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dc.contributor.authorScheithauer, Lina
dc.contributor.authorThiem, Stefanie
dc.contributor.authorSchmelz, Stefan
dc.contributor.authorDellmann, Ansgar
dc.contributor.authorBüssow, Konrad
dc.contributor.authorBrouwer, René M H J
dc.contributor.authorÜnal, Can M
dc.contributor.authorBlankenfeldt, Wulf
dc.contributor.authorSteinert, Michael
dc.date.accessioned2021-02-17T14:13:17Z
dc.date.available2021-02-17T14:13:17Z
dc.date.issued2021-01-24
dc.identifier.citationCell Microbiol. 2021 Jan 24:e13313. doi: 10.1111/cmi.13313. Epub ahead of print.en_US
dc.identifier.pmid33491325
dc.identifier.doi10.1111/cmi.13313
dc.identifier.urihttp://hdl.handle.net/10033/622747
dc.description.abstractProA is a secreted zinc metalloprotease of Legionella pneumophila causing lung damage in animal models of Legionnaires' disease. Here we demonstrate that ProA promotes infection of human lung tissue explants (HLTEs) and dissect the contribution to cell type specific replication and extracellular virulence mechanisms. For the first time, we reveal that co-incubation of HLTEs with purified ProA causes a significant increase of the alveolar septal thickness. This destruction of connective tissue fibres was further substantiated by collagen IV degradation assays. The moderate attenuation of a proA-negative mutant in A549 epithelial cells and THP-1 macrophages suggests that effects of ProA in tissue mainly result from extracellular activity. Correspondingly, ProA contributes to dissemination and serum resistance of the pathogen, which further expands the versatile substrate spectrum of this thermolysin-like protease. The crystal structure of ProA at 1.48 Å resolution showed high congruence to pseudolysin of Pseudomonas aeruginosa, but revealed deviations in flexible loops, the substrate binding pocket S1 ' and the repertoire of cofactors, by which ProA can be distinguished from respective homologues. In sum, this work specified virulence features of ProA at different organisational levels by zooming in from histopathological effects in human lung tissue to atomic details of the protease substrate determination.en_US
dc.language.isoenen_US
dc.publisherWileyen_US
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectLegionella pneumophilaen_US
dc.subjectalveolar septal thicknessen_US
dc.subjectcollagen IVen_US
dc.subjectcrystal structureen_US
dc.subjecthuman lung tissue explantsen_US
dc.subjectzinc metalloprotease ProAen_US
dc.titleZinc metalloprotease ProA of Legionella pneumophila increases alveolar septal thickness in human lung tissue explants by collagen IV degradation.en_US
dc.typeArticleen_US
dc.identifier.eissn1462-5822
dc.contributor.departmentHZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.en_US
dc.identifier.journalCellular microbiologyen_US
dc.source.beginpagee13313
dc.source.endpage
refterms.dateFOA2021-02-17T14:13:17Z
dc.source.journaltitleCellular microbiology
dc.source.countryEngland


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