title: Klebsiella pneumoniae subverts the activation of inflammatory responses in a NOD1-dependent manner.
abstract: Klebsiella pneumoniae is an important cause of community-acquired and nosocomial pneumonia. Subversion of inflammation is essential for pathogen survival during infection. Evidence indicates that K. pneumoniae infections are characterized by lacking an early inflammatory response although the molecular bases are currently unknown. Here we unveil a novel strategy employed by a pathogen to counteract the activation of inflammatory responses. K. pneumoniae attenuates pro-inflammatory mediators-induced IL-8 secretion. Klebsiella antagonizes the activation of NF-κB via the deubiquitinase CYLD and blocks the phosphorylation of mitogen-activated protein kinases (MAPKs) via the MAPK phosphatase MKP-1. Our studies demonstrate that K. pneumoniae has evolved the capacity to manipulate host systems dedicated to control the immune balance. To exert this anti-inflammatory effect, Klebsiella engages NOD1. In NOD1 knock-down cells, Klebsiella neither induces the expression of CYLD and MKP-1 nor blocks the activation of NF-κB and MAPKs. Klebsiella inhibits Rac1 activation; and inhibition of Rac1 activity triggers a NOD1-mediated CYLD and MKP-1 expression which in turn attenuates IL-1β-induced IL-8 secretion. A capsule (CPS) mutant does not attenuate the inflammatory response. However, purified CPS neither reduces IL-1β-induced IL-8 secretion nor induces the expression of CYLD and MKP-1 thereby indicating that CPS is necessary but not sufficient to attenuate inflammation.
authors.affiliation: Program Infection and Immunity, Fundació Caubet-CIMERA Illes Balears, Bunyola, Spain.
authors.forename: Verónica
authors.initials: V
authors.lastname: Regueiro
authors.forename: David
authors.initials: D
authors.lastname: Moranta
authors.forename: Christian G
authors.initials: CG
authors.lastname: Frank
authors.forename: Eider
authors.initials: E
authors.lastname: Larrarte
authors.forename: Javier
authors.initials: J
authors.lastname: Margareto
authors.forename: Catalina
authors.initials: C
authors.lastname: March
authors.forename: Junkal
authors.initials: J
authors.lastname: Garmendia
authors.forename: José A
authors.initials: JA
authors.lastname: Bengoechea
mesh_terms: D000818:Animals; D002460:Cell Line; D000074749:Deubiquitinating Enzyme CYLD; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D057131:Immune Evasion; D007249:Inflammation / Q000276:immunology; D007710:Klebsiella Infections / Q000276:immunology* / Q000382:microbiology*; D007711:Klebsiella pneumoniae / Q000276:immunology* / Q000472:pathogenicity*; D008168:Lung / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D053474:Nod1 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors*
chemical_list: C119067:NOD1 protein, human; D053474:Nod1 Signaling Adaptor Protein; C107953:RAC1 protein, human; D025521:Tumor Suppressor Proteins; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD; D020830:rac1 GTP-Binding Protein