Host Defense Peptides: Bridging Antimicrobial and Immunomodulatory Activities*

Abstract

Host defense peptides are ubiquitous in nature and have been identified in every species for which they have been investigated. Although widely distributed, host defense peptides are characterized by a limited number of physical attributes, namely, small size and high percentages of cationic and hydrophobic residues. Additionally, host defense peptides are categorized into a few distinct structural classes: α-helical, β-sheet, extended, or loop structures. These diverse biomolecules represent an important component in the innate defenses of both prokaryotic and eukaryotic organisms. This is demonstrated by the increased susceptibility to bacterial infections associated with defective host defense peptide expression. Many investigations of host defense peptides have focused on the direct antimicrobial activity associated with these molecules. Indeed, host defense peptides have been demonstrated to kill bacteria by both lytic and nonlytic mechanisms; however, recent investigations have also identified the potential for host defense peptides to induce resistance patterns within bacteria when present at sublethal concentrations. The physiological relevance of these antimicrobial activities has been called into question for many host defense peptides as the in vivo concentrations of these molecules are far below those needed for bacterial killing. Alternatively, there has been a growing appreciation for the ability of host peptides to modulate immune responses. Indeed, these activities have been demonstrated to be physiologically relevant as host defense peptides are capable of acting as chemokines, inducing chemokine production, promoting wound healing and angiogenesis, suppressing inflammation, and modulating the adaptive immune response. Here we review the biological activities associated with host defense peptides as well as the studies related to structure–activity relationship that have served to identify the core components necessary for these associated activities. The development of host defense peptides as potential therapeutics will also be reviewed.