Iron acquisition and oxidative stress response in aspergillus fumigatus

Abstract

BackgroundAspergillus fumigatus is a ubiquitous airborne fungal pathogen that presents a life-threatening health risk to individuals with weakened immune systems. A. fumigatus pathogenicity depends on its ability to acquire iron from the host and to resist host-generated oxidative stress. Gaining a deeper understanding of the molecular mechanisms governing A. fumigatus iron acquisition and oxidative stress response may ultimately help to improve the diagnosis and treatment of invasive aspergillus infections.ResultsThis study follows a systems biology approach to investigate how adaptive behaviors emerge from molecular interactions underlying A. fumigatus iron regulation and oxidative stress response. We construct a Boolean network model from known interactions and simulate how changes in environmental iron and superoxide levels affect network dynamics. We propose rules for linking long term model behavior to qualitative estimates of cell growth and cell death. These rules are used to predict phenotypes of gene deletion strains. The model is validated on the basis of its ability to reproduce literature data not used in model generation.ConclusionsThe model reproduces gene expression patterns in experimental time course data when A. fumigatus is switched from a low iron to a high iron environment. In addition, the model is able to accurately represent the phenotypes of many knockout strains under varying iron and superoxide conditions. Model simulations support the hypothesis that intracellular iron regulates A. fumigatus transcription factors, SreA and HapX, by a post-translational, rather than transcriptional, mechanism. Finally, the model predicts that blocking siderophore-mediated iron uptake reduces resistance to oxidative stress. This indicates that combined targeting of siderophore-mediated iron uptake and the oxidative stress response network may act synergistically to increase fungal cell killing.Electronic supplementary materialThe online version of this article (doi:10.1186/s12918-015-0163-1) contains supplementary material, which is available to authorized users.

Widespread amphotericin B-resistant strains of <em>Aspergillus fumigatus</em> in Hamilton, Canada

“…Interestingly, iron was recently shown to be essential to oxidative stress response in A. fumigatus . 28 In this study, although there was no significant association between catalase activity and AMB susceptibility at the population level, all tested strains produced abundant catalase. It is entirely possible that once the catalase activity reached a certain level, there was little selective advantage to further increase its activity in nature.…”

The iron-responsive microsomal proteome of Aspergillus fumigatus

“…The importance of high affinity iron acquisition strategies to the pathogenicity of A. fumigatus has been well defined [5,6,68]. Strict regulation of these strategies represents an integral mechanism of cellular homeostatic maintenance to avoid generation of deleterious ROS [70]. Proteomic analyses carried out herein indicate significant and functional microsomal proteome remodelling under iron limitation.…”

Siderophore Biosynthesis but Not Reductive Iron Assimilation Is Essential for the Dimorphic Fungus Nomuraea rileyi Conidiation, Dimorphism Transition, Resistance to Oxidative Stress, Pigmented Microsclerotium Formation, and Virulence

“…Iron metabolism is interconnected with the regulatory production of ROS. In A. fumigatus , Brandon et al predicted blocking siderophore-mediated iron uptake reduces resistance to oxidative stress by constructing a Boolean network model (Brandon et al, 2015 ). Remarkably, Chen et al also demonstrated in the citrus fungal pathogen Alternaria alternata that siderophore-mediated iron acquisition has profound effects on ROS detoxification by regulating the NADPH oxidase, the redox activating yes- associated protein 1 regulator, and the high-osmolarity glycerol 1 mitogen-activated protein kinase (Chen et al, 2014 ).…”