Cytotoxic alkyl-quinolones mediate surface-induced virulence in Pseudomonas aeruginosa.

TitleCytotoxic alkyl-quinolones mediate surface-induced virulence in Pseudomonas aeruginosa.
Publication TypeJournal Article
Year of Publication2020
AuthorsVrla, GD, Esposito, M, Zhang, C, Kang, Y, Seyedsayamdost, MR, Gitai, Z
JournalPLoS Pathog
Volume16
Issue9
Paginatione1008867
Date Published2020 09
ISSN1553-7374
KeywordsA549 Cells, Animals, Bacterial Proteins, Humans, Mice, Pseudomonas aeruginosa, Pseudomonas Infections, Quinolones, Quorum Sensing, Signal Transduction, Virulence Factors
Abstract

<p>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.</p>

DOI10.1371/journal.ppat.1008867
Alternate JournalPLoS Pathog
PubMed ID32925969
PubMed Central IDPMC7515202
Grant ListDP1 AI124669 / AI / NIAID NIH HHS / United States
T32 GM007388 / GM / NIGMS NIH HHS / United States