Antiviral activity of the non-steroidal anti-inflammatory drug indomethacin against respiratory syncytial virus

Human respiratory syncytial virus (RSV) is a ubiquitous pathogen belonging to the Pneumoviridae family. The enveloped virion contains a negative-sense single-stranded RNA genome comprising 10 genes. Infection is crucially dependent on the RSV fusion (F)-protein, which mediates fusion between the viral envelope and airway epithelial cells; F-protein is also responsible for fusion of infected cells with adjacent cells, leading to syncytium formation. RSV is the leading cause of hospitalization in young children with acute respiratory infections, and can be life-threatening particularly in infants under 6-months. RSV is also recognized to cause a substantial health burden in older adults. Virus-triggered exacerbated inflammation is associated with severe RSV disease outcomes. Although several F-targeting vaccines and monoclonal antibodies are now available for prevention of RSV disease, there is no effective specific drug treatment for RSV. Herein we show that the non-steroidal anti-inflammatory drug indomethacin possesses antiviral activity against RSV, causing a decrease in infectious virus production in different types of human respiratory cells at low micromolar concentrations. Indomethacin does not affect RSV adsorption or entry into host cells, but acts at the post-entry stage by interfering with F-protein expression. Whereas indomethacin anti-inflammatory action is mediated by cyclooxygenase-1 and -2 (COX-1/2) inhibition, the anti-RSV activity is not mimicked by the potent COX-1/2 inhibitor aspirin, indicating a cyclooxygenase-independent effect. The results suggest that indomethacin, possessing a direct antiviral activity against RSV in addition to anti-inflammatory properties, may provide a useful tool for the treatment of RSV infections.