title: Human host defense peptide LL-37 stimulates virulence factor production and adaptive resistance in Pseudomonas aeruginosa.
abstract: A multitude of different virulence factors as well as the ability to rapidly adapt to adverse environmental conditions are important features for the high pathogenicity of Pseudomonas aeruginosa. Both virulence and adaptive resistance are tightly controlled by a complex regulatory network and respond to external stimuli, such as host signals or antibiotic stress, in a highly specific manner. Here, we demonstrate that physiological concentrations of the human host defense peptide LL-37 promote virulence factor production as well as an adaptive resistance against fluoroquinolone and aminoglycoside antibiotics in P. aeruginosa PAO1. Microarray analyses of P. aeruginosa cells exposed to LL-37 revealed an upregulation of gene clusters involved in the production of quorum sensing molecules and secreted virulence factors (PQS, phenazine, hydrogen cyanide (HCN), elastase and rhamnolipids) and in lipopolysaccharide (LPS) modification as well as an induction of genes encoding multidrug efflux pumps MexCD-OprJ and MexGHI-OpmD. Accordingly, we detected significantly elevated levels of toxic metabolites and proteases in bacterial supernatants after LL-37 treatment. Pre-incubation of bacteria with LL-37 for 2 h led to a decreased susceptibility towards gentamicin and ciprofloxacin. Quantitative Realtime PCR results using a PAO1-pqsE mutant strain present evidence that the quinolone response protein and virulence regulator PqsE may be implicated in the regulation of the observed phenotype in response to LL-37. Further experiments with synthetic cationic antimicrobial peptides IDR-1018, 1037 and HHC-36 showed no induction of pqsE expression, suggesting a new role of PqsE as highly specific host stress sensor.
authors.affiliation: Karlsruhe Institute of Technology (KIT), Institute of Functional Interfaces, Karlsruhe, Germany.
authors.forename: Nikola
authors.initials: N
authors.lastname: Strempel
authors.affiliation: Karlsruhe Institute of Technology (KIT), Institute of Functional Interfaces, Karlsruhe, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Neidig
authors.affiliation: Karlsruhe Institute of Technology (KIT), Institute of Functional Interfaces, Karlsruhe, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Nusser
authors.affiliation: Helmholtz Center for Infection Research, Genome Analytics, Braunschweig, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Geffers
authors.affiliation: UMR CNRS 6014 COBRA, University of Rouen, Evreux, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Vieillard
authors.affiliation: Laboratory of Microbiology Signals and Microenvironment LMSM EA 4312, University of Rouen, Evreux, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Lesouhaitier
authors.affiliation: Karlsruhe Institute of Technology (KIT), Institute of Functional Interfaces, Karlsruhe, Germany.
authors.forename: Gerald
authors.initials: G
authors.lastname: Brenner-Weiss
authors.affiliation: Karlsruhe Institute of Technology (KIT), Institute of Functional Interfaces, Karlsruhe, Germany.
authors.forename: Joerg
authors.initials: J
authors.lastname: Overhage
mesh_terms: D000617:Aminoglycosides / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D054804:Cathelicidins / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D004352:Drug Resistance, Microbial / Q000187:drug effects / Q000235:genetics; D024841:Fluoroquinolones / Q000494:pharmacology; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D019450:Genes, MDR; D006801:Humans; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D009154:Mutation / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity*; D037521:Virulence Factors / Q000096:biosynthesis*
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D001426:Bacterial Proteins; D054804:Cathelicidins; D024841:Fluoroquinolones; D037521:Virulence Factors