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Iron acquisition and oxidative stress response in aspergillus fumigatus.

Brandon M, Howard B, Lawrence C, Laubenbacher R - BMC Syst Biol (2015)

Bottom Line: In addition, the model is able to accurately represent the phenotypes of many knockout strains under varying iron and superoxide conditions.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.

View Article: PubMed Central - PubMed

Affiliation: Center for Cell Analysis and Modeling, University of Connecticut Health Center, 400 Farmington Ave, Farmington, 06030, USA. mbrandon@uchc.edu.

ABSTRACT

Background: Aspergillus 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.

Results: This 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.

Conclusions: The 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.

No MeSH data available.


Related in: MedlinePlus

Stable states of A. fumigatus iron regulatory and oxidative stress response networks. This figure shows the cyclic attractor for each of the four possible external conditions. States transition from top to bottom. Under both low iron conditions ICP is in state 0 (low) the majority of the cycle. Under both high superoxide conditions ROS is in state 1 (high) the majority of the cycle.
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Fig2: Stable states of A. fumigatus iron regulatory and oxidative stress response networks. This figure shows the cyclic attractor for each of the four possible external conditions. States transition from top to bottom. Under both low iron conditions ICP is in state 0 (low) the majority of the cycle. Under both high superoxide conditions ROS is in state 1 (high) the majority of the cycle.

Mentions: In general, the dynamic behavior of discrete models is simulated by starting from an initial state and then enumerating the changing state space as each species is updated over a specified number of iterations called time steps. The result of deterministic simulations, when all species are updated simultaneously at each time step, is shown in Figure 2. This system has no steady state solution for any of the four external conditions. All long term behavior is oscillatory, i.e. the stable states form a limit cycle and 100 % of the 1048576 states converge to the limit cycle displayed.Figure 2


Iron acquisition and oxidative stress response in aspergillus fumigatus.

Brandon M, Howard B, Lawrence C, Laubenbacher R - BMC Syst Biol (2015)

Stable states of A. fumigatus iron regulatory and oxidative stress response networks. This figure shows the cyclic attractor for each of the four possible external conditions. States transition from top to bottom. Under both low iron conditions ICP is in state 0 (low) the majority of the cycle. Under both high superoxide conditions ROS is in state 1 (high) the majority of the cycle.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4418068&req=5

Fig2: Stable states of A. fumigatus iron regulatory and oxidative stress response networks. This figure shows the cyclic attractor for each of the four possible external conditions. States transition from top to bottom. Under both low iron conditions ICP is in state 0 (low) the majority of the cycle. Under both high superoxide conditions ROS is in state 1 (high) the majority of the cycle.
Mentions: In general, the dynamic behavior of discrete models is simulated by starting from an initial state and then enumerating the changing state space as each species is updated over a specified number of iterations called time steps. The result of deterministic simulations, when all species are updated simultaneously at each time step, is shown in Figure 2. This system has no steady state solution for any of the four external conditions. All long term behavior is oscillatory, i.e. the stable states form a limit cycle and 100 % of the 1048576 states converge to the limit cycle displayed.Figure 2

Bottom Line: In addition, the model is able to accurately represent the phenotypes of many knockout strains under varying iron and superoxide conditions.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.

View Article: PubMed Central - PubMed

Affiliation: Center for Cell Analysis and Modeling, University of Connecticut Health Center, 400 Farmington Ave, Farmington, 06030, USA. mbrandon@uchc.edu.

ABSTRACT

Background: Aspergillus 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.

Results: This 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.

Conclusions: The 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.

No MeSH data available.


Related in: MedlinePlus