Assessment of antimicrobial peptide LL-37 as a post-exposure therapy to protect against respiratory tularemia in mice

• Published in: Peptides (New York, N.Y. : 1980) N.Y. : 1980), 2013-05, Vol.43, p.96-101
• Main Authors: Flick-Smith, Helen C., Fox, Marc A., Hamblin, Karleigh A., Richards, Mark I., Jenner, Dominic C., Laws, Thomas R., Phelps, Amanda L., Taylor, Christopher, Harding, Sarah V., Ulaeto, David O., Atkins, Helen S.
• Format: Article
• Language: English
• Subjects: Administration, Intranasal; animal models; Animals; Antimicrobial Cationic Peptides - administration & dosage; Antimicrobial Cationic Peptides - chemistry; Antimicrobial Cationic Peptides - therapeutic use; Antimicrobial peptide; cathelicidins; chemokine CCL2; chemokine CXCL1; death; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Francisella tularensis; Francisella tularensis - drug effects; Francisella tularensis - immunology; Francisella tularensis LVS; humans; Immunomodulation; immunomodulators; infection; innate immunity; interleukin-12; interleukin-6; intranasal administration; live vaccines; LL-37; lungs; macrophages; Macrophages - drug effects; Macrophages - microbiology; Mice; Mice, Inbred BALB C; neutrophils; pathogens; Structure-Activity Relationship; therapeutics; tularemia; Tularemia - drug therapy; Tularemia - immunology
• ISSN: 0196-9781; 1873-5169
• DOI: 10.1016/j.peptides.2013.02.024

•The utility of nasally delivered LL-37 as a post-exposure therapy for tularaemia in mice was examined.•Significant reduction in bacterial growth was seen in LVS infected macrophages treated with LL-37.•LL-37 stimulated increased neutrophil and pro-inflammatory chemokine and cytokine levels in the lung.•3 doses of LL-37 significantly extended mean time to death of mice infected with F. tularensis LVS. 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.