A cyclic antimicrobial peptide produced in primate leukocytes by the ligation of two truncated alpha-defensins

Area of Science:

• Immunology and Microbiology
• Peptide Chemistry
• Primate innate immunity

Background:

• Host defense cells utilize various antimicrobial molecules to combat pathogens.
• Neutrophils and monocytes are key phagocytic cells involved in innate immunity.
• Defensins are a class of antimicrobial peptides with a role in host defense.

Purpose of the Study:

• To identify and characterize novel antimicrobial peptides in rhesus macaque leukocytes.
• To investigate the structure-activity relationship of the identified peptide.
• To understand the biosynthesis and cellular localization of this antimicrobial agent.

Main Methods:

• Analysis of rhesus macaque leukocyte granules.
• Biochemical characterization of the isolated peptide, including structural determination.
• Microbiological assays to determine antimicrobial activity against bacteria and fungi.
• Comparison of cyclic versus open-chain peptide activity under physiological salt conditions.

Main Results:

• Identification of an 18-residue macrocyclic, tridisulfide antibiotic peptide, rhesus theta defensin-1 (RTD-1), in neutrophil and monocyte granules.
• RTD-1 exhibits microbicidal activity against bacteria and fungi at low micromolar concentrations.
• The cyclic conformation of RTD-1 is crucial for its antimicrobial activity, especially under high salt conditions, showing threefold greater activity than its open-chain analog.

Conclusions:

• Rhesus macaques possess a unique macrocyclic defensin, RTD-1, as part of their innate immune system.
• The biosynthesis involves head-to-tail ligation of two nonapeptides, forming a cyclic structure essential for potent antimicrobial function.
• This discovery highlights sophisticated mechanisms for synthesizing and packaging antimicrobial peptides within phagocytes, contributing to the host defense armamentarium.