Zinc metalloprotease ProA of Legionella pneumophila increases alveolar septal thickness in human lung tissue explants by collagen IV degradation

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dc.contributor.authorScheithauer, Lina
dc.contributor.authorThiem, Stefanie
dc.contributor.authorSchmelz, Stefan
dc.contributor.authorDellmann, Ansgar
dc.contributor.authorBuessow, Konrad
dc.contributor.authorBrouwer, Rene M. H. J.
dc.contributor.authorÜnal, Can Murat
dc.contributor.authorBlankenfeldt, Wulf
dc.contributor.authorSteinert, Michael
dc.date.accessioned2021-03-08T09:48:19Z
dc.date.available2021-03-08T09:48:19Z
dc.date.issued2021
dc.departmentTAÜ, Fen Fakültesi, Moleküler Biyoteknoloji Bölümüen_US
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.
dc.identifier.citationScheithauer, L., Thiem, S., Schmelz, S., Dellmann, A., Büssow, K., Brouwer, R. M., ... & Steinert, M. (2021). Zinc metalloprotease ProA of Legionella pneumophila increases alveolar septal thickness in human lung tissue explants by collagen IV degradation. Cellular Microbiology, e13313.
dc.identifier.doi10.1111/cmi.13313
dc.identifier.issn1462-5814
dc.identifier.issn1462-5822
dc.identifier.scopus2-s2.0-85100785639
dc.identifier.scopusqualityQ2
dc.identifier.urihttps://hdl.handle.net/20.500.12846/528
dc.identifier.wosWOS:000616725600001
dc.identifier.wosqualityQ2
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.institutionauthorÜnal, Can Murat
dc.language.isoen
dc.publisherWiley
dc.relation.ispartofCellular Microbiology
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectLegionella Pneumophilaen_US
dc.subjectZinc Metalloproteaseen_US
dc.subjectKristal Yapıen_US
dc.subjectCrystal Structureen_US
dc.titleZinc metalloprotease ProA of Legionella pneumophila increases alveolar septal thickness in human lung tissue explants by collagen IV degradation
dc.typeArticle

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