title: A peptide of heparin cofactor II inhibits endotoxin-mediated shock and invasive Pseudomonas aeruginosa infection.
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.
authors.affiliation: Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, Biomedical Center, Lund, Sweden.
authors.forename: Martina
authors.initials: M
authors.lastname: Kalle
authors.affiliation: Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, Biomedical Center, Lund, Sweden.
authors.forename: Praveen
authors.initials: P
authors.lastname: Papareddy
authors.affiliation: Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, Biomedical Center, Lund, Sweden.
authors.forename: Gopinath
authors.initials: G
authors.lastname: Kasetty
authors.affiliation: Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, Biomedical Center, Lund, Sweden.
authors.forename: Mariena J A
authors.initials: MJ
authors.lastname: van der Plas
authors.affiliation: Division of Infection Medicine, Department of Clinical Sciences, Lund University, Biomedical Center, Lund, Sweden.
authors.forename: Matthias
authors.initials: M
authors.lastname: Mörgelin
authors.affiliation: Department of Pharmacy, Uppsala University, Uppsala, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Malmsten
authors.affiliation: Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, Biomedical Center, Lund, Sweden; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
authors.forename: Artur
authors.initials: A
authors.lastname: Schmidtchen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry / Q000627:therapeutic use*; D001419:Bacteria / Q000187:drug effects; D002176:Candida albicans / Q000187:drug effects; D002460:Cell Line; D004731:Endotoxins / Q000276:immunology; D015844:Heparin Cofactor II / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000276:immunology; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D012772:Shock, Septic / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology
chemical_list: D000890:Anti-Infective Agents; D004731:Endotoxins; D008070:Lipopolysaccharides; D015844:Heparin Cofactor II