The non-antibiotic macrolide EM900 inhibits rhinovirus infection and cytokine production in human airway epithelial cells

Abstract

The anti-inflammatory effects of macrolides may be associated with a reduced frequency of exacerbation of chronic obstructive pulmonary disease (COPD). However, because the long-term use of antibiotics may promote the growth of drug-resistant bacteria, the development of a treatment to prevent COPD exacerbation with macrolides that do not exert anti-bacterial effects is necessary. Additionally, the inhibitory effects of nonantibiotic macrolides on the replication of rhinovirus (RV), which is the major cause of COPD exacerbation, have not been demonstrated. Primary cultures of human tracheal epithelial cells and nasal epithelial cells were pretreated with the nonantibiotic macrolide EM900 for 72 h prior to infection with a major group RV type 14 rhinovirus (RV14) and were further treated with EM900 after infection. Treatment with EM900 before and after infection reduced RV14 titers in the supernatants and viral RNA within the cells. Moreover, cytokine levels, including interleukin (IL)-1β and IL-6, were reduced in the supernatants following RV14 infection. Treatment with EM900 before and after infection also reduced the mRNA and protein expression of intercellular adhesion molecule-1 (ICAM-1), which is the receptor for RV14, after infection and reduced the activation of the nuclear factor kappa-B protein p50 in nuclear extracts after infection. Pretreatment with EM900 reduced the number and fluorescence intensity of the acidic endosomes through which RV RNA enters the cytoplasm. Thus, pretreatment with EM900 may inhibit RV infection by reducing the ICAM-1 levels and acidic endosomes and thus modulate the airway inflammation associated with RV infections.

The clinically used serine protease inhibitor nafamostat reduces influenza virus replication and cytokine production in human airway epithelial cells and viral replication in mice

“…The distribution and fluorescence intensity of acidic endosomes in cells were measured with the LysoSensor DND‐189 dye (Molecular Probes) as previously described 20 . The fluorescence intensity was calculated using a fluorescence image analyzer system (Lumina Vision®; Mitani).…”

Effective drugs used to combat SARS-CoV-2 infection and the current status of vaccines

“…Several other macrolides possibly report observations of Azithromycin’s effectiveness on RNA viruses. Clarithromycin or the non-antibiotic macrolide EM900 are selective on in vitro rhinovirus [ 73 , 74 ]. In vivo , Hydroxychloroquine sulfate may be indicated by reducing pro-inflammatory cytokines and by adjusting the lysosome acidification process in the regulation of the immune response [ 74 ].…”

Immune-Modulation in Chronic Obstructive Pulmonary Disease: Current Concepts and Future Strategies

“…It is able to restore corticosteroid sensitivity by inhibition of PI 3 K signaling under oxidative stress [66]. More recently, another novel 12-membered nonantibiotic macrolide, EM900, has been shown to inhibit rhinovirus (RV) infection by reducing the ICAM-1 levels on epithelial cells and thereby modulates the airway inflammation associated with RV infections [67, 68]. Considering RV is the major cause of COPD exacerbation, macrolides such as EM900 could be a candidate drug for the prevention of COPD exacerbation.…”