{"database":"Cell Collective","file_versions":[],"scores":{"citationCount":10503,"reanalysisCount":0,"viewCount":0,"searchCount":0},"additional":{"omics_type":["Models","Multiomics"],"submitter":["Audrey Crowther"],"version_name":[""],"full_dataset_link":["https://cellcollective.org/#7926/iron-acquisition-and-oxidative-stress-response-in-aspergillus-fumigatus."],"model_score":["17.7"],"default_version":["1"],"ModelFormat":["SBML"],"submitter_affiliation":[""],"submitter_email":[""],"version_id":["1"],"repository":["Cell Collective"],"version_url":["https://cellcollective.org/#7926:1/iron-acquisition-and-oxidative-stress-response-in-aspergillus-fumigatus."],"version_description":[""],"pubmed_abstract":["<h4>Background</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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."],"pubmed_title":["Iron acquisition and oxidative stress response in aspergillus fumigatus."],"pubmed_authors":["Brandon Madison M, Howard Brad B, Lawrence Christopher C, Laubenbacher Reinhard R"],"description_synonyms":["DNA Oxidative, host organism, Superoxide Radical, Antemortem Diagnosis, acquisition by organism of nutrients from host via siderophores, nucleocytoplasm, Polypaecilum, 2410041A17Rik, ACTG, ACTE, iron acquisition by symbiont from host heme, Infestations and Infections, Aspergillus neoellipticus, Nitrative Stress, fs(1)M34, sci, Diagnosis, infectivity, Damage, csp2, Act5, Social Controls, Long Term, ter, l(1)G0420, DmelCG12051, Relative, Readability, Oxidative DNA, Oxidative, responsivity, Nitro-Oxidative Stress, symptoms, Emericella, HOW, How, HEL-176, Impacts, CG4601, 26Fe, Nitro-Oxidative Stresses, Environmental Impacts, Oxidative Injury, Effect, DNA Damage, Formal Social Controls, l(3)j5D5, 24B, average, treatment, A, C, Oxidative Injuries, me75, cyt5C, Gene Expressions, Biology, DHO, entire life cycle, Moods, non-developmental growth of a unicellular organism, long, Oxidative Cleavage, stru, CG18572, metabolic process resulting in cell growth, l(3)S053606, Deletions, Oxidative DNA Damages, CG10293, D17Mit170, Anti-oxidative, T1, Neosartorya fumigata, Social, l(3)j5B5, Environmental Impact, Oxidative Stress Injuries, Oxidative Stresses, Bsg75C, act 42A, disease management, Ac5C, Therapies, CG4027, ACT, Act, Infections and Infestations, necrosis, Strains, Long-Term Effects, Siderochromes, Diagnose, single-organism behavior, Therapy, screening, 0904/17, l(1)G0330, Process, Actin/BAP47, Aspergillus fumigates, CTE-II, metabolism resulting in cell growth, AACT, Longterm Effect, CTE-IIa, act, Ach1, hBACH, ACH1, Normalcy, Chaetosartorya, Tl3, LACH1, Tl2, Acceptance Processes, Diagnoses, act42A, Literatures, GIG25, Acceptance Process, Iron 56, Postmortem, Screenings, Su(b), Alpha-1-antichymotrypsin His-Pro-less, Oxidative and Nitrosative Stress, SZ1, Term, Examinations and Diagnoses, non-developmental cell growth, AFFX-Dros-ACTIN_M_r_at, GIG24, Relative Risks, Pathogenicity, DFNA26, actin, DNA Oxidative Damages, Individual, internal to cell, Postmortem Diagnosis, LACH, GAT, DFNA20, heme acquisition, Diagnoses and Examination, Aspergillus fumigatus var. ellipticus, Postmortem Diagnoses, Factors, DmelCG4027, Risk, Iron, life, l(1)G0117, Control, signs, Infection