Host Defence (Antimicrobial) Peptides and Proteins

Abstract

Host defence (antimicrobial) peptides are small cationic peptides that contain several hydrophobic amino acids. Such peptides typically form amphipathic structures in membrane‐mimicking environments, which contribute to peptide activity on essential membrane‐dependent processes, membrane permeabilisation and/or cell penetration. Host defence peptides (HDPs) have a variety of biological properties, including profound immune‐modulating properties and direct antibacterial, antiviral, antifungal, antiparasitic and anticancer activities. Thus, HDPs are important effectors of the immune system; however, the effector functions of these peptides are often heavily dependent on their microenvironment. The direct antibacterial properties of many peptides are eliminated in the presence of physiologically relevant concentrations of cations and polyanions, although the immune‐modulating properties of these peptides persist under these conditions even in the presence of serum. The immune‐modulating properties are anti‐infective and include chemokine induction and host cell recruitment/differentiation, antiinflammatory activity, promotion of effective adaptive immunity and wound healing activity. Using human peptides as examples, the biological properties of HDPs are discussed herein in an attempt to expose their potential as templates for novel therapeutic agents.

Key Concepts:

  • The direct antimicrobial properties of small cationic peptides are often eliminated in the presence of physiologically relevant concentrations of serum and salt; thus they are more accurately described as host defence peptides.

  • The immunomodulatory properties of host defence peptides are complex, have been confirmed in vivo, and contribute to anti‐infective immunity.

  • Humans express several defensins and one cathelicidin (hCAP‐18/LL‐37).

  • Human defensins and cathelicidins are produced by many cell types and have many biological properties, including the ability to destroy pathogens and alter immune responses.

  • Host defence peptides can be modified to improve their biological activities.

Keywords: host defence peptides; immunomodulatory; innate immunity; antimicrobial peptides; anti‐infective

Figure 1.

Overview of the properties of cationic host defence peptides. In an immune response to infection (microbes denoted by small open circles: ○), host defence peptides engage in interaction with cells of the innate immune system to stimulate multiple mechanisms of anti‐infective immunity as well as direct microbial killing at higher concentrations. Reprinted from Brown and Hancock .

Figure 2.

Bacterial targets of selected host defence peptides and proteins. Direct antimicrobial activity occurs primarily in phagocytic granules and intestinal crypts where there is a high concentration of defence peptides and proteins. Antimicrobial activity is generally directed at critical membrane‐associated processes (e.g. cell wall synthesis and cell division), microbial membrane integrity and intracellular molecules critical to growth and maintenance (in bold).

Figure 3.

Models of HDP‐mediated membrane disruption. In the carpet model, HDPs cover the surface of the target cell like a carpet, which results in significant phospholipid displacement. Upon reaching a threshold concentration, transient pores lined with HDPs are formed. The barrel‐stave model suggests that HDP binding to the surface of the target cell results in peptide aggregation whereby the peptides begin to insert themselves deeper into the membrane, causing the formation of transmembrane pores composed solely of peptides. In contrast, the toroidal pore model suggests that membrane pores are torus‐shaped and composed of HDPs and lipids. Finally, in the aggregate model, transient pores that lack a defined structure are composed of peptides aggregated with membrane lipids. The aggregate model can also explain translocation across the cytoplasmic membrane to access intracellular targets due to the resolution of the aggregate leading to peptide access to the cytoplasm.

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Wuerth, Kelli C, Hilchie, Ashley L, Brown, Kelly L, and Hancock, Robert EW(May 2013) Host Defence (Antimicrobial) Peptides and Proteins. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001212.pub3]