title: The arginine decarboxylase pathways of host and pathogen interact to impact inflammatory pathways in the lung.
abstract: The arginine decarboxylase pathway, which converts arginine to agmatine, is present in both humans and most bacterial pathogens. In humans agmatine is a neurotransmitter with affinities towards α2-adrenoreceptors, serotonin receptors, and may inhibit nitric oxide synthase. In bacteria agmatine serves as a precursor to polyamine synthesis and was recently shown to enhance biofilm development in some strains of the respiratory pathogen Pseudomonas aeruginosa. We determined agmatine is at the center of a competing metabolism in the human lung during airways infections and is influenced by the metabolic phenotypes of the infecting pathogens. Ultra performance liquid chromatography with mass spectrometry detection was used to measure agmatine in human sputum samples from patients with cystic fibrosis, spent supernatant from clinical sputum isolates, and from bronchoalvelolar lavage fluid from mice infected with P. aeruginosa agmatine mutants. Agmatine in human sputum peaks during illness, decreased with treatment and is positively correlated with inflammatory cytokines. Analysis of the agmatine metabolic phenotype in clinical sputum isolates revealed most deplete agmatine when grown in its presence; however a minority appeared to generate large amounts of agmatine presumably driving sputum agmatine to high levels. Agmatine exposure to inflammatory cells and in mice demonstrated its role as a direct immune activator with effects on TNF-α production, likely through NF-κB activation. P. aeruginosa mutants for agmatine detection and metabolism were constructed and show the real-time evolution of host-derived agmatine in the airways during acute lung infection. These experiments also demonstrated pathogen agmatine production can upregulate the inflammatory response. As some clinical isolates have adapted to hypersecrete agmatine, these combined data would suggest agmatine is a novel target for immune modulation in the host-pathogen dynamic.
authors.affiliation: Pulmonary, Allergy, Critical Care and Sleep Division, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Nick B
authors.initials: NB
authors.lastname: Paulson
authors.affiliation: Pulmonary, Allergy, Critical Care and Sleep Division, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Gilbertsen
authors.affiliation: Department of Chemistry, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Dalluge
authors.affiliation: Division of Pediatric Pulmonology, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Cole W
authors.initials: CW
authors.lastname: Welchlin
authors.affiliation: Division of Biostatistics, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Hughes
authors.affiliation: Division of Allergy, Pulmonary, Critical Care and Sleep Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Han
authors.affiliation: Division of Allergy, Pulmonary, Critical Care and Sleep Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
authors.affiliation: Division of Pediatric Pulmonology, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Laguna
authors.affiliation: Pulmonary, Allergy, Critical Care and Sleep Division, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Williams
mesh_terms: D000376:Agmatine / Q000378:metabolism; D000818:Animals; D018441:Biofilms; D002262:Carboxy-Lyases / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D005260:Female; D054884:Host-Pathogen Interactions; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000382:microbiology; D008137:Longitudinal Studies; D008168:Lung / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D016296:Mutagenesis; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010641:Phenotype; D018410:Pneumonia, Bacterial / Q000378:metabolism; D011446:Prospective Studies; D011550:Pseudomonas aeruginosa / Q000201:enzymology*; D013183:Sputum / Q000378:metabolism / Q000382:microbiology
chemical_list: D016328:NF-kappa B; D000376:Agmatine; D019001:Nitric Oxide Synthase; D002262:Carboxy-Lyases; C019722:arginine decarboxylase