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

Benoit Briard,Anne Beauvais,Virginie Lair,Gaëtan L A Mislin,Marie-Christine Prévost,Perrine Bomme,Beatrix E Lechner,Jean-Paul Latgé,Hubertus Haas

doi:10.1038/srep08220

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.

Highlights

The opportunistic fungal pathogen Aspergillus fumigatus is increasingly found as a coinfecting agent along with Pseudomonas aeruginosa in cystic fibrosis patients
Four main phenazines have been identified in P. aeruginosa: Phenazine-1-carboxylic acid (Phenazine-1-carboxylate, phenazine-1-carboxylic acid (PCA)), which is produced from chorismic acid
We found that A. fumigatus Sod2p was the major factor involved in resistance against the reactive oxygen species (ROS) and reactive nitrogen species (RNS) induced by phenazines

Summary

Introduction

The opportunistic fungal pathogen Aspergillus fumigatus is increasingly found as a coinfecting agent along with Pseudomonas aeruginosa in cystic fibrosis patients. 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. Phenazines are small diffusible quorum sensing molecules which penetrate all kind of cells[1] These natural pigments comprise blue for pyocyanin (PYO), yellow for phenazine-1-carboxylic acid (PCA) and phenazine-1-carboxamide (PCN) and orange for 1-hydroxyphenazine (1-HP). They are considered as the main virulence factor of P. aeruginosa against a broad range of target organisms, including other bacteria, fungi and mammalian cells[1,2,3]. YAP1-deficiency increases the susceptibility of A. fumigatus to both H2O2 and menadione

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