TY - JOUR T1 - A human lung explant model for the study of antiviral drugs JF - European Respiratory Journal JO - Eur Respir J VL - 42 IS - Suppl 57 SP - 4843 AU - Ben Nicholas AU - Karl Staples AU - Stefan Moese AU - Jon Ward AU - Patrick Dennison AU - Tom Havelock AU - Timothy Hinks AU - Khalid Amer AU - Edwin Woo AU - Martin Chamberlain AU - Neeta Singh AU - Malcolm North AU - Sandy Pink AU - Tom Wilkinson AU - Ratko Djukanovic Y1 - 2013/09/01 UR - http://erj.ersjournals.com/content/42/Suppl_57/4843.abstract N2 - Influenza A causes considerable morbidity and mortality. Growing viral resistance to therapeutics that target viral proteins, such as neuraminidase and M2-channel inhibitors, has led to increased interest in anti-viral compounds with effects on host-cell mechanisms. We report a novel experimental approach that circumvents the inter-species differences in immune responses to respiratory viruses which limit the value of animal models for the development of anti-viral drugs that target host defences. Using genome-wide siRNA screening in the A549 human epithelial cell line, we first identified vacuolar ATPases (vATPases) as a key host mechanism for influenza infection. A specific vATPase inhibitor was found markedly to attenuate influenza-A infection in monolayer cultures. We next developed a human lung explant model to test the effectiveness of the vATPase inhibitor when compared with the current frontline anti-influenza therapeutic, oseltamivir. Using flow cytometry in conjunction with anti-viral nucleoprotein antibody applied to collagenase-dispersed bronchial and lung parenchymal tissues, infection was localised to epithelial cells and macrophages. The vATPase inhibitor completely inhibited epithelial cell infection, virus shedding and the associated induction of pro-inflammatory cytokines/chemokines, whereas oseltamivir was only partially effective. This study, therefore, demonstrates the value of the human lung explant model for pre-clinical development of anti-viral therapeutics. ER -