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A Peptide of Heparin Cofactor II Inhibits Endotoxin-Mediated Shock and Invasive Pseudomonas aeruginosa Infection.

Kalle, Martina LU ; Papareddy, Praveen LU orcid ; Kasetty, Gopinath LU ; van der Plas, Mariena LU ; Mörgelin, Matthias LU ; Malmsten, Martin LU and Schmidtchen, Artur LU (2014) In PLoS ONE 9(7).
Abstract
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... (More)
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. (Less)
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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
PLoS ONE
volume
9
issue
7
article number
e102577
publisher
Public Library of Science (PLoS)
external identifiers
  • pmid:25047075
  • wos:000339558100047
  • scopus:84904568109
  • pmid:25047075
ISSN
1932-6203
DOI
10.1371/journal.pone.0102577
language
English
LU publication?
yes
id
f73ed111-f3bd-4ed7-b5cd-56405d725f3d (old id 4581551)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/25047075?dopt=Abstract
date added to LUP
2016-04-01 13:29:21
date last changed
2021-10-06 01:32:29
@article{f73ed111-f3bd-4ed7-b5cd-56405d725f3d,
  abstract     = {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.},
  author       = {Kalle, Martina and Papareddy, Praveen and Kasetty, Gopinath and van der Plas, Mariena and Mörgelin, Matthias and Malmsten, Martin and Schmidtchen, Artur},
  issn         = {1932-6203},
  language     = {eng},
  number       = {7},
  publisher    = {Public Library of Science (PLoS)},
  series       = {PLoS ONE},
  title        = {A Peptide of Heparin Cofactor II Inhibits Endotoxin-Mediated Shock and Invasive Pseudomonas aeruginosa Infection.},
  url          = {https://lup.lub.lu.se/search/files/3400909/5159875},
  doi          = {10.1371/journal.pone.0102577},
  volume       = {9},
  year         = {2014},
}