The innate anti-viral effects of Azithromycin and other novel macrolides

Abstract

Asthma exacerbations are highly associated with respiratory viral infections, particularly rhinovirus (RV) infection. Currently, standard asthma medication does not include anti-viral agents despite the role viruses play. Asthmatics have also demonstrated impaired innate interferon responses to viral infection thus compounding the requirement for an anti-viral treatment. Macrolides are a class of compound often used to treat bacterial infections, Azithromycin has previously shown anti-inflammatory activity in addition to it’s potent antibiotic effects. In 2010, Gielen et al demonstrated that Azithromycin possesses anti-viral activity in an in vitro model of RV infection in human bronchial epithelial cells (HBECs). In this thesis we build on the findings of Gielen et al; we demonstrate that Azithromycin is able to augment RV-induced type I and type III interferon (IFN) and interferon stimulated gene (ISG) expression whilst reducing viral replication in HBECs cultured ex vivo from asthmatic donors. We also demonstrate that oral administration of Azithromycin is able to partially augment IFN production in a mouse model of RV infection. We elucidate a potential mechanism of action of Azithromycin’s anti-viral activity in non-asthmatic HBECs, identifying mitochondria-associated anti-viral signalling protein (MAVS) as a potential target of Azithromycin’s actions. Finally we demonstrate the development of a novel screening assay for the detection of novel macrolides with potential anti-viral activity, eventually identifying a novel macrolide (MAC5) as a compound with greater IFN augmenting ability than Azithromycin. We also identify a MAC5 analogue (MAC5K) that possesses potential anti-viral, anti-inflammatory and limited antibiotic activity.