Erythromycin Inhibits Rhinovirus Infection in Cultured Human Tracheal Epithelial Cells

Abstract

To examine the effects of erythromycin on rhinovirus (RV) infection in airway epithelium, primary cultures of human tracheal epithelial cells were infected with the RV major subgroup, RV14, and the minor subgroup, RV2. Infection was confirmed by increases in viral RNA of the infected cells and viral titers of the supernatants. RV14 upregulated the expression of the mRNA and protein of intercellular adhesion molecule-1 (ICAM-1), the major RV receptor, and it increased the cytokine production. Erythromycin reduced the supernatant RV14 titers, RV14 RNA, the susceptibility to RV14 infection, and the production of ICAM-1 and cytokines. Erythromycin also reduced the supernatant RV2 titers, RV2 RNA, the susceptibility to RV2 infection, and cytokine production, although the inhibitory effects of erythromycin on the expression of the low-density lipoprotein receptor, the minor RV receptor, were small. Erythromycin reduced the nuclear factor-kappaB activation by RV14 and decreased the number of acidic endosomes in the epithelial cells. These results suggest that erythromycin inhibits infection by the major RV subgroup by reducing ICAM-1 and infection by both RV subgroups by blocking the RV RNA entry into the endosomes. Erythromycin may also modulate airway inflammation by reducing the production of proinflammatory cytokines and ICAM-1 induced by RV infection.

Novel antiviral properties of azithromycin in cystic fibrosis airway epithelial cells

“…Indeed, previous studies showed that augmentation of antiviral activity was not dependent on RV serotype [12]. In contrast to our findings, SUZUKI et al [10] showed decreased minor-type RV replication despite unmodified expression of LDLR by macrolide treatment. The discrepancy of our observations with these data might be explained by different macrolides used (azithromycin versus erythromycin), different duration of macrolide pre-treatment (24 h versus 3 days), different concentrations (50 versus 10 μM), different cell sources (bronchial versus tracheal epithelial cells) or different strains of minor-type RV used (RV1B versus RV2).…”

“…In our study, we further demonstrated that azithromycin treatment had antiviral properties characterised by a seven-fold reduced RV1B replication in CF bronchial cells. Our findings confirm previous observations showing antiviral properties of macrolides such as azithromycin [12], erythromycin [10], clarithromycin [9] and bafilomycin A1 [11] in RV-infected airway epithelial cells. In addition, we observed that the decreased RV1B load after azithromycin treatment was not attributable to azithromycin-induced cytotoxicity.…”

“…cell adhesion molecule 1, which is the cell surface entry receptor for the major group of RVs, as a possible anti-RV mechanism of macrolide treatment [9][10][11]. Interestingly, this suggests that macrolides have antiviral effects on both minor-and major-type RV infection independently of the expression of the respective surface entry receptor.…”

“…Beyond their well-established antibacterial effects, a novel and potentially promising property of macrolides is the inhibition of respiratory viral infections in vitro in healthy airway epithelial cells [9][10][11][12]. Azithromycin potentially works by stimulating the host antiviral responses through the induction of interferons (IFNs) and IFN-stimulated genes (ISGs) [12].…”

Viral Respiratory Tract Infections in Cystic Fibrosis

“…90% of rhinovirus serotypes gain entry into epithelial cells using ICAM-1 cellular receptors and blockade of these receptors in experimental studies have shown reduced infection severity (Turner, Wecker et al 1999), but further study is required before this treatment option becomes widely available. Macrolide antibiotics, Bafilomycin A1 and Erythromycin have been shown to inhibit ICAM-1 epithelial expression and hypothesis about their potential as anti-inflammatory agents have yet to be definitive, as clinical proof is either negative or inconclusive (Suzuki, Yamaya et al 2002).…”