Pseudomonas aeruginosa manipulates redox and iron homeostasis of its microbiota partner Aspergillus fumigatus via phenazines.

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Abstract

The opportunistic fungal pathogen Aspergillus fumigatus is increasingly found as a coinfecting agent along with Pseudomonas aeruginosa in cystic fibrosis patients. Amongst the numerous molecules secreted by P. aeruginosa during its growth, phenazines constitute a major class. P. aeruginosa usually secreted four phenazines, pyocyanin (PYO), phenazine-1-carboxamide (PCN), 1-hydroxyphenazine (1-HP) and phenazine-1-carboxylic acid (PCA). These phenazines inhibited the growth of A. fumigatus but the underlying mechanisms and the impact of these four phenazines on A. fumigatus biology were not known. In the present study, we analyzed the functions of the four phenazines and their mode of action on A. fumigatus. All four phenazines showed A. fumigatus growth inhibitory effects by inducing production of reactive oxygen species (ROS), specifically O2(·-), and reactive nitrogen species (RNS), ONOO(-). A. fumigatus Sod2p was the major factor involved in resistance against the ROS and RNS induced by phenazines. Sub-inhibitory concentrations of PYO, PCA and PCN promote A. fumigatus growth by an independent iron-uptake acquisition. Of the four phenazines 1-HP had a redox-independent function; being able to chelate metal ions 1-HP induced A. fumigatus iron starvation. Our data show the fine-interactions existing between A. fumigatus and P. aeruginosa, which can lead to stimulatory or antagonistic effects.

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Iron and Pseudomonas aeruginosa biofilm formation.

Ehud Banin, Michael Vasil, E. Peter Greenberg (2005)

Iron serves as a signal in Pseudomonas aeruginosa biofilm development. We examined the influence of mutations in known and putative iron acquisition-signaling genes on biofilm morphology. In iron-sufficient medium, mutants that cannot obtain iron through the high-affinity pyoverdine iron acquisition system form thin biofilms similar to those formed by the parent under low iron conditions. If an iron source for a different iron acquisition system is provided to a pyoverdine mutant, normal biofilm development occurs. This enabled us to identify iron uptake gene clusters that likely serve in transport of ferric citrate and ferrioxamine. We suggest that the functional iron signal for P. aeruginosa biofilm development is active transport of chelated iron or the level of internal iron. If the signal is internal iron levels, then a factor likely to be involved in iron signaling is the cytoplasmic ferric uptake regulator protein, Fur, which controls expression of iron-responsive genes. In support of a Fur involvement, we found that with low iron a Fur mutant was able to organize into more mature biofilms than was the parent. The two known Fur-controlled small regulatory RNAs (PrrF1 and F2) do not appear to mediate iron control of biofilm development. This information establishes a mechanistic basis for iron control of P. aeruginosa biofilm formation.

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Siderophore Biosynthesis But Not Reductive Iron Assimilation Is Essential for Aspergillus fumigatus Virulence

Markus Schrettl, Elaine Bignell, Claudia Kragl … (2004)

The ability to acquire iron in vivo is essential for most microbial pathogens. Here we show that Aspergillus fumigatus does not have specific mechanisms for the utilization of host iron sources. However, it does have functional siderophore-assisted iron mobilization and reductive iron assimilation systems, both of which are induced upon iron deprivation. Abrogation of reductive iron assimilation, by inactivation of the high affinity iron permease (FtrA), has no effect on virulence in a murine model of invasive aspergillosis. In striking contrast, A. fumigatus l-ornithine-N 5-monooxygenase (SidA), which catalyses the first committed step of hydroxamate-type siderophore biosynthesis, is absolutely essential for virulence. Thus, A. fumigatus SidA is an essential virulence attribute. Combined with the absence of a sidA ortholog—and the fungal siderophore system in general—in mammals, these data demonstrate that the siderophore biosynthetic pathway represents a promising new target for the development of antifungal therapies.

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The akuB(KU80) mutant deficient for nonhomologous end joining is a powerful tool for analyzing pathogenicity in Aspergillus fumigatus.

Marcela Savoldi-Barbosa, Cosme da Silva, Marcia Kress … (2005)

To increase the frequency of homologous recombination, we inactivated the KU80 homologue in Aspergillus fumigatus (named akuB(KU80)). Homologous integration reached about 80% for both calcineurin A (calA) and polyketide synthase pksP (alb1) genes in the akuB(KU80) mutant to 3 and 5%, respectively, when using a wild-type A. fumigatus strain. Deletion of akuB(KU80) had no influence on pathogenicity in a low-dose murine infection model.