title: CD44 deficiency is associated with increased bacterial clearance but enhanced lung inflammation during Gram-negative pneumonia.
abstract: Klebsiella pneumoniae is a frequently isolated causative pathogen in respiratory tract infections. CD44 is a transmembrane adhesion molecule that has been implicated in several immunological processes. To determine the role of CD44 during Klebsiella pneumonia, we intranasally infected wild-type and CD44 knockout (KO) mice with 10(2) to 10(4) colony-forming units of K. pneumoniae or administered Klebsiella lipopolysaccharide. During lethal infection, CD44 deficiency was associated with reduced bacterial growth and dissemination accompanied by enhanced pulmonary inflammation. After infection with lower Klebsiella doses, CD44 KO mice but not wild-type mice demonstrated mortality. After infection with even lower bacterial doses, which were cleared by most mice of both strains, CD44 KO mice displayed enhanced lung inflammation 4 and 10 days postinfection, indicating that CD44 is important for the resolution of pulmonary inflammation after nonlethal pneumonia. In accordance, CD44 KO mice showed a diminished resolution of lung inflammation 4 days after intrapulmonary delivery of lipopolysaccharide. CD44 deficiency was associated with the accumulation of hyaluronan together with reduced gene expression levels of the negative regulators of Toll-like receptor signaling, interleukin-1R-associated kinase M, A20, and suppressor of cytokine signaling 3. In conclusion, the absence of CD44 affects various components and phases of the host response during Klebsiella pneumonia, reducing bacterial outgrowth and dissemination and enhancing pulmonary pathology during lethal infection, and diminishing the resolution of lung inflammation during sublethal infection.
authors.affiliation: Center for Infection and Immunity Amsterdam, Department of Pathology, Academic Medical Center, Meibergdreef 9, Room G2-130, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Gerritje J W
authors.initials: GJ
authors.lastname: van der Windt
authors.forename: Sandrine
authors.initials: S
authors.lastname: Florquin
authors.forename: Alex F
authors.initials: AF
authors.lastname: de Vos
authors.forename: Cornelis
authors.initials: C
authors.lastname: van't Veer
authors.forename: Karla C S
authors.initials: KC
authors.lastname: Queiroz
authors.forename: Jiurong
authors.initials: J
authors.lastname: Liang
authors.forename: Dianhua
authors.initials: D
authors.lastname: Jiang
authors.forename: Paul W
authors.initials: PW
authors.lastname: Noble
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
mesh_terms: D000818:Animals; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000276:immunology*; D006820:Hyaluronic Acid / Q000737:chemistry / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007710:Klebsiella Infections / Q000276:immunology* / Q000473:pathology; D007711:Klebsiella pneumoniae / Q000378:metabolism* / Q000472:pathogenicity; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011014:Pneumonia / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D018410:Pneumonia, Bacterial / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D018960:Hyaluronan Receptors; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D006820:Hyaluronic Acid; D053592:Interleukin-1 Receptor-Associated Kinases; C507772:Irak3 protein, mouse; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse