A peptide of heparin cofactor II inhibits endotoxin-mediated shock and invasive pseudomonas aeruginosa infection

Sepsis and septic shock remain important medical problems with high mortality rates. Today's treatment is based mainly on using antibiotics to target the bacteria, without addressing the systemic inflammatory response, which is a major contributor to mortality in sepsis. Therefore, novel treatm...

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Main Authors: Kalle, Martina, Papareddy, Praveen, Kasetty, Gopinath, van der Plas, Mariena J. A., Mörgelin, Matthias, Malmsten, Martin, Schmidtchen, Artur
Other Authors: Bozza, Patricia T.
Format: Article
Language:English
Published: 2014
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Online Access:https://hdl.handle.net/10356/104805
http://hdl.handle.net/10220/20286
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Institution: Nanyang Technological University
Language: English
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spelling sg-ntu-dr.10356-1048052022-02-16T16:30:07Z A peptide of heparin cofactor II inhibits endotoxin-mediated shock and invasive pseudomonas aeruginosa infection Kalle, Martina Papareddy, Praveen Kasetty, Gopinath van der Plas, Mariena J. A. Mörgelin, Matthias Malmsten, Martin Schmidtchen, Artur Bozza, Patricia T. Lee Kong Chian School of Medicine (LKCMedicine) DRNTU::Science::Biological sciences Sepsis and septic shock remain important medical problems with high mortality rates. Today's treatment is based mainly on using antibiotics to target the bacteria, without addressing the systemic inflammatory response, which is a major contributor to mortality in sepsis. Therefore, novel treatment options are urgently needed to counteract these complex sepsis pathologies. Heparin cofactor II (HCII) has recently been shown to be protective against Gram-negative infections. The antimicrobial effects were mapped to helices A and D of the molecule. Here we show that KYE28, a 28 amino acid long peptide representing helix D of HCII, is antimicrobial against the Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa, the Gram-positive Bacillus subtilis and Staphylococcus aureus, as well as the fungus Candida albicans. Moreover, KYE28 binds to LPS and thereby reduces LPS-induced pro-inflammatory responses by decreasing NF-κB/AP-1 activation in vitro. In mouse models of LPS-induced shock, KYE28 significantly enhanced survival by dampening the pro-inflammatory cytokine response. Finally, in an invasive Pseudomonas infection model, the peptide inhibited bacterial growth and reduced the pro-inflammatory response, which lead to a significant reduction of mortality. In summary, the peptide KYE28, by simultaneously targeting bacteria and LPS-induced pro-inflammatory responses represents a novel therapeutic candidate for invasive infections. Published version 2014-08-15T02:08:38Z 2019-12-06T21:40:11Z 2014-08-15T02:08:38Z 2019-12-06T21:40:11Z 2014 2014 Journal Article Kalle, M., Papareddy, P., Kasetty, G., van der Plas, M. J. A., Mörgelin, M., Malmsten, M., et al. (2014). A Peptide of Heparin Cofactor II Inhibits Endotoxin-Mediated Shock and Invasive Pseudomonas aeruginosa Infection. PLoS ONE, 9(7), e102577-. 1932-6203 https://hdl.handle.net/10356/104805 http://hdl.handle.net/10220/20286 10.1371/journal.pone.0102577 25047075 en PLoS ONE © 2014 Kalle et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic DRNTU::Science::Biological sciences
spellingShingle DRNTU::Science::Biological sciences
Kalle, Martina
Papareddy, Praveen
Kasetty, Gopinath
van der Plas, Mariena J. A.
Mörgelin, Matthias
Malmsten, Martin
Schmidtchen, Artur
A peptide of heparin cofactor II inhibits endotoxin-mediated shock and invasive pseudomonas aeruginosa infection
description Sepsis and septic shock remain important medical problems with high mortality rates. Today's treatment is based mainly on using antibiotics to target the bacteria, without addressing the systemic inflammatory response, which is a major contributor to mortality in sepsis. Therefore, novel treatment options are urgently needed to counteract these complex sepsis pathologies. Heparin cofactor II (HCII) has recently been shown to be protective against Gram-negative infections. The antimicrobial effects were mapped to helices A and D of the molecule. Here we show that KYE28, a 28 amino acid long peptide representing helix D of HCII, is antimicrobial against the Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa, the Gram-positive Bacillus subtilis and Staphylococcus aureus, as well as the fungus Candida albicans. Moreover, KYE28 binds to LPS and thereby reduces LPS-induced pro-inflammatory responses by decreasing NF-κB/AP-1 activation in vitro. In mouse models of LPS-induced shock, KYE28 significantly enhanced survival by dampening the pro-inflammatory cytokine response. Finally, in an invasive Pseudomonas infection model, the peptide inhibited bacterial growth and reduced the pro-inflammatory response, which lead to a significant reduction of mortality. In summary, the peptide KYE28, by simultaneously targeting bacteria and LPS-induced pro-inflammatory responses represents a novel therapeutic candidate for invasive infections.
author2 Bozza, Patricia T.
author_facet Bozza, Patricia T.
Kalle, Martina
Papareddy, Praveen
Kasetty, Gopinath
van der Plas, Mariena J. A.
Mörgelin, Matthias
Malmsten, Martin
Schmidtchen, Artur
format Article
author Kalle, Martina
Papareddy, Praveen
Kasetty, Gopinath
van der Plas, Mariena J. A.
Mörgelin, Matthias
Malmsten, Martin
Schmidtchen, Artur
author_sort Kalle, Martina
title A peptide of heparin cofactor II inhibits endotoxin-mediated shock and invasive pseudomonas aeruginosa infection
title_short A peptide of heparin cofactor II inhibits endotoxin-mediated shock and invasive pseudomonas aeruginosa infection
title_full A peptide of heparin cofactor II inhibits endotoxin-mediated shock and invasive pseudomonas aeruginosa infection
title_fullStr A peptide of heparin cofactor II inhibits endotoxin-mediated shock and invasive pseudomonas aeruginosa infection
title_full_unstemmed A peptide of heparin cofactor II inhibits endotoxin-mediated shock and invasive pseudomonas aeruginosa infection
title_sort peptide of heparin cofactor ii inhibits endotoxin-mediated shock and invasive pseudomonas aeruginosa infection
publishDate 2014
url https://hdl.handle.net/10356/104805
http://hdl.handle.net/10220/20286
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