A peptide of heparin cofactor II inhibits endotoxin-mediated shock and invasive Pseudomonas aeruginosa infection
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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.
In: PLOS ONE, Vol. 9, No. 7, 2014, p. e102577.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - A peptide of heparin cofactor II inhibits endotoxin-mediated shock and invasive Pseudomonas aeruginosa infection
AU - Kalle, Martina
AU - Papareddy, Praveen
AU - Kasetty, Gopinath
AU - van der Plas, Mariena J A
AU - Mörgelin, Matthias
AU - Malmsten, Martin
AU - Schmidtchen, Artur
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
KW - Amino Acid Sequence
KW - Animals
KW - Anti-Infective Agents
KW - Bacteria
KW - Candida albicans
KW - Cell Line
KW - Endotoxins
KW - Heparin Cofactor II
KW - Humans
KW - Lipopolysaccharides
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Molecular Sequence Data
KW - Pseudomonas Infections
KW - Pseudomonas aeruginosa
KW - Shock, Septic
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1371/journal.pone.0102577
DO - 10.1371/journal.pone.0102577
M3 - Journal article
C2 - 25047075
VL - 9
SP - e102577
JO - PLoS ONE
JF - PLoS ONE
SN - 1932-6203
IS - 7
ER -
ID: 186451038