title: Tryptophan catabolism in Pseudomonas aeruginosa and potential for inter-kingdom relationship.
abstract: Pseudomonas aeruginosa (Pa) is a Gram-negative bacteria frequently involved in healthcare-associated pneumonia with poor clinical outcome. To face the announced post-antibiotic era due to increasing resistance and lack of new antibiotics, new treatment strategies have to be developed. Immunomodulation of the host response involved in outcome could be an alternative therapeutic target in Pa-induced lung infection. Kynurenines are metabolites resulting from tryptophan catabolism and are known for their immunomodulatory properties. Pa catabolizes tryptophan through the kynurenine pathway. Interestingly, many host cells also possess the kynurenine pathway, whose metabolites are known to control immune system homeostasis. Thus, bacterial metabolites may interfere with the host's immune response. However, the kynurenine pathway in Pa, including functional enzymes, types and amounts of secreted metabolites remains poorly known. Using liquid chromatography coupled to mass spectrometry and different strains of Pa, we determined types and levels of metabolites produced by Pa ex vivo in growth medium, and the relevance of this production in vivo in a murine model of acute lung injury.
  
  
  
  Ex vivo, Pa secretes clinically relevant kynurenine levels (μM to mM). Pa also secretes kynurenic acid and 3-OH-kynurenine, suggesting that the bacteria possess both a functional kynurenine aminotransferase and kynurenine monooxygenase. The bacterial kynurenine pathway is the major pathway leading to anthranilate production both ex vivo and in vivo. In the absence of the anthranilate pathway, the kynurenine pathway leads to kynurenic acid production.
  
  
  
  Pa produces and secretes several metabolites of the kynurenine pathway. Here, we demonstrate the existence of new metabolic pathways leading to synthesis of bioactive molecules, kynurenic acid and 3-OH-kynurenine in Pa. The kynurenine pathway in Pa is critical to produce anthranilate, a crucial precursor of some Pa virulence factors. Metabolites (anthranilate, kynurenine, kynurenic acid) are produced at sustained levels both ex vivo and in vivo leading to a possible immunomodulatory interplay between bacteria and host. These data may imply that pulmonary infection with bacteria highly expressing the kynurenine pathway enzymes could influence the equilibrium of the host's tryptophan metabolic pathway, known to be involved in the immune response to infection. Further studies are needed to explore the effects of these metabolic changes on the pathophysiology of Pa infection.
authors.affiliation: Université Lille CHU Lille, EA 7366 - Recherche translationnelle: relations hôte pathogènes, F-59000, Lille, France.
authors.forename: Perrine
authors.initials: P
authors.lastname: Bortolotti
authors.affiliation: Laboratoire de Toxicologie - Pôle de Biologie-Pathologie-Génétique - CHRU de Lille - France, EA4483 - IMPECS, Université Lille Nord de France, Lille, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Hennart
authors.affiliation: Université Lille CHU Lille, EA 7366 - Recherche translationnelle: relations hôte pathogènes, F-59000, Lille, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Thieffry
authors.affiliation: Université Lille CHU Lille, EA 7366 - Recherche translationnelle: relations hôte pathogènes, F-59000, Lille, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Jausions
authors.affiliation: Université Lille CHU Lille, EA 7366 - Recherche translationnelle: relations hôte pathogènes, F-59000, Lille, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Faure
authors.affiliation: Translational host pathogen research group, Faculté de Médecine de Lille UDSL, Univ Lille Nord de France, Lille, France.
authors.forename: Teddy
authors.initials: T
authors.lastname: Grandjean
authors.affiliation: Translational host pathogen research group, Faculté de Médecine de Lille UDSL, Univ Lille Nord de France, Lille, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Thepaut
authors.affiliation: Translational host pathogen research group, Faculté de Médecine de Lille UDSL, Univ Lille Nord de France, Lille, France.
authors.forename: Rodrigue
authors.initials: R
authors.lastname: Dessein
authors.affiliation: Laboratoire de Toxicologie - Pôle de Biologie-Pathologie-Génétique - CHRU de Lille - France, EA4483 - IMPECS, Université Lille Nord de France, Lille, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Allorge
authors.affiliation: Faculté de Médecine de Lille UDSL, Univ Lille Nord de France, Lille, France.
authors.forename: Benoit P
authors.initials: BP
authors.lastname: Guery
authors.affiliation: Translational host pathogen research group, Faculté de Médecine de Lille UDSL, Univ Lille Nord de France, Lille, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Faure
authors.affiliation: Translational host pathogen research group, Faculté de Médecine de Lille UDSL, Univ Lille Nord de France, Lille, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Kipnis
authors.affiliation: Laboratoire TIMC-TheREx (UMR5525 CNRS-UGA) Université Grenoble Alpes, Faculté de médecine, La Tronche, France.|Unité médicale de Biochimie des enzymes et des protéines, CHUGA de Grenoble , CS10207, Grenoble, 38043, Rhone alpes, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Toussaint
authors.affiliation: Laboratoire TIMC-TheREx (UMR5525 CNRS-UGA) Université Grenoble Alpes, Faculté de médecine, La Tronche, France. alegouellec@chu-grenoble.fr.|Unité médicale de Biochimie des enzymes et des protéines, CHUGA de Grenoble , CS10207, Grenoble, 38043, Rhone alpes, France. alegouellec@chu-grenoble.fr.
authors.forename: Audrey
authors.initials: A
authors.lastname: Le Gouellec
mesh_terms: D055371:Acute Lung Injury / Q000382:microbiology; D000818:Animals; D004195:Disease Models, Animal; D054884:Host-Pathogen Interactions; D007113:Immunity, Innate; D007736:Kynurenic Acid / Q000378:metabolism; D007737:Kynurenine / Q000378:metabolism; D053858:Metabolic Networks and Pathways; D051379:Mice; D051189:Murinae; D011552:Pseudomonas Infections / Q000276:immunology / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000201:enzymology / Q000378:metabolism*; D000637:Transaminases / Q000378:metabolism; D014364:Tryptophan / Q000378:metabolism*; D062367:ortho-Aminobenzoates / Q000378:metabolism
chemical_list: D062367:ortho-Aminobenzoates; C031385:anthranilic acid; D007737:Kynurenine; D014364:Tryptophan; D000637:Transaminases; C021481:kynurenine-oxoglutarate transaminase; D007736:Kynurenic Acid
keywords: Anthranilate; Kynurenic acid; Kynurenine; Pseudomonas aeruginosa; Tryptophan