Respiratory syncytial virus (RSV) is a leading cause of respiratory tract
infection in infants, causing significant morbidity and mortality. No vaccine or specific, effective treatment is currently available. A more complete understanding of the key components of effective host response to RSV, and novel preventative and therapeutic interventions, are urgently required. Cathelicidins are host defence peptides, expressed in the inflamed lung, with key microbicidal and modulatory roles in innate host defence against infection. Here we demonstrate that the human cathelicidin LL-37 mediates an antiviral effect on RSV by inducing direct damage to the viral envelope, disrupting viral particles and decreasing virus binding to, and infection of, human epithelial cells in vitro. In addition, exogenously applied LL-37 is protective against RSV-mediated disease in vivo, in a murine model of pulmonary RSV infection, demonstrating maximal efficacy when applied concomitantly with virus. Furthermore, endogenous murine cathelicidin, induced by infection, has a fundamental role in protection against disease in vivo following infection with RSV. Finally, higher nasal levels of LL-37 are associated with protection in a healthy human adult RSV infection model. These data lead us to propose that cathelicidins are a key, non-redundant component of host defence against pulmonary infection with RSV; functioning as a first point of contact “antiviral shield”, and having additional later phase roles in minimising the severity of disease outcome. Consequently, cathelicidins represent an inducible target for preventative strategies against RSV infection and may inform the design of novel therapeutic analogues for use in established infection.