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dc.contributor.authorJäger, Jens
dc.contributor.authorMarwitz, Sebastian
dc.contributor.authorTiefenau, Jana
dc.contributor.authorRasch, Janine
dc.contributor.authorShevchuk, Olga
dc.contributor.authorKugler, Christian
dc.contributor.authorGoldmann, Torsten
dc.contributor.authorSteinert, Michael
dc.date.accessioned2017-08-08T11:25:42Z
dc.date.available2017-08-08T11:25:42Z
dc.date.issued2014-01
dc.identifier.citationHuman lung tissue explants reveal novel interactions during Legionella pneumophila infections. 2014, 82 (1):275-85 Infect. Immun.en
dc.identifier.issn1098-5522
dc.identifier.pmid24166955
dc.identifier.doi10.1128/IAI.00703-13
dc.identifier.urihttp://hdl.handle.net/10033/621049
dc.description.abstractHistological and clinical investigations describe late stages of Legionnaires' disease but cannot characterize early events of human infection. Cellular or rodent infection models lack the complexity of tissue or have nonhuman backgrounds. Therefore, we developed and applied a novel model for Legionella pneumophila infection comprising living human lung tissue. We stimulated lung explants with L. pneumophila strains and outer membrane vesicles (OMVs) to analyze tissue damage, bacterial replication, and localization as well as the transcriptional response of infected tissue. Interestingly, we found that extracellular adhesion of L. pneumophila to the entire alveolar lining precedes bacterial invasion and replication in recruited macrophages. In contrast, OMVs predominantly bound to alveolar macrophages. Specific damage to septa and epithelia increased over 48 h and was stronger in wild-type-infected and OMV-treated samples than in samples infected with the replication-deficient, type IVB secretion-deficient DotA(-) strain. Transcriptome analysis of lung tissue explants revealed a differential regulation of 2,499 genes after infection. The transcriptional response included the upregulation of uteroglobin and the downregulation of the macrophage receptor with collagenous structure (MARCO). Immunohistochemistry confirmed the downregulation of MARCO at sites of pathogen-induced tissue destruction. Neither host factor has ever been described in the context of L. pneumophila infections. This work demonstrates that the tissue explant model reproduces realistic features of Legionnaires' disease and reveals new functions for bacterial OMVs during infection. Our model allows us to characterize early steps of human infection which otherwise are not feasible for investigations.
dc.language.isoenen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subject.meshAdhesins, Bacterialen
dc.subject.meshBacterial Adhesionen
dc.subject.meshGene Expression Regulation, Bacterialen
dc.subject.meshHumansen
dc.subject.meshInterferon-gammaen
dc.subject.meshLegionella pneumophilaen
dc.subject.meshLegionnaires' Diseaseen
dc.subject.meshLungen
dc.subject.meshMacrophages, Alveolaren
dc.subject.meshModels, Biologicalen
dc.subject.meshRNA, Bacterialen
dc.subject.meshTranscriptomeen
dc.titleHuman lung tissue explants reveal novel interactions during Legionella pneumophila infections.en
dc.typeArticleen
dc.contributor.departmentHelmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.en
dc.identifier.journalInfection and immunityen
refterms.dateFOA2018-06-13T02:28:24Z
html.description.abstractHistological and clinical investigations describe late stages of Legionnaires' disease but cannot characterize early events of human infection. Cellular or rodent infection models lack the complexity of tissue or have nonhuman backgrounds. Therefore, we developed and applied a novel model for Legionella pneumophila infection comprising living human lung tissue. We stimulated lung explants with L. pneumophila strains and outer membrane vesicles (OMVs) to analyze tissue damage, bacterial replication, and localization as well as the transcriptional response of infected tissue. Interestingly, we found that extracellular adhesion of L. pneumophila to the entire alveolar lining precedes bacterial invasion and replication in recruited macrophages. In contrast, OMVs predominantly bound to alveolar macrophages. Specific damage to septa and epithelia increased over 48 h and was stronger in wild-type-infected and OMV-treated samples than in samples infected with the replication-deficient, type IVB secretion-deficient DotA(-) strain. Transcriptome analysis of lung tissue explants revealed a differential regulation of 2,499 genes after infection. The transcriptional response included the upregulation of uteroglobin and the downregulation of the macrophage receptor with collagenous structure (MARCO). Immunohistochemistry confirmed the downregulation of MARCO at sites of pathogen-induced tissue destruction. Neither host factor has ever been described in the context of L. pneumophila infections. This work demonstrates that the tissue explant model reproduces realistic features of Legionnaires' disease and reveals new functions for bacterial OMVs during infection. Our model allows us to characterize early steps of human infection which otherwise are not feasible for investigations.


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