title: Assessment of antimicrobial peptide LL-37 as a post-exposure therapy to protect against respiratory tularemia in mice.
abstract: Early activation of the innate immune response is important for protection against infection with Francisella tularensis live vaccine strain (LVS) in mice. The human cathelicidin antimicrobial peptide LL-37 is known to have immunomodulatory properties, and therefore exogenously administered LL-37 may be suitable as an early post-exposure therapy to protect against LVS infection. LL-37 has been evaluated for immunostimulatory activity in uninfected mice and for activity against LVS in macrophage assays and protective efficacy when administered post-challenge in a mouse model of respiratory tularemia. Increased levels of pro-inflammatory cytokine IL-6, chemokines monocyte chemoattractant protein 1 (MCP-1) and CXCL1 with increased neutrophil influx into the lungs were observed in uninfected mice after intranasal administration of LL-37. Following LVS challenge, LL-37 administration resulted in increased IL-6, IL-12 p70, IFNγ and MCP-1 production, a slowing of LVS growth in the lung, and a significant extension of mean time to death compared to control mice. However, protection was transient, with the LL-37 treated mice eventually succumbing to infection. As this short course of nasally delivered LL-37 was moderately effective at overcoming the immunosuppressive effects of LVS infection this suggests that a more sustained treatment regimen may be an effective therapy against this pathogen.
authors.affiliation: Biomedical Sciences Department, Defence Science and Technology Laboratory, Porton Down, Salisbury, Wiltshire SP4 0JQ, United Kingdom. hcfsmith@dstl.gov.uk
authors.forename: Helen C
authors.initials: HC
authors.lastname: Flick-Smith
authors.forename: Marc A
authors.initials: MA
authors.lastname: Fox
authors.forename: Karleigh A
authors.initials: KA
authors.lastname: Hamblin
authors.forename: Mark I
authors.initials: MI
authors.lastname: Richards
authors.forename: Dominic C
authors.initials: DC
authors.lastname: Jenner
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Laws
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Phelps
authors.forename: Christopher
authors.initials: C
authors.lastname: Taylor
authors.forename: Sarah V
authors.initials: SV
authors.lastname: Harding
authors.forename: David O
authors.initials: DO
authors.lastname: Ulaeto
authors.forename: Helen S
authors.initials: HS
authors.lastname: Atkins
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005604:Francisella tularensis / Q000187:drug effects / Q000276:immunology; D056747:Immunomodulation; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D013329:Structure-Activity Relationship; D014406:Tularemia / Q000188:drug therapy* / Q000276:immunology; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins