title: Identification of cell-penetrating peptides that are bactericidal to Neisseria meningitidis and prevent inflammatory responses upon infection.
abstract: Meningococcal disease is characterized by a fast progression and a high mortality rate. Cell-penetrating peptides (CPPs), developed as vectors for cargo delivery into eukaryotic cells, share structural features with antimicrobial peptides. A screen identified two CPPs, transportan-10 (TP10) and model amphipathic peptide (MAP), with bactericidal action against Neisseria meningitidis. Both peptides were active in human whole blood at micromolar concentrations, while hemolysis remained negligible. Additionally, TP10 exhibited significant antibacterial activity in vivo. Uptake of SYTOX green into live meningococci was observed within minutes after TP10 treatment, suggesting that TP10 may act by membrane permeabilization. Apart from its bactericidal activity, TP10 suppressed inflammatory cytokine release from macrophages infected with N. meningitidis as well as from macrophages stimulated with enterobacterial and meningococcal lipopolysaccharide (LPS). Finally, incubation with TP10 reduced the binding of LPS to macrophages. This novel endotoxin-inhibiting property of TP10, together with its antimicrobial activity in vivo, indicates the possibility to design peptide-based therapies for infectious diseases.
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
authors.forename: Olaspers Sara
authors.initials: OS
authors.lastname: Eriksson
authors.forename: Miriam
authors.initials: M
authors.lastname: Geörg
authors.forename: Hong
authors.initials: H
authors.lastname: Sjölinder
authors.forename: Rannar
authors.initials: R
authors.lastname: Sillard
authors.forename: Staffan
authors.initials: S
authors.lastname: Lindberg
authors.forename: Ulo
authors.initials: U
authors.lastname: Langel
authors.forename: Ann-Beth
authors.initials: AB
authors.lastname: Jonsson
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000276:immunology / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis / Q000302:isolation & purification / Q000494:pharmacology; D002462:Cell Membrane; D057846:Cell-Penetrating Peptides / Q000138:chemical synthesis / Q000302:isolation & purification* / Q000494:pharmacology*; D016207:Cytokines / Q000276:immunology; D004353:Drug Evaluation, Preclinical; D019004:Galanin / Q000276:immunology / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051916:Membrane Cofactor Protein / Q000235:genetics / Q000378:metabolism; D008589:Meningococcal Infections / Q000188:drug therapy; D051379:Mice; D008822:Mice, Transgenic; D009345:Neisseria meningitidis / Q000187:drug effects*; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000494:pharmacology*; D014862:Wasp Venoms / Q000276:immunology / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D023181:Antimicrobial Cationic Peptides; C497857:CD46 protein, human; D057846:Cell-Penetrating Peptides; D016207:Cytokines; D008070:Lipopolysaccharides; D051916:Membrane Cofactor Protein; D011993:Recombinant Fusion Proteins; D014862:Wasp Venoms; C110068:transportan; D019004:Galanin