Investigating the requirement for host cell chloride ion channels during human respiratory syncytial virus infection

Abstract

Ion channels are a diverse class of transmembrane proteins, which selectively allow ions across cellular membranes, influencing a multitude of cellular processes. Modulation of these channels by viruses is emerging as an important host-pathogen interaction, and has been demonstrated to regulate critical stages of the virus multiplication cycle including entry, replication and egress. Human respiratory syncytial virus (HRSV) causes severe respiratory tract infections (RTIs) globally and is one of the most lethal respiratory pathogens for infants in developing countries, with many cases leading to severe lower respiratory tract infections, and the development of bronchiolitis. Evidence also suggests that childhood HRSV infection contributes towards the increased incidence of adult asthma. There is no HRSV vaccine, and the only treatment is immunoprophylaxis that is prohibitively expensive and only moderately effective; thus new treatment options are required. In this study, by infecting human lung epithelial cells with HRSV in the presence of various broad-range channel modulators, Cl- channels were identified to play an important role during HRSV infection. Time of addition assays using these broad-acting Cl- channel blockers identified the stages within the HRSV lifecycle that were dependant on Cl- channel activity, and the use of family-specific Cl- channel blocking drugs identified a small sub-family of Cl-channels which, when inhibited, resulted in significantly reduced HRSV multiplication. We are now identifying the specific Cl- channel(s) facilitating the multiplication of HRSV using genetic means, and well as assessing the importance of Cl- channels in replication cycles of other negative sense RNA viruses.