Synthetic cationic peptide IDR-1002 provides protection against bacterial infections through chemokine induction and enhanced leukocyte recruitment

Nijnik, A, Madera, L, Ma, SH, Waldbrook, M, Elliott, MR, Easton, DM, Mayer, ML, Mullaly, SC, Kindrachuk, J, Jenssen, H and Hancock, REW (2010) Synthetic cationic peptide IDR-1002 provides protection against bacterial infections through chemokine induction and enhanced leukocyte recruitment. Journal of Immunology, 184 5: 2539-2550. doi:10.4049/jimmunol.0901813


Author Nijnik, A
Madera, L
Ma, SH
Waldbrook, M
Elliott, MR
Easton, DM
Mayer, ML
Mullaly, SC
Kindrachuk, J
Jenssen, H
Hancock, REW
Title Synthetic cationic peptide IDR-1002 provides protection against bacterial infections through chemokine induction and enhanced leukocyte recruitment
Journal name Journal of Immunology   Check publisher's open access policy
ISSN 0022-1767
Publication date 2010-03-01
Sub-type Article (original research)
DOI 10.4049/jimmunol.0901813
Open Access Status Not yet assessed
Volume 184
Issue 5
Start page 2539
End page 2550
Total pages 12
Place of publication United States
Publisher American Association of Immunologists
Language eng
Abstract With the rapid rise in the incidence of multidrug resistant infections, there is substantial interest in host defense peptides as templates for production of new antimicrobial therapeutics. Natural peptides are multifunctional mediators of the innate immune response, with some direct antimicrobial activity and diverse immunomodulatory properties. We have previously developed an innate defense regulator (IDR) 1, with protective activity against bacterial infection mediated entirely through its effects on the immunity of the host, as a novel approach to anti-infective therapy. In this study, an immunomodulatory peptide IDR-1002 was selected from a library of bactenecin derivatives based on its substantially more potent ability to induce chemokines in human PBMCs. The enhanced chemokine induction activity of the peptide in vitro correlated with stronger protective activity in vivo in the Staphylococcus aureus-invasive infection model, with a >5-fold reduction in the protective dose in direct comparison with IDR-1. IDR-1002 also afforded protection against the Gram-negative bacterial pathogen Escherichia coli. Chemokine induction by IDR-1002 was found to be mediated through a Gi-coupled receptor and the PI3K, NF-κB, and MAPK signaling pathways. The protective activity of the peptide was associated with in vivo augmentation of chemokine production and recruitment of neutrophils and monocytes to the site of infection. These results highlight the importance of the chemokine induction activity of host defense peptides and demonstrate that the optimization of the ex vivo chemokine-induction properties of peptides is a promising method for the rational development of immunomodulatory IDR peptides with enhanced anti-infective activity. Copyright © 2010 by The American Association of Immunologists, Inc.
Keyword Animal experiment
Bacterial infection
Cytokine production
Controlled study
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Veterinary Science Publications
 
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Created: Thu, 09 Jun 2011, 03:08:19 EST by Dr Donna M Easton on behalf of School of Veterinary Science