and Infestation, Actin, Controls, Treatments, beta-actin/Bap47, Fe, experimental procedures, Nitro-Oxidative, l(1)G0486, Phenotypes, l(1)G0245, Health, Eisen, actin5C, l(1)G0009, Superoxide, ACTL3, Lach1, Oxidative Stress Injury, anon-EST:Liang-2.39, DNA, iron, Polypaecilum <Aspergillus>, Regulation, Strains and Sprains, BACH, Oxidative Damage, l(1)Ab, Regulations, Act5c, Oxidative Stress, lifespan, l(1)G0010, experimental, Effects, Antioxidative, Processes, Petromyces, P62, Antioxidative Stress, ACT5C, Gene, CG12051, Serpin A3, Normalcies, Transcription Factor, Bach, Gene Deletions, Stresses, l(1)G0025, Oxidative Nitrative, Stress Injury, Mass, Oxidative Cleavages, Screening, 1863, Mood, Cell growth-inhibiting gene 24|25 protein, Low, Antemortem, Sprains, Oxidative Damages, Normalities, protoplasm, reactivity, study, hierro, Transcription, act5C, Injury, methods, l(3)s2612, protoplast, Longterm, entire lifespan, experimental section, BRWS2, Siderophore, Diagnoses and Examinations, Deletion, Long-Term, Expressions, fs(1)829, Act42a, anon-EST:fe2D2, Infestation and Infection, DmelCG4216, 1700027G07Rik, Anti oxidative Stress, Oxidative DNA Damage, Antioxidative Stresses, DmelCG18572, accidental cell death, DmelCG10293, Long-Term Effect, Expression, T11, Behaviors, Act-5C, Cte-II, l(1)G0177, Individual Health, Antemortem Diagnoses, 42A, findings, CPS, cou, Formal Social Control, clone 2.39, Affects, Sprain, dJ393D12.2, fer, Factor, Anti-oxidative Stresses, qkr, l(3)S090417, Superoxide Anion, Examination and Diagnoses, Cell, Impact, Environmental, cell expansion, Oxidative Nitrative Stress, uptake, Lr, CAD, Social Control, Mass Screenings, beta-actin, Oxidative Nitrative Stresses, KH93F, Systems, Long Term Effects, Strain, M32055, Infection, Act42, ACTA3, Death, Relative Risk, who, l(1)G0079, Acceptance, ferrum, Anti-oxidative Stress, DNA Oxidative Damage, Normality, Sartorya fumigata, PYR1, VSCM, Risks, CG4216, act 5C, Who/How, Iron-56, Understanding, Cleavage, Longterm Effects, Actin5C., Therapeutic, Aspergillus fumigatus Fresen., Stress, Bra, Environments, qkr[93F], DRORUD, Treatment, virulence, regulation, BAP47, ACTSG, response, Nitro Oxidative Stress, acquisition by symbiont of nutrients from host via siderophores, Bap47, hypothesis, Phialosimplex"],"pubmed_title_synonyms":["DNA Oxidative, Oxidative Stress, acquisition by organism of nutrients from host via siderophores, Antioxidative, Aspergillus fumigates, iron acquisition by symbiont from host heme, Antioxidative Stress, Nitrative Stress, Aspergillus neoellipticus, Anti-oxidative Stresses, Damage, Stresses, Oxidative Nitrative Stress, Oxidative Nitrative, Oxidative DNA, Oxidative, Stress Injury, Oxidative and Nitrosative Stress, Oxidative Nitrative Stresses, responsivity, Nitro-Oxidative Stress, Oxidative Cleavages, DNA Oxidative Damages, Nitro-Oxidative Stresses, Oxidative Injury, DNA Damage, heme acquisition, Oxidative Damages, reactivity, Aspergillus fumigatus var. ellipticus, Oxidative Injuries, Injury, 1863., Anti-oxidative Stress, DNA Oxidative Damage, Sartorya fumigata, Oxidative Cleavage, Cleavage, Oxidative DNA Damages, Anti-oxidative, Neosartorya fumigata, Nitro-Oxidative, Oxidative Stress