Potential roles of histones in host defense as antimicrobial agents

Antimicrobial peptides (AMPs), which are widely distributed in various organisms, comprise part of the host innate defense system to kill or damage bacterial and fungal pathogens. Amphibian skin is known to produce various AMPs, and is used as a source material in attempts to identify novel therapeutic AMPs. More than one hundred frog AMPs have been identified to date. In our previous study, we isolated histone H2B with antibacterial properties from the skin of the Schlegel's green tree frog Rhacophorus schlegelii. Although antimicrobial histone H2B has not been obtained from the skin of any species other than R. schlegelii, histones and histone-derived fragments with antimicrobial activities have been found in some specific cells of a diverse range of organisms from shrimps to humans. At least a portion of these fragments are known to be produced from "precursor histones" via specific cleavage by endogenous proteases. These antimicrobial histones and the fragments that act as physiological barriers of cells have a variety of antimicrobial actions and functions, including bacterial cell membrane permeabilization, penetration into the membrane followed by binding to bacterial DNA and/or RNA, binding to bacterial lipopolysaccharide (LPS) in the membrane, neutralizing the toxicity of bacterial LPS, and entrapping pathogens as a component of neutrophil extracellular traps (NETs). This review discusses the literature regarding the isolation, antimicrobial properties, and modes of action of antimicrobial histones and fragmented histones along with a brief introduction of typical amphibian skin AMPs.