Cytotoxic alkyl-quinolones mediate surface-induced virulence in Pseudomonas aeruginosa.
Surface attachment, an early step in the colonization of multiple host environments, activates the virulence of the human pathogen P. aeruginosa. However, the downstream toxins that mediate surface-dependent P. aeruginosa virulence remain unclear, as do the signaling pathways that lead to their acti...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2020-09-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1008867 |
| _version_ | 1818926904996003840 |
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| author | Geoffrey D Vrla Mark Esposito Chen Zhang Yibin Kang Mohammad R Seyedsayamdost Zemer Gitai |
| author_facet | Geoffrey D Vrla Mark Esposito Chen Zhang Yibin Kang Mohammad R Seyedsayamdost Zemer Gitai |
| author_sort | Geoffrey D Vrla |
| collection | DOAJ |
| description | Surface attachment, an early step in the colonization of multiple host environments, activates the virulence of the human pathogen P. aeruginosa. However, the downstream toxins that mediate surface-dependent P. aeruginosa virulence remain unclear, as do the signaling pathways that lead to their activation. Here, we demonstrate that alkyl-quinolone (AQ) secondary metabolites are rapidly induced upon surface association and act directly on host cells to cause cytotoxicity. Surface-induced AQ cytotoxicity is independent of other AQ functions like quorum sensing or PQS-specific activities like iron sequestration. We further show that packaging of AQs in outer-membrane vesicles (OMVs) increases their cytotoxicity to host cells but not their ability to stimulate downstream quorum sensing pathways in bacteria. OMVs lacking AQs are significantly less cytotoxic, suggesting these molecules play a role in OMV cytotoxicity, in addition to their previously characterized role in OMV biogenesis. AQ reporters also enabled us to dissect the signal transduction pathways downstream of the two known regulators of surface-dependent virulence, the quorum sensing receptor, LasR, and the putative mechanosensor, PilY1. Specifically, we show that PilY1 regulates surface-induced AQ production by repressing the AlgR-AlgZ two-component system. AlgR then induces RhlR, which can induce the AQ biosynthesis operon under specific conditions. These findings collectively suggest that the induction of AQs upon surface association is both necessary and sufficient to explain surface-induced P. aeruginosa virulence. |
| first_indexed | 2024-12-20T03:04:32Z |
| format | Article |
| id | doaj.art-f1764276022a42e9a704f9167407e6fa |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-20T03:04:32Z |
| publishDate | 2020-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-f1764276022a42e9a704f9167407e6fa2022-12-21T19:55:39ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742020-09-01169e100886710.1371/journal.ppat.1008867Cytotoxic alkyl-quinolones mediate surface-induced virulence in Pseudomonas aeruginosa.Geoffrey D VrlaMark EspositoChen ZhangYibin KangMohammad R SeyedsayamdostZemer GitaiSurface attachment, an early step in the colonization of multiple host environments, activates the virulence of the human pathogen P. aeruginosa. However, the downstream toxins that mediate surface-dependent P. aeruginosa virulence remain unclear, as do the signaling pathways that lead to their activation. Here, we demonstrate that alkyl-quinolone (AQ) secondary metabolites are rapidly induced upon surface association and act directly on host cells to cause cytotoxicity. Surface-induced AQ cytotoxicity is independent of other AQ functions like quorum sensing or PQS-specific activities like iron sequestration. We further show that packaging of AQs in outer-membrane vesicles (OMVs) increases their cytotoxicity to host cells but not their ability to stimulate downstream quorum sensing pathways in bacteria. OMVs lacking AQs are significantly less cytotoxic, suggesting these molecules play a role in OMV cytotoxicity, in addition to their previously characterized role in OMV biogenesis. AQ reporters also enabled us to dissect the signal transduction pathways downstream of the two known regulators of surface-dependent virulence, the quorum sensing receptor, LasR, and the putative mechanosensor, PilY1. Specifically, we show that PilY1 regulates surface-induced AQ production by repressing the AlgR-AlgZ two-component system. AlgR then induces RhlR, which can induce the AQ biosynthesis operon under specific conditions. These findings collectively suggest that the induction of AQs upon surface association is both necessary and sufficient to explain surface-induced P. aeruginosa virulence.https://doi.org/10.1371/journal.ppat.1008867 |
| spellingShingle | Geoffrey D Vrla Mark Esposito Chen Zhang Yibin Kang Mohammad R Seyedsayamdost Zemer Gitai Cytotoxic alkyl-quinolones mediate surface-induced virulence in Pseudomonas aeruginosa. PLoS Pathogens |
| title | Cytotoxic alkyl-quinolones mediate surface-induced virulence in Pseudomonas aeruginosa. |
| title_full | Cytotoxic alkyl-quinolones mediate surface-induced virulence in Pseudomonas aeruginosa. |
| title_fullStr | Cytotoxic alkyl-quinolones mediate surface-induced virulence in Pseudomonas aeruginosa. |
| title_full_unstemmed | Cytotoxic alkyl-quinolones mediate surface-induced virulence in Pseudomonas aeruginosa. |
| title_short | Cytotoxic alkyl-quinolones mediate surface-induced virulence in Pseudomonas aeruginosa. |
| title_sort | cytotoxic alkyl quinolones mediate surface induced virulence in pseudomonas aeruginosa |
| url | https://doi.org/10.1371/journal.ppat.1008867 |
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