title: Lipoproteins/peptides are sepsis-inducing toxins from bacteria that can be neutralized by synthetic anti-endotoxin peptides.
abstract: Sepsis, a life-threatening syndrome with increasing incidence worldwide, is triggered by an overwhelming inflammation induced by microbial toxins released into the bloodstream during infection. A well-known sepsis-inducing factor is the membrane constituent of Gram-negative bacteria, lipopolysaccharide (LPS), signalling via Toll-like receptor-4. Although sepsis is caused in more than 50% cases by Gram-positive and mycoplasma cells, the causative compounds are still poorly described. In contradicting investigations lipoproteins/-peptides (LP), lipoteichoic acids (LTA), and peptidoglycans (PGN), were made responsible for eliciting this pathology. Here, we used human mononuclear cells from healthy donors to determine the cytokine-inducing activity of various LPs from different bacterial origin, synthetic and natural, and compared their activity with that of natural LTA and PGN. We demonstrate that LP are the most potent non-LPS pro-inflammatory toxins of the bacterial cell walls, signalling via Toll-like receptor-2, not only in vitro, but also when inoculated into mice: A synthetic LP caused sepsis-related pathological symptoms in a dose-response manner. Additionally, these mice produced pro-inflammatory cytokines characteristic of a septic reaction. Importantly, the recently designed polypeptide Aspidasept(®) which has been proven to efficiently neutralize LPS in vivo, inhibited cytokines induced by the various non-LPS compounds protecting animals from the pro-inflammatory activity of synthetic LP.
authors.affiliation: Universidad de Navarra, Dept. de Microbiología y Parasitología, Irunlarrea 1, 31008 Pamplona, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Martinez de Tejada
authors.affiliation: Divisions of Biophysics, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Parkallee 1-40, 23845 Borstel, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Heinbockel
authors.affiliation: Universidad de Navarra, Dept. de Microbiología y Parasitología, Irunlarrea 1, 31008 Pamplona, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Ferrer-Espada
authors.affiliation: Innate Immunity, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Parkallee 1-40, 23845 Borstel, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Heine
authors.affiliation: Cellular Microbiology, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Parkallee 1-40, 23845 Borstel, Germany.|Bioanalytical Chemistry, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Parkallee 1-40, 23845 Borstel, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Alexander
authors.affiliation: Universidad de Navarra, Dept. de Microbiología y Parasitología, Irunlarrea 1, 31008 Pamplona, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Bárcena-Varela
authors.affiliation: Clinical and Experimental Pathology, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Parkallee 1-40, 23845 Borstel, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Goldmann
authors.affiliation: Divisions of Biophysics, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Parkallee 1-40, 23845 Borstel, Germany.
authors.forename: Wilmar
authors.initials: W
authors.lastname: Correa
authors.affiliation: EMC microcollections, Sindelfinger Straße 3, 72070 Tübingen, Germany.
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Wiesmüller
authors.affiliation: Bioanalytical Chemistry, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Parkallee 1-40, 23845 Borstel, Germany.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Gisch
authors.affiliation: Universidad de Navarra, Dept. de Microbiología y Parasitología, Irunlarrea 1, 31008 Pamplona, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Sánchez-Gómez
authors.affiliation: National Institute of Advanced Industrial Science and Technology AIST, Takamatsu, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fukuoka
authors.affiliation: Universitätsklinikum Aachen, Department of Intensive Care and Intermediate Care, Pauwelsstr. 30, 52074 Aachen, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Schürholz
authors.affiliation: Divisions of Biophysics, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Parkallee 1-40, 23845 Borstel, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gutsmann
authors.affiliation: Divisions of Biophysics, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Parkallee 1-40, 23845 Borstel, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Brandenburg
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000401:mortality; D004731:Endotoxins / Q000009:adverse effects* / Q000037:antagonists & inhibitors*; D005260:Female; D006090:Gram-Negative Bacteria / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000737:chemistry; D008074:Lipoproteins / Q000009:adverse effects* / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D010457:Peptidoglycan / Q000009:adverse effects; D018805:Sepsis / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism / Q000401:mortality; D013211:Staphylococcus aureus / Q000276:immunology; D013682:Teichoic Acids / Q000009:adverse effects
chemical_list: D000900:Anti-Bacterial Agents; D016207:Cytokines; D004731:Endotoxins; D008070:Lipopolysaccharides; D008074:Lipoproteins; D010455:Peptides; D010457:Peptidoglycan; D013682:Teichoic Acids; C009900:lipoteichoic acid