Enhancement of host defense against pathogens by antimicrobial peptides : a new approach to combat microbial drug resistance

Does, A.M. van der (2011)

Doctoral Thesis

Due to their abilities to eliminate pathogens and modulate host__s immune responses, antimicrobial peptides are considered as potential alternatives for the treatment of infections with (multi-drug resistant) pathogens. In this thesis the immunomodulatory actions of two peptides have been investigated in order to gain insight in their mechanism of antimicrobial action; human lactoferrin-derived antimicrobial peptide hLF1-11 and the human cathelicidin LL-37. As hLF1-11 is active against infections in animals within a short period, we hypothesized immunomodulatory effects of hLF1-11 on innate immune cells. Results described in this thesis show that hLF1-11 enhances the inflammatory response of monocytes and modulates monocyte-macrophage differentiation resulting in macrophages that display enhanced antimicrobial effector functions. In addition, hLF1-11 drives monocyte-dendritic cell differentiation toward DCs that promote antifungal responses and induce Th17 polarization. Myeloperoxidase was identified as the intracellular target of hLF1-11 mediating immunomodulatory effects of this peptide. We also found that LL-37 was able to modulate monocyte-macrophage differentiation, however different than hLF1-11 as this resulted in macrophages with a pro-inflammatory phenotype. Together, these data underscore the bright future of antimicrobial peptides with immune modulating activity as these peptides might be developed further into a novel class of anti-infectives to which microbial drug-resistance is unlikely to develop quickly.

• Antimicrobial peptide
• Drug resistance
• Immunomodulatory
• Innate
• LL-37
• Phagocytosis

• All authors: Does, A.M. van der
• Supervisor: Dissel, J.T. van
• Co-supervisor: Nibbering, P.H.
• Qualification: Doctor (dr.)
• Awarding Institution: Leiden University Medical Center (LUMC), Leiden University
• Date: 2011-03-29
• ISBN (print): 9789461081391
• Sponsorship: SenterNovem ISO44096