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Siderophore-mediated signaling regulates virulence factor production in Pseudomonasaeruginosa - PubMed

  • ️Tue Jan 01 2002

Siderophore-mediated signaling regulates virulence factor production in Pseudomonasaeruginosa

Iain L Lamont et al. Proc Natl Acad Sci U S A. 2002.

Abstract

Numerous bacteria secrete low molecular weight compounds termed siderophores that have a high affinity for iron ions. Siderophores have a well-documented role as iron-scavenging chemicals, chelating iron ions in the environment whereupon the ferrisiderophores reenter the bacterial cells by means of specific cell-surface receptors. The iron is then released for incorporation into bacterial proteins. Here we show that in addition to its role as an iron-scavenger, the siderophore pyoverdine that is secreted by Pseudomonas aeruginosa regulates the production of at least three virulence factors (exotoxin A, an endoprotease, and pyoverdine itself), which are major contributors to the ability of this bacterium to cause disease. Regulation occurs through a transmembrane signaling system that includes an outer membrane receptor for ferripyoverdine, a signal-transducing protein that is predicted to extend from the periplasm into the cytoplasm, and a sigma factor. Expression of genes that form part of the regulon is triggered by pyoverdine so that this siderophore acts as a signaling molecule to control the production of secreted products. Recognition that a siderophore acts as a signaling molecule has important implications for the understanding of interactions between bacterial cells.

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Figures

Figure 1
Figure 1

Activities of the pvdE and pvdS promoters. The P. aeruginosa strains shown were grown in King's B medium, and β-galactosidase was assayed. (A) pvdE promoter activity was assayed with plasmid pMP190∷PpvdE. (B) pvdS promoter activity was assayed with pMP190∷PpvdS. + Pvd, pyoverdine was added to a concentration of 60 μM.

Figure 2
Figure 2

Expression from the pvdE promoter in response to varying concentrations of pyoverdine. P. aeruginosa PAO1pvdF containing pMP190∷PpvdE was grown in King's B medium containing pyoverdine at the concentrations shown, and β-galactosidase was assayed. EU, β-galactosidase enzyme units.

Figure 3
Figure 3

Production of exotoxin A in response to the signaling pathway. Culture supernatants for the strains shown, which had been grown with or without the addition of pyoverdine, were serially diluted. and the presence of exotoxin A was determined with an anti-exotoxin antibody. toxA promoter activity was determined by measuring the amounts of β-galactosidase produced by strains carrying the toxA-lacZ reporter fusion plasmid construct pPZ-toxA. All SDs were less than 12%. ND, not determined.

Figure 4
Figure 4

Alignment of the sequences of FpvR, PupR, and FecR. The sequence of FpvR (PA2388 in the P. aeruginosa PAO1 genomic sequence) was aligned with those of PupR and FecR. Positions where identical or similar residues are present in at least two of the sequences are highlighted with identical residues shaded black and similar residues (A and G; D and E; F, W and Y; I, L, M, and V; N and Q; S and T; R and K) shaded gray. FpvR has 27.4% identity (49.0% similarity) with PupR and 35.1% identity (43.0% similarity) with FecR. Sites where fusion of β-lactamase with the N-terminal portion of FecR resulted in sensitivity (−) (cytoplasmic or intramembrane) or resistance (+) (periplasmic) to ampicillin (43) are indicated, and the predicted membrane-spanning region of FecR is underlined. A broken line indicates the region of FpvR that is predicted with TMHMM and TMPRED to constitute a transmembrane helix. The asterisk (*) corresponds to the site where a mutation was introduced into the gene encoding FpvR (see text).

Figure 5
Figure 5

Model of the FpvA/FpvR/PvdS signaling pathway. (Ferri)pyoverdine complexes bind the FpvA receptor protein, transmitting a signal to the FpvR protein that otherwise suppresses the activity of PvdS. PvdS then binds to RNA polymerase, causing expression of genes required for synthesis of pyoverdine and PrpL protease (prpL) and of the ptxR gene that encodes a transcriptional activator of the toxA gene.

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