Injuries, Oxidative Stresses, Anti oxidative Stress, Oxidative DNA Damage, Aspergillus fumigatus Fresen., Antioxidative Stresses, Stress, Oxidative Stress Injury, DNA, response, acquisition by symbiont of nutrients from host via siderophores, Nitro Oxidative Stress, Oxidative Damage"],"name_synonyms":["DNA Oxidative, Oxidative Stress, acquisition by organism of nutrients from host via siderophores, Antioxidative, Aspergillus fumigates, iron acquisition by symbiont from host heme, Antioxidative Stress, Nitrative Stress, Aspergillus neoellipticus, Anti-oxidative Stresses, Damage, Stresses, Oxidative Nitrative Stress, Oxidative Nitrative, Oxidative DNA, Oxidative, Stress Injury, Oxidative and Nitrosative Stress, Oxidative Nitrative Stresses, responsivity, Nitro-Oxidative Stress, Oxidative Cleavages, DNA Oxidative Damages, Nitro-Oxidative Stresses, Oxidative Injury, DNA Damage, heme acquisition, Oxidative Damages, reactivity, Aspergillus fumigatus var. ellipticus, Oxidative Injuries, Injury, 1863., Anti-oxidative Stress, DNA Oxidative Damage, Sartorya fumigata, Oxidative Cleavage, Cleavage, Oxidative DNA Damages, Anti-oxidative, Neosartorya fumigata, Nitro-Oxidative, Oxidative Stress Injuries, Oxidative Stresses, Anti oxidative Stress, Oxidative DNA Damage, Aspergillus fumigatus Fresen., Antioxidative Stresses, Stress, Oxidative Stress Injury, DNA, response, acquisition by symbiont of nutrients from host via siderophores, Nitro Oxidative Stress, Oxidative Damage"],"pubmed_abstract_synonyms":["DNA Oxidative, host organism, Superoxide Radical, Antemortem Diagnosis, acquisition by organism of nutrients from host via siderophores, nucleocytoplasm, Polypaecilum, 2410041A17Rik, ACTG, ACTE, iron acquisition by symbiont from host heme, Infestations and Infections, Aspergillus neoellipticus, Nitrative Stress, fs(1)M34, sci, Diagnosis, necrosis., infectivity, Damage, csp2, Act5, Social Controls, Long Term, ter, l(1)G0420, DmelCG12051, Relative, Readability, Oxidative DNA, Oxidative, responsivity, Nitro-Oxidative Stress, symptoms, Emericella, HOW, How, HEL-176, Impacts, CG4601, 26Fe, Nitro-Oxidative Stresses, Environmental Impacts, Oxidative Injury, Effect, DNA Damage, Formal Social Controls, l(3)j5D5, 24B, average, treatment, A, C, Oxidative Injuries, me75, cyt5C, Gene Expressions, Biology, DHO, entire life cycle, Moods, non-developmental growth of a unicellular organism, long, Oxidative Cleavage, stru, CG18572, metabolic process resulting in cell growth, l(3)S053606, Deletions, Oxidative DNA Damages, CG10293, D17Mit170, Anti-oxidative, T1, Neosartorya fumigata, Social, l(3)j5B5, Environmental Impact, Oxidative Stress Injuries, Oxidative Stresses, Bsg75C, act 42A, disease management, Ac5C, Therapies, CG4027, ACT, Act, Infections and Infestations, necrosis, Strains, Long-Term Effects, Siderochromes, Diagnose, single-organism behavior, Therapy, screening, 0904/17, l(1)G0330, Process, Actin/BAP47, Aspergillus fumigates, CTE-II, metabolism resulting in cell growth, AACT, Longterm Effect, CTE-IIa, act, Ach1, hBACH, ACH1, Normalcy, Chaetosartorya, Tl3, LACH1, Tl2, results, Acceptance Processes, Diagnoses, act42A, Literatures, GIG25, Acceptance Process, Iron 56, Postmortem, Screenings, Su(b), Alpha-1-antichymotrypsin