title: Cathelicidin host defence peptide augments clearance of pulmonary Pseudomonas aeruginosa infection by its influence on neutrophil function in vivo.
abstract: Cathelicidins are multifunctional cationic host-defence peptides (CHDP; also known as antimicrobial peptides) and an important component of innate host defence against infection. In addition to microbicidal potential, these peptides have properties with the capacity to modulate inflammation and immunity. However, the extent to which such properties play a significant role during infection in vivo has remained unclear. A murine model of acute P. aeruginosa lung infection was utilised, demonstrating cathelicidin-mediated enhancement of bacterial clearance in vivo. The delivery of exogenous synthetic human cathelicidin LL-37 was found to enhance a protective pro-inflammatory response to infection, effectively promoting bacterial clearance from the lung in the absence of direct microbicidal activity, with an enhanced early neutrophil response that required both infection and peptide exposure and was independent of native cathelicidin production. Furthermore, although cathelicidin-deficient mice had an intact early cellular inflammatory response, later phase neutrophil response to infection was absent in these animals, with significantly impaired clearance of P. aeruginosa. These findings demonstrate the importance of the modulatory properties of cathelicidins in pulmonary infection in vivo and highlight a key role for cathelicidins in the induction of protective pulmonary neutrophil responses, specific to the infectious milieu. In additional to their physiological roles, CHDP have been proposed as future antimicrobial therapeutics. Elucidating and utilising the modulatory properties of cathelicidins has the potential to inform the development of synthetic peptide analogues and novel therapeutic approaches based on enhancing innate host defence against infection with or without direct microbicidal targeting of pathogens.
authors.affiliation: MRC Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Paula E
authors.initials: PE
authors.lastname: Beaumont
authors.affiliation: MRC Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Brian
authors.initials: B
authors.lastname: McHugh
authors.affiliation: MRC Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Emily
authors.initials: E
authors.lastname: Gwyer Findlay
authors.affiliation: MRC Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Annie
authors.initials: A
authors.lastname: Mackellar
authors.affiliation: MRC Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Mackenzie
authors.affiliation: Division of Dermatology, Department of Medicine, University of California at San Diego and VA San Diego Health Care System, San Diego, California, United States of America.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Gallo
authors.affiliation: Edinburgh Infectious Diseases, The Chancellor's Building, New Royal Infirmary, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
authors.forename: John R W
authors.initials: JR
authors.lastname: Govan
authors.affiliation: MRC Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom; Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: A John
authors.initials: AJ
authors.lastname: Simpson
authors.affiliation: MRC Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Davidson
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008171:Lung Diseases / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000187:drug effects*; D011552:Pseudomonas Infections / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D011550:Pseudomonas aeruginosa / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins