Aspergillus fumigatus Copper Export Machinery and Reactive Oxygen Intermediate Defense Counter Host Copper-Mediated Oxidative Antimicrobial Offense.

The Fenton-chemistry-generating properties of copper ions are considered a potent phagolysosome defense against pathogenic microbes, yet our understanding of underlying host/microbe dynamics remains unclear. We address this issue in invasive aspergillosis and demonstrate that host and fungal responses inextricably connect copper and reactive oxygen intermediate (ROI) mechanisms. Loss of the copper-binding transcription factor AceA yields an Aspergillus fumigatus strain displaying increased sensitivity to copper and ROI in vitro, increased intracellular copper concentrations, decreased survival in challenge with murine alveolar macrophages (AMΦs), and reduced virulence in a non-neutropenic murine model. ΔaceA survival is remediated by dampening of host ROI (chemically or genetically) or enhancement of copper-exporting activity (CrpA) in A. fumigatus. Our study exposes a complex host/microbe multifactorial interplay that highlights the importance of host immune status and reveals key targetable A. fumigatus counter-defenses.

• Publication year

  2017

• Venue

  Cell Reports

• Publication date

  2017-05-02

• Fields of study

  Biology, Medicine, Chemistry, Environmental Science

• Identifiers
  DOI 10.1016/j.celrep.2017.04.019PMID 28467895PMCID PMC5512462
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Supplementary Figure S1

  2019cited by this paper
• Genome‐wide transcriptome analysis of Aspergillus fumigatus exposed to osmotic stress reveals regulators of osmotic and cell wall stresses that are SakAHOG1 and MpkC dependent

  2017cited by this paper
• Comparative transcriptome analysis revealing dormant conidia and germination associated genes in Aspergillus species: an essential role for AtfA in conidial dormancy

  2016cited by this paper
• Zinc and Manganese Chelation by Neutrophil S100A8/A9 (Calprotectin) Limits Extracellular Aspergillus fumigatus Hyphal Growth and Corneal Infection

  2016cited by this paper
• An Adaptation to Low Copper in Candida albicans Involving SOD Enzymes and the Alternative Oxidase

  2016cited by this paper
• Role of Granulocyte-Macrophage Colony-Stimulating Factor Signaling in Regulating Neutrophil Antifungal Activity and the Oxidative Burst During Respiratory Fungal Challenge.

  2016cited by this paper
• Spiroindolone NITD609 is a novel antimalarial drug that targets the P-type ATPase PfATP4.

  2016cited by this paper
• Host-Imposed Copper Poisoning Impacts Fungal Micronutrient Acquisition during Systemic Candida albicans Infections

  2016cited by this paper
• Candida albicans adapts to host copper during infection by swapping metal cofactors for superoxide dismutase

  2015cited by this paper
• Ion Regulation in the Malaria Parasite.

  2015cited by this paper
• Neutrophils in host defense: new insights from zebrafish

  2015cited by this paper
• Copper at the Fungal Pathogen-Host Axis*

  2015cited by this paper
• The Role of Copper and Zinc Toxicity in Innate Immune Defense against Bacterial Pathogens*

  2015cited by this paper
• Fungal Pathogens: Survival and Replication within Macrophages.

  2015cited by this paper
• Identification of high-affinity copper transporters in Aspergillus fumigatus.

  2014cited by this paper
• Mycobacterium tuberculosis P-Type ATPases: Possible Targets for Drug or Vaccine Development

  2014cited by this paper
• Reciprocal functions of Cryptococcus neoformans copper homeostasis machinery during pulmonary infection and meningoencephalitis

  2014cited by this paper
• Nox enzymes and new thinking on reactive oxygen: a double-edged sword revisited.

  2014cited by this paper
• Interference of Aspergillus fumigatus with the immune response

  2014cited by this paper
• NADPH oxidases: an overview from structure to innate immunity-associated pathologies

  2014cited by this paper
• Distinct Innate Immune Phagocyte Responses to Aspergillus fumigatus Conidia and Hyphae in Zebrafish Larvae

  2014cited by this paper
• The complex roles of NADPH oxidases in fungal infection

  2014cited by this paper
• The role of AtfA and HOG MAPK pathway in stress tolerance in conidia of Aspergillus fumigatus.

  2014cited by this paper
• Disorders of heavy metals.

  2014cited by this paper
• Candida albicans SOD5 represents the prototype of an unprecedented class of Cu-only superoxide dismutases required for pathogen defense

  2014cited by this paper
• Iron and copper as virulence modulators in human fungal pathogens

  2014cited by this paper
• Redox and Src family kinase signaling control leukocyte wound attraction and neutrophil reverse migration

  2014cited by this paper
• Regulation of Copper Toxicity by Candida albicans GPA2

  2013cited by this paper
• Cryptococcus neoformans copper detoxification machinery is critical for fungal virulence.

  2013cited by this paper
• Aft2, a Novel Transcription Regulator, Is Required for Iron Metabolism, Oxidative Stress, Surface Adhesion and Hyphal Development in Candida albicans

  2013cited by this paper
• Laccases Involved in 1,8-Dihydroxynaphthalene Melanin Biosynthesis in Aspergillus fumigatus Are Regulated by Developmental Factors and Copper Homeostasis

  2013cited by this paper
• Granulocyte macrophage-colony stimulating factor induced Zn sequestration enhances macrophage superoxide and limits intracellular pathogen survival.

  2013influential reference
• The Aspergillus Genome Database: multispecies curation and incorporation of RNA-Seq data to improve structural gene annotations

  2013cited by this paper
• Regulation of Cation Balance in Saccharomyces cerevisiae

  2013cited by this paper
• Primary immunodeficiencies underlying fungal infections

  2013cited by this paper
• Role of CTR4 in the Virulence of Cryptococcus neoformans

  2012cited by this paper
• Copper at the Front Line of the Host-Pathogen Battle

  2012cited by this paper
• Copper redistribution in murine macrophages in response to Salmonella infection.

  2012cited by this paper
• Copper Homeostasis at the Host-Pathogen Interface*

  2012cited by this paper
• The copper regulon of the human fungal pathogen Cryptococcus neoformans H99

  2011cited by this paper
• Invasive Pulmonary Aspergillosis in Non-Neutropenic Patients: Analysis of a 14-Month Prospective Clinical Experience

  2011cited by this paper
• Phagocyte responses towards Aspergillus fumigatus.

  2011cited by this paper
• Sur7 Promotes Plasma Membrane Organization and Is Needed for Resistance to Stressful Conditions and to the Invasive Growth and Virulence of Candida albicans

  2011cited by this paper
• Live Imaging of Disseminated Candidiasis in Zebrafish Reveals Role of Phagocyte Oxidase in Limiting Filamentous Growth

  2011cited by this paper
• The Small GTPase RacA Mediates Intracellular Reactive Oxygen Species Production, Polarized Growth, and Virulence in the Human Fungal Pathogen Aspergillus fumigatus

  2010cited by this paper
• Menkes disease

  2010cited by this paper
• Functional analysis of the superoxide dismutase family in Aspergillus fumigatus

  2010cited by this paper
• A tissue-scale gradient of hydrogen peroxide mediates rapid wound detection in zebrafish

  2009cited by this paper
• Candida albicans cell surface superoxide dismutases degrade host-derived reactive oxygen species to escape innate immune surveillance

  2009cited by this paper
• FastTree: Computing Large Minimum Evolution Trees with Profiles instead of a Distance Matrix

  2009cited by this paper
• A Role for the ATP7A Copper-transporting ATPase in Macrophage Bactericidal Activity*

  2009cited by this paper
• Pathogenesis of Aspergillus fumigatus in Invasive Aspergillosis

  2009cited by this paper
• Innate Immunity to Aspergillus Species

  2009cited by this paper
• Transcriptional profiling for Aspergillusnidulans HogA MAPK signaling pathway in response to fludioxonil and osmotic stress.

  2009cited by this paper
• In vivo correction of a Menkes disease model using antisense oligonucleotides

  2008cited by this paper
• Origins and unconventional behavior of neutrophils in developing zebrafish.

  2008cited by this paper
• H3K9 Methylation Regulates Growth and Development in Aspergillus fumigatus

  2008cited by this paper
• Role of a CUF1/CTR4 copper regulatory axis in the virulence of Cryptococcus neoformans.

  2007cited by this paper
• Transcriptional Regulation of Chemical Diversity in Aspergillus fumigatus by LaeA

  2007cited by this paper
• Atp7a determines a hierarchy of copper metabolism essential for notochord development.

  2006cited by this paper
• Copper lowering therapy with tetrathiomolybdate as an antiangiogenic strategy in cancer.

  2005cited by this paper
• Elemental Analysis of Mycobacterium avium-, Mycobacterium tuberculosis-, and Mycobacterium smegmatis-Containing Phagosomes Indicates Pathogen-Induced Microenvironments within the Host Cell’s Endosomal System1

  2005cited by this paper
• How superoxide radical damages the cell

  2005cited by this paper
• Characterization of Cryptococcus neoformans variety gattii SOD2 reveals distinct roles of the two superoxide dismutases in fungal biology and virulence

  2005cited by this paper
• A Mutational Study in the Transmembrane Domain of Ccc2p, the Yeast Cu(I)-ATPase, Shows Different Roles for Each Cys-Pro-Cys Cysteine*

  2004cited by this paper
• Characterization of Cu,Zn superoxide dismutase (SOD1) gene knock‐out mutant of Cryptococcus neoformans var. gattii: role in biology and virulence

  2003cited by this paper
• Killing of Aspergillus fumigatus by Alveolar Macrophages Is Mediated by Reactive Oxidant Intermediates

  2003cited by this paper
• Superoxide Dismutase Influences the Virulence of Cryptococcus neoformans by Affecting Growth within Macrophages

  2003cited by this paper
• Superoxide dismutases in Candida albicans: transcriptional regulation and functional characterization of the hyphal-induced SOD5 gene.

  2003cited by this paper
• MAFFT: a novel method for rapid multiple sequence alignment based on fast Fourier transform.

  2002cited by this paper
• Genetic involvement of a cAMP-dependent protein kinase in a G protein signaling pathway regulating morphological and chemical transitions in Aspergillus nidulans.

  2001cited by this paper
• Molecular Cloning: A Laboratory Manual

  2001cited by this paper
• The high copper tolerance of Candida albicans is mediated by a P-type ATPase.

  2000cited by this paper
• Functional Independence of the Two Cysteine-rich Activation Domains in the Yeast Mac1 Transcription Factor*

  2000cited by this paper
• Aspergillus fumigatus and Aspergillosis

  1999cited by this paper
• Ontogeny and behaviour of early macrophages in the zebrafish embryo.

  1999cited by this paper
• Identification of a copper‐induced intramolecular interaction in the transcription factor Mac1 from Saccharomyces cerevisiae

  1998cited by this paper
• GRISEA, a copper-modulated transcription factor from Podospora anserina involved in senescence and morphogenesis, is an ortholog of MAC1 in Saccharomyces cerevisiae

  1998cited by this paper
• Menkes syndrome and animal models.

  1998cited by this paper
• Copper-mediated repression of the activation domain in the yeast Mac1p transcription factor.

  1997cited by this paper
• Selection of multiple disruption events in Aspergillus fumigatus using the orotidine-5′-decarboxylase gene, pyrG, as a unique transformation marker

  1996cited by this paper
• Mouse model of X–linked chronic granulomatous disease, an inherited defect in phagocyte superoxide production

  1995cited by this paper
• CRS5 encodes a metallothionein-like protein in Saccharomyces cerevisiae.

  1994cited by this paper
• Studies on the inhibitory mechanism of iodonium compounds with special reference to neutrophil NADPH oxidase.

  1993cited by this paper
• MAC1, a nuclear regulatory protein related to Cu‐dependent transcription factors is involved in Cu/Fe utilization and stress resistance in yeast.

