The immunology of host defence peptides: beyond antimicrobial activity

Journal name:
Nature Reviews Immunology
Volume:
16,
Pages:
321–334
Year published:
DOI:
doi:10.1038/nri.2016.29
Published online
Corrected online

Abstract

Host defence peptides (HDPs) are short, cationic amphipathic peptides with diverse sequences that are produced by various cells and tissues in all complex life forms. HDPs have important roles in the body's response to infection and inflammation. This Review focuses on human HDPs and explores the diverse immunomodulatory effects of HDPs from a systems biology perspective, which highlights the interconnected nature of the effect (or effects) of HDPs on the host. Studies have demonstrated that HDPs are expressed throughout the body and mediate a broad range of activities, which explains their association with various inflammatory diseases and autoimmune disorders. The diverse actions of HDPs, such as their roles in wound healing and in the maintenance of the microbiota, are also explored, in addition to potential therapeutic applications.

At a glance

Figures

  1. LL-37 interacts directly and indirectly with a broad range of genes and proteins.
    Figure 1: LL-37 interacts directly and indirectly with a broad range of genes and proteins.

    a | A network interaction diagram showing zero-order interactions of the cathelicidin LL-37. These interacting proteins have diverse functions within the cell, including glucose metabolism and cytoskeletal dynamics (glyceraldehyde-3-phosphate dehydrogenase (GAPDH)), transcription (JUN, FOS, cAMP-responsive element-binding protein 1 (CREB1), vitamin D3 receptor (VDR) and SPI1)) and inflammation (cathepsin G (CTSG)). b | LL-37 has more than 1,000 first-order interaction partners (that is, direct interactors and proteins known to interact with the direct interactors (indicated by grey dots)), highlighting the complexity of the actions of the host defence peptide LL-37 within the cell. Network diagrams were created using NetworkAnalyst8. ELANE, neutrophil elastase; IGF1R, insulin-like growth factor 1 receptor; KLK, kallikrein; MAPK, mitogen-activated protein kinase; P2X7R, P2X7 purinergic receptor; PGC, PPAR-γ co-activator; PRTN3, proteinase 3.

  2. The complex response of KLA-stimulated mouse macrophages to HBD3.
    Figure 2: The complex response of KLA-stimulated mouse macrophages to HBD3.

    a | A network interaction diagram that shows proteins belonging to the Fcγ receptor-dependent phagocytosis pathway (green), interleukin signalling pathway (blue) and lipid and lipoprotein metabolism pathway (red). These are a subset of the genes that changed expression after treatment with human β-defensin 3 (HBD3), as determined using GEO2R126. Although these pathways accomplish divergent functions within the cell, they are interconnected and share several common proteins (purple). b | Summary of the expression patterns of cytokine signalling genes in macrophages activated with endotoxin alone or endotoxin together with HBD3. Although cytokine signalling is thought to be dampened by the presence of the cathelicidin LL-37, many genes belonging to this pathway are upregulated by HBD3. The network diagram and expression data were generated using NetworkAnalyst8. KLA, KDO2–lipid A.

  3. Diversity of HDP activities within the body and relationship with disease states.
    Figure 3: Diversity of HDP activities within the body and relationship with disease states.

    Host defence peptides (HDPs) are produced by various different cell types throughout the body. Highlighted here are HDPs that are produced by the epithelial cells of the skin, lungs and gut, as well as the immune cells of the circulatory system. On the skin, certain HDPs, such as the cathelicidin LL-37, human β-defensins (HBDs) and human neutrophil peptides (HNPs), are constitutively expressed by keratinocytes and mast cells, whereas the expression of others can be strongly induced in response to injury or infection, which attracts immune cells to the area surrounding the damaged tissue. In the lungs, HDPs produced by airway epithelial cells help to protect from invading microorganisms. In the gut, Paneth cells produce large amounts of human α-defensin 5 (HD5) and HD6 at the base of intestinal crypts, helping to prevent infection from pathogenic bacteria and maintain homeostasis of the commensal microorganism community. In the circulatory system, many immune cell types express HDPs in response to infection and inflammation. These HDPs can have multiple effects throughout the body, depending on the location where they are produced and the types of cells that are present. A dysregulation of HDP expression at any of these sites can contribute to various disease states. Examples of diseases associated with each body site in which altered production of HDPs has been observed are shown on the right. COPD, chronic obstructive pulmonary disease; IBD, inflammatory bowel disease.

Change history

Corrected online 28 April 2016
In the original version of this article, the first subheading of Table 1 was incorrect. It should read Cathelicidin LL-37. This has now been corrected online and for the print version. We apologize for this error.

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Affiliations

  1. Center for Microbial Diseases Research, University of British Columbia, Vancouver, British Columbia, V6H 3Z6, Canada.

    • Robert E.W. Hancock,
    • Evan F. Haney &
    • Erin E. Gill

Competing interests statement

R.E.W.H. is developing innate defence regulator (IDR) peptides as therapeutics and vaccine adjuvants, and has filed several patents in this area, all of which are assigned to his employer, the University of British Columbia. Two of his IDR peptides have been licensed to Elanco Animal Health Inc., for use in treatment of animals and as vaccine adjuvants, and one has been licensed to the Pan-provincial Vaccine Enterprise, for development as a component of vaccine adjuvant formulations. E.F.H. is a co-inventor on one of these patents. Recently, R.E.W.H. formed a new virtual company, ABT Innovations Inc., to promote commercialization of the University of British Columbia peptide patents. E.E.G. declares no competing interests.

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  • Robert E.W. Hancock

    R.E.W. (Bob) Hancock is a professor of microbiology and immunology at the University of British Columbia, Vancouver, Canada, an associate faculty member of the Wellcome Trust Sanger Institute and a Canada Research Chair in Health and Genomics. His research interests include small cationic peptides as novel antimicrobials and modulators of innate immunity, the development of novel treatments for antibiotic-resistant infections, the systems biology of innate immunity, inflammatory diseases and Pseudomonas aeruginosa, and antibiotic uptake and resistance.

  • Evan F. Haney

    Evan F. Haney received his Ph.D. in biochemistry from the University of Calgary, Alberta, Canada, and is currently a postdoctoral fellow in the Department of Microbiology and Immunology at the University of British Columbia, Vancouver, Canada, working under the supervision of R.E.W. Hancock. He is interested in optimizing synthetic peptides for various biological applications and is using high-throughput screening methodology and computational modelling to evaluate the sequence requirements of antibiofilm and immunomodulatory peptides.

  • Erin E. Gill

    Erin E. Gill earned her Ph.D. in genetics from the University of British Columbia, Vancouver, Canada, and completed a postdoctoral fellowship at Simon Fraser University, Burnaby, British Columbia, Canada, where she studied the transcriptome of Pseudomonas aeruginosa. She is currently a research associate in the Hancock laboratory at the University of British Columbia. Her current research uses gene expression data to investigate the host response to infection and disease to identify diagnostic signatures and potential targets for novel therapies or drug repurposing.

Supplementary information

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  1. Supplementary information S1 (table) (195 KB)

    HDP expression patterns and affected cell types and functions.

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