Abstract
BackgroundAvian beta-defensins (AvBD) are small, cationic, antimicrobial peptides. The potential application of AvBDs as alternatives to antibiotics has been the subject of interest. However, the mechanisms of action remain to be fully understood. The present study characterized the structure-function relationship of AvBD-6 and AvBD-12, two peptides with different net positive charges, similar hydrophobicity and distinct tissue expression profiles.ResultsAvBD-6 was more potent than AvBD-12 against E. coli, S. Typhimurium, and S. aureus as well as clinical isolates of extended spectrum beta lactamase (ESBL)-positive E. coli and K. pneumoniae. AvBD-6 was more effective than AvBD-12 in neutralizing LPS and interacting with bacterial genomic DNA. Increasing bacterial concentration from 105 CFU/ml to 109 CFU/ml abolished AvBDs’ antimicrobial activity. Increasing NaCl concentration significantly inhibited AvBDs’ antimicrobial activity, but not the LPS-neutralizing function. Both AvBDs were mildly chemotactic for chicken macrophages and strongly chemotactic for CHO-K1 cells expressing chicken chemokine receptor 2 (CCR2). AvBD-12 at higher concentrations also induced chemotactic migration of murine immature dendritic cells (DCs). Disruption of disulfide bridges abolished AvBDs’ chemotactic activity. Neither AvBDs was toxic to CHO-K1, macrophages, or DCs.ConclusionsAvBDs are potent antimicrobial peptides under low-salt conditions, effective LPS-neutralizing agents, and broad-spectrum chemoattractant peptides. Their antimicrobial activity is positively correlated with the peptides’ net positive charges, inversely correlated with NaCl concentration and bacterial concentration, and minimally dependent on intramolecular disulfide bridges. In contrast, their chemotactic property requires the presence of intramolecular disulfide bridges. Data from the present study provide a theoretical basis for the design of AvBD-based therapeutic and immunomodulatory agents.
Highlights
Avian beta-defensins (AvBD) are small, cationic, antimicrobial peptides
To understand the molecular mechanisms by which AvBDs contribute to host innate and acquired immunity, we have studied the transcriptional profiles of AvBD genes and characterized the antimicrobial activities of AvBDs with different net positive charges and tissue expression profiles [28, 29]
Typhimurium and AvBD-12 against S. aureus was negatively affected by increased salt concentration which was consistent with findings from previous investigations of cationic antimicrobial peptides [2, 15, 38, 39]
Summary
Avian beta-defensins (AvBD) are small, cationic, antimicrobial peptides. The mechanisms of action remain to be fully understood. The present study characterized the structure-function relationship of AvBD-6 and AvBD-12, two peptides with different net positive charges, similar hydrophobicity and distinct tissue expression profiles. Defensins are small cationic antimicrobial peptides containing six disulfide-paired cysteines [1]. Many defensins show broad-spectrum antimicrobial activities against bacteria, fungi, and some enveloped viruses, the mechanisms of action remain to be fully understood [8,9,10,11]. The antimicrobial mechanism of defensins primarily depends on several structural features, such as cationic charge and hydrophobicity, and is mainly divided into two classes, membrane-disruption and intracellular target [6, 12]. In addition to direct actions on microbial membrane, several studies have revealed intracellular functions of translocated antimicrobial peptides, such as interfering with cytoplasmic membrane septum formation and cell-wall synthesis, binding to nucleic acids, and inhibiting enzymes [2, 11, 15]
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