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.

Interspecies cathelicidin comparison reveals divergence in antimicrobial activity, TLR modulation, chemokine induction and regulation of phagocytosis

“…The induction of low chemokine levels could be another explanation for the stimulation of chemotaxis by CRAMP and LL-377273. However, LL-37 has been shown to increase neutrophil influx in a murine lung model during inflammation, but without alteration of cytokine or chemokine expression74. Further research will be needed to understand to what extent direct chemotaxis and chemokine induction play a role in leukocyte recruitment during both steady state situations and in the context of an infection.…”

IL-1β–Induced Protection of Keratinocytes against Staphylococcus aureus-Secreted Proteases Is Mediated by Human β-Defensin 2

“…Although several HDPs appear to have impaired expression in AD, hBD2 is reported to have the closest correlation with AD severity and skin infections (Clausen et al., 2013). In addition to direct antibacterial and antiviral properties (Gwyer Findlay et al., 2013, Lehrer et al., 1989, Mookherjee and Hancock, 2007), hBD2 also has modulatory effects on both the innate and adaptive immune system and promotes wound healing (Beaumont et al., 2014, Choi et al., 2012, Semple and Dorin, 2012, Yeung et al., 2011). Modulatory functions of HDP have key roles in the pathogenesis of psoriasis (Morizane and Gallo, 2012) and rosacea (Yamasaki et al., 2007) but are undescribed in AD.…”

CXCL14 Displays Antimicrobial Activity against Respiratory Tract Bacteria and Contributes to Clearance of Streptococcus pneumoniae Pulmonary Infection

“…This is in line with several other in vivo studies. For instance, studies in mice overexpressing cathelicidin and in cathelicidin-deficient mice demonstrated also a role for AMPs in pulmonary clearance of P. aeruginosa and Klebsiella pneumoniae (48)(49)(50). Similarly, BD-1-deficient mice revealed a delayed clearance of H. influenzae from lungs (51).…”