title: Cathelicidins Have Direct Antiviral Activity against Respiratory Syncytial Virus In Vitro and Protective Function In Vivo in Mice and Humans.
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.
authors.affiliation: Medical Research Council Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom;
authors.forename: Silke M
authors.identifier: http://orcid.org/0000-0002-2190-7096
authors.initials: SM
authors.lastname: Currie
authors.affiliation: Medical Research Council Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom;
authors.forename: Emily
authors.initials: E
authors.lastname: Gwyer Findlay
authors.affiliation: Medical Research Council Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom;
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: McFarlane
authors.affiliation: Medical Research Council Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom;
authors.forename: Paul M
authors.identifier: http://orcid.org/0000-0001-5294-3340
authors.initials: PM
authors.lastname: Fitch
authors.affiliation: Institute for Quantitative Biology, Biochemistry and Biotechnology, School of Biological Sciences, The University of Edinburgh, Edinburgh EH9 3BF, United Kingdom;
authors.forename: Bettina
authors.identifier: http://orcid.org/0000-0002-7962-4849
authors.initials: B
authors.lastname: Böttcher
authors.affiliation: Institute of Evolutionary Biology, School of Biological Sciences, The University of Edinburgh, Edinburgh EH9 3BF, United Kingdom; and.
authors.forename: Nick
authors.identifier: http://orcid.org/0000-0003-4391-1587
authors.initials: N
authors.lastname: Colegrave
authors.affiliation: National Heart and Lung Institute, Imperial College London, London W2 1PG, United Kingdom.
authors.forename: Allan
authors.initials: A
authors.lastname: Paras
authors.affiliation: National Heart and Lung Institute, Imperial College London, London W2 1PG, United Kingdom.
authors.forename: Agnieszka
authors.identifier: http://orcid.org/0000-0002-2843-3073
authors.initials: A
authors.lastname: Jozwik
authors.affiliation: National Heart and Lung Institute, Imperial College London, London W2 1PG, United Kingdom.
authors.forename: Christopher
authors.identifier: http://orcid.org/0000-0003-0914-920X
authors.initials: C
authors.lastname: Chiu
authors.affiliation: Medical Research Council Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom;
authors.forename: Jürgen
authors.identifier: http://orcid.org/0000-0002-6899-748X
authors.initials: J
authors.lastname: Schwarze
authors.affiliation: Medical Research Council Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom; donald.davidson@ed.ac.uk.
authors.forename: Donald J
authors.identifier: http://orcid.org/0000-0002-8782-199X
authors.initials: DJ
authors.lastname: Davidson
mesh_terms: D000328:Adult; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D015331:Cohort Studies; D004195:Disease Models, Animal; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020545:Respiratory Mucosa / Q000276:immunology* / Q000821:virology; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology*; D012136:Respiratory Syncytial Viruses / Q000276:immunology*; D012141:Respiratory Tract Infections / Q000276:immunology*; D014759:Viral Envelope Proteins / Q000378:metabolism; D053585:Virus Attachment; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D014759:Viral Envelope Proteins; D054804:Cathelicidins