  1993cited by this paper
• Effects of copper status on neutrophil function, superoxide dismutase, and copper distribution in steers.

  1991cited by this paper
• ACE1, a copper-dependent transcription factor, activates expression of the yeast copper, zinc superoxide dismutase gene.

  1991cited by this paper
• The DNA and Cu binding functions of ACE1 are interdigitated within a single domain.

  1990cited by this paper
• Respiratory burst and candidacidal activity of peritoneal macrophages are impaired in copper-deficient rats.

  1990cited by this paper
• A cysteine-rich nuclear protein activates yeast metallothionein gene transcription

  1989cited by this paper
• Menadione-treated synaptosomes as a model for post-ischaemic neuronal damage.

  1988cited by this paper
• ACE1 regulates expression of the Saccharomyces cerevisiae metallothionein gene

  1988cited by this paper
• Yeast metallothionein function in metal ion detoxification.

  1986cited by this paper
• Phagocytosis and immunoglobulin levels in hypocupremic infants

  1985cited by this paper
• The metabolism of menadione (2-methyl-1,4-naphthoquinone) by isolated hepatocytes. A study of the implications of oxidative stress in intact cells.

  1982cited by this paper
• Menkes's steely hair syndrome.

  1976cited by this paper

• Integrative assessment of heavy metal risks in mining polluted sediments and soils of Aguascalientes, Mexico.

  2025cites this paper
• FpnA, the Aspergillus fumigatus homolog of human ferroportin, mediates resistance to nickel, cobalt and gallium but does not function in iron homeostasis

  2025cites this paper
• Aspergillus fumigatus biology, immunopathogenicity and drug resistance

  2025cites this paper
• Oxidoreductase gene fabG contributes to fungal development, cell wall integrity, and virulence in Aspergillus fumigatus

  2025cites this paper
• Evolution of the pathogenic mold Aspergillus fumigatus on high copper levels identifies novel resistance genes

  2024cites this paper
• Metals at the Host-Fungal Pathogen Battleground.

  2024cites this paper
• Insights into copper sensing and tolerance in Pneumocystis species

  2024cites this paper
• Comparative genomics reveals putative copper tolerance genes in a Fusarium oxysporum strain

  2024cites this paper
• Molecular aspects of copper homeostasis in fungi.

  2024cites this paper
• Manipulation of host phagocytosis by fungal pathogens and therapeutic opportunities

  2024cites this paper
• Electrically polarized nanoscale surfaces generate reactive oxygenated and chlorinated species for deactivation of microorganisms

  2024cites this paper
• The arbuscular mycorrhizal fungus Rhizophagus irregularis uses the copper exporting ATPase RiCRD1 as a major strategy for copper detoxification.

  2023cites this paper
• Copper acquisition and detoxification machineries are conserved in dimorphic fungi

  2023cites this paper
• How metals fuel fungal virulence, yet promote anti-fungal immunity

  2023cites this paper
• Synthesis, X-ray Structure, Hirshfeld Surface Analysis and Antimicrobial Assessment of Tetranuclear s-Triazine Hydrazine Schiff Base Ligand

  2023cites this paper
• A network-based model of Aspergillus fumigatus elucidates regulators of development and defensive natural products of an opportunistic pathogen

  2023cites this paper
• Mutational Analysis of Aspergillus fumigatus Volatile Oxylipins in a Drosophila Eclosion Assay

  2023cites this paper
• Trace copper-mediated asexual development via a superoxide dismutase and induction of AobrlA in Aspergillus oryzae

  2023cites this paper
• Synthesis of a Novel Unexpected Cu(II)–Thiazolidine Complex—X-ray Structure, Hirshfeld Surface Analysis, and Biological Studies

  2022cites this paper
• Whole-genome sequencing of biofilm-forming and chromium-resistant mangrove fungus Aspergillus niger BSC-1

  2022cites this paper
• Neutrophil and Macrophage NADPH Oxidase 2 Differentially Control Responses to Inflammation and to Aspergillus fumigatus in Mice

