title: Paneth cell α-defensin 6 (HD-6) is an antimicrobial peptide.
abstract: Defensins protect human barriers from commensal and pathogenic microorganisms. Human α-defensin 6 (HD-6) is produced exclusively by small intestinal Paneth cells but, in contrast to other antimicrobial peptides (AMPs) for HD-6, no direct antibacterial killing activity has been detected so far. Herein, we systematically tested how environmental factors, like pH and reducing conditions, affect antimicrobial activity of different defensins against anaerobic bacteria of the human intestinal microbiota. Remarkably, by mimicking the intestinal milieu we detected for the first time antibacterial activity of HD-6. Activity was observed against anaerobic gut commensals but not against some pathogenic strains. Antibiotic activity was attributable to the reduced peptide and independent of free cysteines or a conserved histidine residue. Furthermore, the oxidoreductase thioredoxin, which is also expressed in Paneth cells, is able to reduce a truncated physiological variant of HD-6. Ultrastructural analyses revealed that reduced HD-6 causes disintegration of cytoplasmic structures and alterations in the bacterial cell envelope, while maintaining extracellular net-like structures. We conclude that HD-6 is an antimicrobial peptide. Our data suggest two distinct antimicrobial mechanisms by one peptide: HD-6 kills specific microbes depending on the local environmental conditions, whereas known microbial trapping by extracellular net structures is independent of the reducing milieu.
authors.affiliation: 1] Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany [2] University of Tuebingen, Tuebingen, Germany [3] Department of Microbiology and Immunology, School of Medicine, University of California, Davis, California, USA.
authors.forename: B O
authors.initials: BO
authors.lastname: Schroeder
authors.affiliation: 1] Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany [2] University of Tuebingen, Tuebingen, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Ehmann
authors.affiliation: 1] Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany [2] University of Tuebingen, Tuebingen, Germany.
authors.forename: J C
authors.initials: JC
authors.lastname: Precht
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, University of California, Davis, California, USA.
authors.forename: P A
authors.initials: PA
authors.lastname: Castillo
authors.affiliation: 1] Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany [2] University of Tuebingen, Tuebingen, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Küchler
authors.affiliation: Max-Planck-Institute for Developmental Biology, Electron Microscopy Unit, Tuebingen, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Berger
authors.affiliation: Department of Dermatology, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schaller
authors.affiliation: Department of Internal Medicine I, Robert Bosch Hospital, Stuttgart, Germany.
authors.forename: E F
authors.initials: EF
authors.lastname: Stange
authors.affiliation: 1] Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany [2] University of Tuebingen, Tuebingen, Germany [3] Department of Internal Medicine I, Robert Bosch Hospital, Stuttgart, Germany [4] Department of Internal Medicine I, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Wehkamp
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001439:Bacteroides / Q000187:drug effects / Q000254:growth & development / Q000648:ultrastructure; D001644:Bifidobacterium / Q000187:drug effects / Q000254:growth & development / Q000648:ultrastructure; D002176:Candida albicans / Q000187:drug effects / Q000254:growth & development / Q000648:ultrastructure; D004925:Escherichia / Q000187:drug effects / Q000254:growth & development / Q000648:ultrastructure; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007779:Lactobacillus acidophilus / Q000187:drug effects / Q000254:growth & development / Q000648:ultrastructure; D008826:Microbial Sensitivity Tests; D010084:Oxidation-Reduction; D019879:Paneth Cells / Q000276:immunology / Q000378:metabolism; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000254:growth & development / Q000648:ultrastructure; D019779:Salmonella enterica / Q000187:drug effects / Q000254:growth & development / Q000648:ultrastructure; D013210:Staphylococcus / Q000187:drug effects / Q000254:growth & development / Q000648:ultrastructure; D013291:Streptococcus / Q000187:drug effects / Q000254:growth & development / Q000648:ultrastructure; D023084:alpha-Defensins / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; C517765:DEFA6 protein, human; D023084:alpha-Defensins