His-Pro-less, Oxidative and Nitrosative Stress, SZ1, Term, Examinations and Diagnoses, non-developmental cell growth, AFFX-Dros-ACTIN_M_r_at, GIG24, Relative Risks, Pathogenicity, DFNA26, actin, DNA Oxidative Damages, Individual, internal to cell, Postmortem Diagnosis, LACH, GAT, DFNA20, heme acquisition, Diagnoses and Examination, Aspergillus fumigatus var. ellipticus, Postmortem Diagnoses, Factors, DmelCG4027, Risk, Iron, life, l(1)G0117, Control, signs, Infection and Infestation, Actin, Controls, Treatments, beta-actin/Bap47, Fe, Nitro-Oxidative, l(1)G0486, Phenotypes, l(1)G0245, Health, Eisen, actin5C, l(1)G0009, Superoxide, ACTL3, Lach1, Oxidative Stress Injury, anon-EST:Liang-2.39, DNA, iron, Polypaecilum <Aspergillus>, Regulation, Strains and Sprains, BACH, Oxidative Damage, l(1)Ab, Regulations, Act5c, Oxidative Stress, lifespan, l(1)G0010, Effects, Antioxidative, Processes, Petromyces, P62, Antioxidative Stress, ACT5C, Gene, CG12051, Serpin A3, Normalcies, Transcription Factor, Bach, Gene Deletions, Stresses, l(1)G0025, Oxidative Nitrative, Stress Injury, Mass, Oxidative Cleavages, Screening, 1863, Mood, Cell growth-inhibiting gene 24|25 protein, Low, Antemortem, Sprains, Oxidative Damages, Normalities, protoplasm, reactivity, study, hierro, Transcription, act5C, Injury, l(3)s2612, protoplast, Longterm, entire lifespan, BRWS2, Siderophore, Diagnoses and Examinations, Deletion, Long-Term, Expressions, fs(1)829, Act42a, anon-EST:fe2D2, Infestation and Infection, DmelCG4216, 1700027G07Rik, Anti oxidative Stress, Oxidative DNA Damage, Antioxidative Stresses, DmelCG18572, accidental cell death, DmelCG10293, Long-Term Effect, Expression, T11, Behaviors, Act-5C, Cte-II, l(1)G0177, Individual Health, Antemortem Diagnoses, 42A, findings, CPS, cou, Formal Social Control, clone 2.39, Affects, Sprain, dJ393D12.2, fer, Factor, Anti-oxidative Stresses, qkr, l(3)S090417, Superoxide Anion, Examination and Diagnoses, Cell, Impact, Environmental, cell expansion, Oxidative Nitrative Stress, uptake, Lr, CAD, Social Control, Mass Screenings, beta-actin, Oxidative Nitrative Stresses, KH93F, Systems, Long Term Effects, Strain, M32055, Infection, Act42, background, ACTA3, Death, Relative Risk, who, l(1)G0079, Acceptance, ferrum, Anti-oxidative Stress, DNA Oxidative Damage, Normality, Sartorya fumigata, PYR1, VSCM, Risks, CG4216, act 5C, Who/How, Iron-56, Understanding, Cleavage, introduction, Longterm Effects, Therapeutic, Aspergillus fumigatus Fresen., Stress, Bra, Environments, qkr[93F], DRORUD, Treatment, virulence, regulation, BAP47, ACTSG, response, Nitro Oxidative Stress, acquisition by symbiont of nutrients from host via siderophores, Bap47, hypothesis, Actin5C, Phialosimplex"],"citation_count":["10503"],"additional_accession":[]},"is_claimable":false,"name":"Iron acquisition and oxidative stress response in aspergillus fumigatus.","description":"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. 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. 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.","dates":{"created":"2017-04-24","publication":"","submission":"2017-05-19","last_modified":"2017-05-19"},"accession":"7926","cross_references":{"pubmed":["25908096"]}}