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Antimicrobial and Immunomodulatory Activity of PMAP-23 Derived Peptides
Edwin J A Veldhuizen1, Maaike R Scheenstra2, Johanna L M Tjeerdsma-van Bokhoven2
1Department of Infectious Diseases and Immunology, Division of Molecular Host Defence, Faculty of Veterinary Medicine, Utrecht University, P.O. Box 80.165, 3508TD, Utrecht. Netherlands.
Introduction:
The Porcine Myeloid Antibacterial Peptide (PMAP)-23 is a porcine host defence peptide with strong antibacterial activity against Gram-positive and Gram-negative bacteria, and fungi.
Objective:
PMAP-23 and truncated/mutated derivatives were tested for antibacterial and immunomodulatory activities to determine core elements of the peptide required for functionality.
Methods:
PMAP-23 and truncated and/or mutated derivatives were synthesized. Antibacterial activity against Gram positive and negative bacteria was determined using colony counting assays. Cytotoxicity was measured against red blood cells and epithelial cells. Peptide induced cytokine production of epithelial cells was determined by ELISA. LPS neutralization was measured using isothermal titration calorimetry and inhibition of LPS induced cytokine production by macrophages. The effect of peptides on phagocytosis was performed by measuring uptake of fluorescently labelled beads by porcine macrophages.
Results:
Truncation of the peptide did not lead to a strong reduction in antibacterial activity, but interestingly, all C-terminal truncated forms were strongly inhibited by salt addition, unlike the full length peptide or the two N-terminally truncated peptides. None of the peptides were hemolytic or toxic in concentrations up to 40 μM. Full length PMAP-23 induced IL-8 production in porcine epithelial cells, however, this activity was lost in all truncated peptides. None of the peptides bound LPS and subsequently did not inhibit LPS-induced cytokine production of monocytes. Finally, all PMAP-23 derived peptides reduced the uptake of beads by freshly isolated monocytes.
Conclusion:
PMAP-23 is mainly antibacterial with only limited immunomodulating capacity; the full length peptide is required for the full spectrum of activities.
Insights
The full-length Porcine Myeloid Antibacterial Peptide (PMAP)-23 exhibits potent antibacterial properties. Truncated versions retain some antibacterial function but lose crucial immunomodulatory activities, highlighting the importance of the complete peptide structure.
Area of Science:
- Biochemistry
- Immunology
- Microbiology
Background:
- Porcine Myeloid Antibacterial Peptide (PMAP)-23 is a host defense peptide with broad-spectrum antimicrobial activity.
- Its potential for therapeutic applications necessitates a detailed understanding of its structure-activity relationship.
Purpose of the Study:
- To investigate the antibacterial and immunomodulatory functions of PMAP-23 and its derivatives.
- To identify the essential structural elements of PMAP-23 responsible for its activity.
Main Methods:
- Synthesis and characterization of PMAP-23 and its truncated/mutated analogs.
- Assessment of antibacterial efficacy using colony counting assays.
- Evaluation of cytotoxicity, cytokine induction (IL-8), LPS binding, and phagocytosis inhibition.
Main Results:
- PMAP-23 derivatives showed retained antibacterial activity, with C-terminal truncations being salt-sensitive.
- No observed cytotoxicity at tested concentrations.
- Immunomodulatory functions, including IL-8 induction and LPS neutralization, were lost in truncated peptides.
- All PMAP-23 derivatives impaired phagocytosis by porcine macrophages.
Conclusions:
- PMAP-23 possesses significant antibacterial activity with limited immunomodulatory capacity.
- The full-length peptide structure is essential for its complete functional spectrum, including both antibacterial and immunomodulatory roles.