  2022cites this paper
• Copper starvation induces antimicrobial isocyanide integrated into two distinct biosynthetic pathways in fungi

  2022cites this paper
• A novel Zn2-Cys6 transcription factor clcA contributes to copper homeostasis in Aspergillus fumigatus

  2022cites this paper
• Evaluation of endoglucanase and xylanase production by Aspergillus tamarii cultivated in agro-industrial lignocellulosic biomasses

  2022cites this paper
• Ambient Availability of Amino Acids, Proteins, and Iron Impacts Copper Resistance of Aspergillus fumigatus

  2022cites this paper
• Molecular Characterization and the Essential Biological Function of the Metal Chaperone Protein MtmA in Aspergillus fumigatus

  2022influential citation
• Antifungal Effect of Copper Nanoparticles against Fusarium kuroshium, an Obligate Symbiont of Euwallacea kuroshio Ambrosia Beetle

  2022cites this paper
• Lead, copper, zinc and aluminum tolerance in contrasting ecotypes of Scrophularia striata

  2022cites this paper
• The Negative Effect of Protein Phosphatase Z1 Deletion on the Oxidative Stress Tolerance of Candida albicans Is Synergistic with Betamethasone Exposure

  2021cites this paper
• Antimicrobial and antifungal properties of NiCu-PANI/PVA quaternary nanocomposite synthesized by chemical oxidative polymerization of polyaniline.

  2021cites this paper
• Primary Metabolism of Human Pathogenic Fungi, Importance for Virulence and Potential for Drug Development

  2021cites this paper
• Transcriptional Profiling of the Candida auris Response to Exogenous Farnesol Exposure

  2021cites this paper
• Fungal–Metal Interactions: A Review of Toxicity and Homeostasis

  2021cites this paper
• From Flies to Men: ROS and the NADPH Oxidase in Phagocytes

  2021cites this paper
• Copper in infectious disease: Using both sides of the penny.

  2021cites this paper
• Investigation of a Staphylococcus argenteus Strain Involved in a Chronic Prosthetic-Joint Infection

  2020cites this paper
• Changes in mammalian copper homeostasis during microbial infection.

  2020cites this paper
• Characterization of Acinetobacter baumannii Copper Resistance Reveals a Role in Virulence

  2020cites this paper
• Three-Dimensional Light Sheet Fluorescence Microscopy of Lungs To Dissect Local Host Immune-Aspergillus fumigatus Interactions

  2020cites this paper
• Facile synthesis of copper doping hierarchical hollow porous hydroxyapatite beads by rapid gelling strategy.

  2020cites this paper
• Zebrafish Model System in Antimicrobial Drug Discovery

  2020cites this paper
• Increased Cd2+ biosorption capability of Aspergillus nidulans elicited by crpA deletion

  2020cites this paper
• Copper Tolerance Mediated by FgAceA and FgCrpA in Fusarium graminearum

  2020cites this paper
• Dual-purpose isocyanides produced by Aspergillus fumigatus contribute to cellular copper sufficiency and exhibit antimicrobial activity

  2020cites this paper
• Metabolic Adaptation of Paracoccidioides brasiliensis in Response to in vitro Copper Deprivation

  2020cites this paper
• Absent regulation of iron acquisition by the copper regulator Mac1 in A. fumigatus.

  2020cites this paper
• Fungal oxylipins direct programmed developmental switches in filamentous fungi

  2020cites this paper
• The Role of Zinc in Copper Homeostasis of Aspergillus fumigatus

  2020cites this paper
• Copper detoxification machinery of the brain-eating amoeba Naegleria fowleri involves copper-translocating ATPase and the antioxidant system

  2020cites this paper
• Trade-Off Relation between Fungicide Sensitivity and Melanin Biosynthesis in Plant Pathogenic Fungi

  2020cites this paper
• The sino-nasal warzone: transcriptomic and genomic studies on sino-nasal aspergillosis in dogs

  2020cites this paper
• Molecular Characteristics of the Conserved Aspergillus nidulans Transcription Factor Mac1 and Its Functions in Response to Copper Starvation

  2019cites this paper
• Redox Proteomic Analysis Reveals Oxidative Modifications of Proteins by Increased Levels of Intracellular Reactive Oxygen Species during Hypoxia Adaptation of Aspergillus fumigatus

  2019cites this paper
• The monothiol glutaredoxin GrxD is essential for sensing iron starvation in Aspergillus fumigatus

  2019cites this paper
• Response mechanism of mine-isolated fungus Aspergillus niger IOC 4687 to copper stress determined by proteomics.

