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

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.

Characteristics of Aspergillus fumigatus in Association with Stenotrophomonas maltophilia in an In Vitro Model of Mixed Biofilm

“…fumigatus or S . maltophilia and other microorganisms [15, 32–35], but never between these two microorganisms. The originality of this study was to develop for the first time an in vitro model of mixed biofilm of A .…”

“…aeruginosa can have stimulatory or antagonistic biological effects on A . fumigatus depending on its concentrations [15]. …”

“…aeruginosa exhibit antibiosis to A . fumigatus by direct contact and secreted extracellular molecules [15, 16]. Microscopic observations of bacteria-fungi interactions showed that at least some antagonistic bacteria actively move towards fungal hyphae and colonize their surface [17].…”

Harnessing Bacterial Signals for Suppression of Biofilm Formation in the Nosocomial Fungal Pathogen Aspergillus fumigatus

“…In the case of CF, A. fumigatus has been isolated in up to 60% of patients with Pseudomonas aeruginosa infection, suggesting a close relationship between established colonization by P. aeruginosa and superinfection by A. fumigatus (Paugam et al, 2010; Briard et al, 2015). Interkingdom interactions between A. fumigatus and bacterial competitors has been described previously, with significant attention focused on the interaction with P. aeruginosa (McAlester et al, 2008; Mowat et al, 2010; Briard et al, 2015; Ferreira et al, 2015; Zheng et al, 2015). Perhaps somewhat surprisingly, given their co-occurrence, many of these studies describe an antagonistic influence of P. aeruginosa secreted factors on A. fumigatus biofilm formation.…”

How can the cystic fibrosis respiratory microbiome influence our clinical decision-making?

“…Interactions between bacterial and fungal pathogens in the CF airways are already well-known. For example, the phenazines secreted by P. aeruginosa are known to inhibit the growth of Aspergillus fumigatus at high concentrations but promote growth at sub-inhibitory concentrations [66], while pseudomonas-derived volatile organic compounds can trigger invasion of the lung parenchyma by A. fumigatus [67]. The recent description of complex fungal communities that showed evidence of adaptation to the CF airways and stability during pulmonary exacerbation or treatment [68], suggests such interactions maybe be widespread.…”