Cathelicidins Have Direct Antiviral Activity against Respiratory Syncytial Virus In Vitro and Protective Function In Vivo in Mice and Humans.

Silke M Currie,Nick Colegrave,Donald J Davidson,Agnieszka Jozwik,Jürgen Schwarze,Allan Paras,Emily Gwyer Findlay,Paul M Fitch,Christopher Chiu,Amanda J Mcfarlane,Bettina Böttcher

doi:10.4049/jimmunol.1502478

Abstract

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 defense peptides, expressed in the inflamed lung, with key microbicidal and modulatory roles in innate host defense against infection. In this article, 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 postinfection 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, nonredundant component of host defense against pulmonary infection with RSV, functioning as a first point of contact antiviral shield and having additional later-phase roles in minimizing 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 analogs for use in established infection.

Highlights

We demonstrate that the human cathelicidin LL-37 mediates an antiviral effect on Respiratory syncytial virus (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
We have previously demonstrated that the human cathelicidin LL-37 has dose-dependent antiviral activity against RSV in vitro [7]
To determine whether LL-37 directly interacts with RSV, we assessed peptide binding to virion particles by ELISA

Summary

Introduction

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. Having established that mCRAMP had anti-RSV activity in vitro, the extent to which the peptide was expressed in the murine lung in vivo was determined in uninfected mice and on day 1 postinfection with RSV, both in the presence and the absence of concomitant LL-37 treatment.

Results

Conclusion