Zinc Metalloprotease ProA from <i>Legionella pneumophila</i> Inhibits the Pro-Inflammatory Host Response by Degradation of Bacterial Flagellin
The environmental bacterium <i>Legionella pneumophila</i> is an intracellular pathogen of various protozoan hosts and able to cause Legionnaires’ disease, a severe pneumonia in humans. By encoding a wide selection of virulence factors, the infectious agent possesses several strategies to...
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MDPI AG
2022-04-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/12/5/624 |
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| author | Lina Scheithauer Stefanie Thiem Can M. Ünal Ansgar Dellmann Michael Steinert |
| author_facet | Lina Scheithauer Stefanie Thiem Can M. Ünal Ansgar Dellmann Michael Steinert |
| author_sort | Lina Scheithauer |
| collection | DOAJ |
| description | The environmental bacterium <i>Legionella pneumophila</i> is an intracellular pathogen of various protozoan hosts and able to cause Legionnaires’ disease, a severe pneumonia in humans. By encoding a wide selection of virulence factors, the infectious agent possesses several strategies to manipulate its host cells and evade immune detection. In the present study, we demonstrate that the <i>L. pneumophila</i> zinc metalloprotease ProA functions as a modulator of flagellin-mediated TLR5 stimulation and subsequent activation of the pro-inflammatory NF-κB pathway. We found ProA to be capable of directly degrading immunogenic FlaA monomers but not the polymeric form of bacterial flagella. These results indicate a role of the protease in antagonizing immune stimulation, which was further substantiated in HEK-Blue<sup>TM</sup> hTLR5 Detection assays. Addition of purified proteins, bacterial suspensions of <i>L. pneumophila</i> mutant strains as well as supernatants of human lung tissue explant infection to this reporter cell line demonstrated that ProA specifically decreases the TLR5 response via FlaA degradation. Conclusively, the zinc metalloprotease ProA serves as a powerful regulator of exogenous flagellin and presumably creates an important advantage for <i>L. pneumophila</i> proliferation in mammalian hosts by promoting immune evasion. |
| first_indexed | 2024-03-10T03:17:01Z |
| format | Article |
| id | doaj.art-eeae2c6779274438ac7ef0f9e2471929 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T03:17:01Z |
| publishDate | 2022-04-01 |
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| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-eeae2c6779274438ac7ef0f9e24719292023-11-23T10:13:09ZengMDPI AGBiomolecules2218-273X2022-04-0112562410.3390/biom12050624Zinc Metalloprotease ProA from <i>Legionella pneumophila</i> Inhibits the Pro-Inflammatory Host Response by Degradation of Bacterial FlagellinLina Scheithauer0Stefanie Thiem1Can M. Ünal2Ansgar Dellmann3Michael Steinert4Institut für Mikrobiologie, Technische Universität Braunschweig, Spielmannstr. 7, 38106 Braunschweig, GermanyInstitut für Mikrobiologie, Technische Universität Braunschweig, Spielmannstr. 7, 38106 Braunschweig, GermanyInstitut für Mikrobiologie, Technische Universität Braunschweig, Spielmannstr. 7, 38106 Braunschweig, GermanyInstitut für Pathologie, Städtisches Klinikum Braunschweig, Celler Straße 38, 38114 Braunschweig, GermanyInstitut für Mikrobiologie, Technische Universität Braunschweig, Spielmannstr. 7, 38106 Braunschweig, GermanyThe environmental bacterium <i>Legionella pneumophila</i> is an intracellular pathogen of various protozoan hosts and able to cause Legionnaires’ disease, a severe pneumonia in humans. By encoding a wide selection of virulence factors, the infectious agent possesses several strategies to manipulate its host cells and evade immune detection. In the present study, we demonstrate that the <i>L. pneumophila</i> zinc metalloprotease ProA functions as a modulator of flagellin-mediated TLR5 stimulation and subsequent activation of the pro-inflammatory NF-κB pathway. We found ProA to be capable of directly degrading immunogenic FlaA monomers but not the polymeric form of bacterial flagella. These results indicate a role of the protease in antagonizing immune stimulation, which was further substantiated in HEK-Blue<sup>TM</sup> hTLR5 Detection assays. Addition of purified proteins, bacterial suspensions of <i>L. pneumophila</i> mutant strains as well as supernatants of human lung tissue explant infection to this reporter cell line demonstrated that ProA specifically decreases the TLR5 response via FlaA degradation. Conclusively, the zinc metalloprotease ProA serves as a powerful regulator of exogenous flagellin and presumably creates an important advantage for <i>L. pneumophila</i> proliferation in mammalian hosts by promoting immune evasion.https://www.mdpi.com/2218-273X/12/5/624<i>L. pneumophila</i>ProAFlaAhuman lung tissue explantsTLR5 |
| spellingShingle | Lina Scheithauer Stefanie Thiem Can M. Ünal Ansgar Dellmann Michael Steinert Zinc Metalloprotease ProA from <i>Legionella pneumophila</i> Inhibits the Pro-Inflammatory Host Response by Degradation of Bacterial Flagellin Biomolecules <i>L. pneumophila</i> ProA FlaA human lung tissue explants TLR5 |
| title | Zinc Metalloprotease ProA from <i>Legionella pneumophila</i> Inhibits the Pro-Inflammatory Host Response by Degradation of Bacterial Flagellin |
| title_full | Zinc Metalloprotease ProA from <i>Legionella pneumophila</i> Inhibits the Pro-Inflammatory Host Response by Degradation of Bacterial Flagellin |
| title_fullStr | Zinc Metalloprotease ProA from <i>Legionella pneumophila</i> Inhibits the Pro-Inflammatory Host Response by Degradation of Bacterial Flagellin |
| title_full_unstemmed | Zinc Metalloprotease ProA from <i>Legionella pneumophila</i> Inhibits the Pro-Inflammatory Host Response by Degradation of Bacterial Flagellin |
| title_short | Zinc Metalloprotease ProA from <i>Legionella pneumophila</i> Inhibits the Pro-Inflammatory Host Response by Degradation of Bacterial Flagellin |
| title_sort | zinc metalloprotease proa from i legionella pneumophila i inhibits the pro inflammatory host response by degradation of bacterial flagellin |
| topic | <i>L. pneumophila</i> ProA FlaA human lung tissue explants TLR5 |
| url | https://www.mdpi.com/2218-273X/12/5/624 |
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