonary bacterial load during virus-induced exacerbations. Exogenous interferon-β reverses these effects. FP suppression of interferon may occur through inhibition of TLR3- and RIG-I virus-sensing pathways. Mice deficient in the type I interferon-α/β receptor (IFNAR1−/−) have suppressed antimicrobial peptide and enhanced mucin responses to rhinovirus infection. This study identifies type I interferon as a central regulator of antibacterial immunity and mucus production. Suppression of interferon by ICS during virus-induced COPD exacerbations likely mediates pneumonia risk and raises suggestion that inhaled interferon-β therapy may protect.

Inhibitory effects of glycopyrronium, formoterol, and budesonide on coronavirus HCoV-229E replication and cytokine production by primary cultures of human nasal and tracheal epithelial cells

“…In the present study, significant mRNA levels of IFN-b, IFNl 1 and IFN-g were detected in cells, the production of which was reduced by treatment with drugs, although the concentrations of IFN-b, IFN-l 1 , and IFN-g in the ASL and basolateral supernatant were undetectable. These findings are consistent with those of a previous study demonstrating that rhinoviral infection induced innate immunity by stimulating the interferon system in human airway epithelial cells and that treatment with fluticasone reduced IFN production [37]. The reduced production of IFN-b, IFN-l 1 , and IFN-g could be associated with decreased HCoV-229E replication or the suppression of toll-like receptor 3 [37,38].…”

“…Here, we used HNE and HTE cells because we previously used these cells in infection studies [11,12,15,46]. However, because bronchi and alveoli are the main sites of the pathogenesis of COPD and bronchial asthma exacerbations, bronchial and alveolar epithelial cells were used to reveal the effects of viral infection on exacerbations and the effects of drugs [37,47]. Therefore, further studies using bronchial and alveolar epithelial cells will be needed to confirm HCoV-229E replication and the effects of drugs.…”

In vivo experimental models of infection and disease

“…169 Treatment with corticosteroid therapy (fluticasone proprionate) suppressed IFN responses to RV and reduced airway inflammation, leading to increased mucus production and reduced antimicrobial responses. 170 Effects on viral load, mucin production, and antibacterial response could be reversed by administration of recombinant IFNβ. 170 Despite promising findings in mouse models, quercetin has not entered clinical trials for the treatment of RV infection, likely due to a previous randomized community clinical trial in 2010 that showed little benefit of quercetin supplementation on upper respiratory infections.…”

“…170 Effects on viral load, mucin production, and antibacterial response could be reversed by administration of recombinant IFNβ. 170 Despite promising findings in mouse models, quercetin has not entered clinical trials for the treatment of RV infection, likely due to a previous randomized community clinical trial in 2010 that showed little benefit of quercetin supplementation on upper respiratory infections. 171 These findings may highlight the limitation of mouse models, which (while valuable) do not always fully recapitulate human disease mechanisms.…”

“…190 In the same elastase-induced model, fluticasone proprionate treatment reduced IFN responses, increased viral load, suppressed airway immune cell numbers (lymphocytes and neutrophils), suppressed inflammatory cytokines (IL-6, TNFα), and increased mucus production, following RV-A1 exacerbation. 170 The differences in the experimental approaches required to elicit an RV-induced exacerbation in these different studies is likely due to the quality of virus inoculum used by the different investigators, which as explained previously, is influenced by purification approach. The first study used only crude virus-infected cell lysates, whereas the later study employed a highly purified virus inoculum.…”