  2019cites this paper
• Phagocytic predation by the fungivorous amoeba Protostelium aurantium targets metal ion and redox homeostasis

  2019cites this paper
• 3D light sheet fluorescence microscopy of lungs to dissect local host immune - Aspergillus fumigatus interactions

  2019cites this paper
• Role of the Fusarium oxysporum metallothionein Mt1 in resistance to metal toxicity and virulence.

  2019cites this paper
• New insights into copper homeostasis in filamentous fungi

  2019influential citation
• Aspergillus fumigatus and Aspergillosis in 2019

  2019cites this paper
• Copper Utilization, Regulation, and Acquisition by Aspergillus fumigatus

  2019influential citation
• Nutritional Heterogeneity Among Aspergillus fumigatus Strains Has Consequences for Virulence in a Strain- and Host-Dependent Manner

  2019cites this paper
• Copper Homeostasis in Aspergillus fumigatus: Opportunities for Therapeutic Development

  2019cites this paper
• Menacing Mold: Recent Advances in Aspergillus Pathogenesis and Host Defense.

  2019cites this paper
• A call to arms: Mustering secondary metabolites for success and survival of an opportunistic pathogen

  2019cites this paper
• The Aspergillus fumigatus transcription factor AceA is involved not only in Cu but also in Zn detoxification through regulating transporters CrpA and ZrcA

  2018cites this paper
• Contact killing and antimicrobial properties of copper

  2018cites this paper
• Heavy Metal-Induced Expression of PcaA Provides Cadmium Tolerance to Aspergillus fumigatus and Supports Its Virulence in the Galleria mellonella Model

  2018cites this paper
• The Zebrafish as a Model Host for Invasive Fungal Infections

  2018cites this paper
• Macrophage activation by IFN-γ triggers restriction of phagosomal copper from intracellular pathogens

  2018cites this paper
• Copper signalling: causes and consequences

  2018cites this paper
• A copper transcription factor, AfMac1, regulates both iron and copper homeostasis in the opportunistic fungal pathogen Aspergillus fumigatus.

  2018cites this paper
• Contribution of ATPase copper transporters in animal but not plant virulence of the crossover pathogen Aspergillus flavus

  2018cites this paper
• Identification of Antifungal Targets Based on Computer Modeling

  2018cites this paper
• Genome‐wide analysis of the regulation of Cu metabolism in Cryptococcus neoformans

  2018cites this paper
• Aspergillus fumigatus Copper Export Machinery and Reactive Oxygen Intermediate Defense Counter Host Copper-Mediated Oxidative Antimicrobial Offense.

  2017cites this paper
• Mechanisms of copper and zinc homeostasis in pathogenic black fungi.

  2017cites this paper
• Copper Resistance in Aspergillus nidulans Relies on the PI-Type ATPase CrpA, Regulated by the Transcription Factor AceA

  2017cites this paper
• Metal-homeostasis in the pathobiology of the opportunistic human fungal pathogen Aspergillus fumigatus.

  2017cites this paper
• Cryptococcus neoformans Iron-Sulfur Protein Biogenesis Machinery Is a Novel Layer of Protection against Cu Stress

  2017cites this paper
• When green and red mycology meet: Impressions from an interdisciplinary forum on virulence mechanisms of phyto- and human-pathogenic fungi

  2017cites this paper
• Cu-sensing transcription factor Mac1 coordinates with the Ctr transporter family to regulate Cu acquisition and virulence in Aspergillus fumigatus.

  2017cites this paper