title: Pseudomonas aeruginosa proteolytically alters the interleukin 22-dependent lung mucosal defense.
abstract: The IL-22 signaling pathway is critical for regulating mucosal defense and limiting bacterial dissemination. IL-22 is unusual among interleukins because it does not directly regulate the function of conventional immune cells, but instead targets cells at outer body barriers, such as respiratory epithelial cells. Consequently, IL-22 signaling participates in the maintenance of the lung mucosal barrier by controlling cell proliferation and tissue repair, and enhancing the production of specific chemokines and anti-microbial peptides. Pseudomonas aeruginosa is a major pathogen of ventilator-associated pneumonia and causes considerable lung tissue damage. A feature underlying the pathogenicity of this bacterium is its capacity to persist and develop in the host, particularly in the clinical context of nosocomial lung infections. We aimed to investigate the ability of P. auruginosa to disrupt immune-epithelial cells cross-talk. We found that P. aeruginosa escapes the host mucosal defenses by degrading IL-22, leading to severe inhibition of IL-22-mediated immune responses. We demonstrated in vitro that, protease IV, a type 2 secretion system-dependent serine protease, is responsible for the degradation of IL-22 by P. aeruginosa. Moreover, the major anti-proteases molecules present in the lungs were unable to inhibit protease IV enzymatic activity. In addition, tracheal aspirates of patients infected by P. aeruginosa contain protease IV activity which further results in IL-22 degradation. This so far undescribed cleavage of IL-22 by a bacterial protease is likely to be an immune-evasion strategy that contributes to P. aeruginosa-triggered respiratory infections.
authors: a Institut National de la Santé et de la Recherche Médicale, Center d'Etude des Pathologies Respiratoires (CEPR), INSERM UMR 1100 , Tours , France.|b Université François Rabelais de Tours , Tours , France.|c CHRU de Tours , Service de Réanimation Polyvalente , Tours , France.
authors: Antoine
authors: 0000-0002-4884-8620
authors: A
authors: Guillon
authors: a Institut National de la Santé et de la Recherche Médicale, Center d'Etude des Pathologies Respiratoires (CEPR), INSERM UMR 1100 , Tours , France.|b Université François Rabelais de Tours , Tours , France.
authors: Deborah
authors: D
authors: Brea
authors: a Institut National de la Santé et de la Recherche Médicale, Center d'Etude des Pathologies Respiratoires (CEPR), INSERM UMR 1100 , Tours , France.|b Université François Rabelais de Tours , Tours , France.
authors: Eric
authors: E
authors: Morello
authors: d Department of Microbiology and Immunology , University of Mississippi Medical Center , Jackson , MS , USA.
authors: Aihua
authors: A
authors: Tang
authors: a Institut National de la Santé et de la Recherche Médicale, Center d'Etude des Pathologies Respiratoires (CEPR), INSERM UMR 1100 , Tours , France.|b Université François Rabelais de Tours , Tours , France.|c CHRU de Tours , Service de Réanimation Polyvalente , Tours , France.
authors: Youenn
authors: Y
authors: Jouan
authors: a Institut National de la Santé et de la Recherche Médicale, Center d'Etude des Pathologies Respiratoires (CEPR), INSERM UMR 1100 , Tours , France.|b Université François Rabelais de Tours , Tours , France.
authors: Reuben
authors: R
authors: Ramphal
authors: a Institut National de la Santé et de la Recherche Médicale, Center d'Etude des Pathologies Respiratoires (CEPR), INSERM UMR 1100 , Tours , France.
authors: Brice
authors: 0000-0002-5159-8706
authors: B
authors: Korkmaz
authors: e Institut Pasteur de Lille, Center d'Infection et d'Immunité de Lille , Lille , France.|f Université Lille Nord de France , Lille , France.|g Centre National de la Recherche Scientifique , UMR 8204 , Lille , France.|h Institut National de la Santé et de la Recherche Médicale, U1019 , Lille , France.
authors: Magdiel
authors: M
authors: Perez-Cruz
authors: e Institut Pasteur de Lille, Center d'Infection et d'Immunité de Lille , Lille , France.|f Université Lille Nord de France , Lille , France.|g Centre National de la Recherche Scientifique , UMR 8204 , Lille , France.|h Institut National de la Santé et de la Recherche Médicale, U1019 , Lille , France.
authors: Francois
authors: 0000-0003-3373-1814
authors: F
authors: Trottein
authors: d Department of Microbiology and Immunology , University of Mississippi Medical Center , Jackson , MS , USA.
authors: Richard J
authors: 0000-0001-9931-6061
authors: RJ
authors: O'Callaghan
authors: e Institut Pasteur de Lille, Center d'Infection et d'Immunité de Lille , Lille , France.|f Université Lille Nord de France , Lille , France.|g Centre National de la Recherche Scientifique , UMR 8204 , Lille , France.|h Institut National de la Santé et de la Recherche Médicale, U1019 , Lille , France.
authors: Philippe
authors: P
authors: Gosset
authors: a Institut National de la Santé et de la Recherche Médicale, Center d'Etude des Pathologies Respiratoires (CEPR), INSERM UMR 1100 , Tours , France.|b Université François Rabelais de Tours , Tours , France.
authors: Mustapha
authors: 0000-0002-5792-7742
authors: M
authors: Si-Tahar
mesh_terms: D000818:Animals; D003428:Cross Infection; D006801:Humans; D057131:Immune Evasion; D007378:Interleukins / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008168:Lung / Q000276:immunology* / Q000382:microbiology* / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D010447:Peptide Hydrolases / Q000096:biosynthesis / Q000378:metabolism; D018410:Pneumonia, Bacterial / Q000276:immunology / Q000382:microbiology; D059748:Proteolysis; D011552:Pseudomonas Infections / Q000276:immunology* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000201:enzymology / Q000378:metabolism* / Q000472:pathogenicity; D015398:Signal Transduction; D000097043:Interleukin-22
chemical_list: D007378:Interleukins; D010447:Peptide Hydrolases; D000097043:Interleukin-22; C030732:protease IV
keywords: Pseudomonas aeruginosa; infection; interleukin 22; lung; proteases