Aspergillus fumigatus Copper Export Machinery and Reactive Oxygen Intermediate Defense Counter Host Copper-Mediated Oxidative Antimicrobial Offense
Summary: 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 funga...
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| Format: | Article |
| Language: | English |
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Elsevier
2017-05-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124717304941 |
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doaj-153c382f8c2f412281161132bf7a71b6 |
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Article |
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DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Philipp Wiemann Adi Perevitsky Fang Yun Lim Yana Shadkchan Benjamin P. Knox Julio A. Landero Figueora Tsokyi Choera Mengyao Niu Andrew J. Steinberger Marcel Wüthrich Rachel A. Idol Bruce S. Klein Mary C. Dinauer Anna Huttenlocher Nir Osherov Nancy P. Keller |
| spellingShingle |
Philipp Wiemann Adi Perevitsky Fang Yun Lim Yana Shadkchan Benjamin P. Knox Julio A. Landero Figueora Tsokyi Choera Mengyao Niu Andrew J. Steinberger Marcel Wüthrich Rachel A. Idol Bruce S. Klein Mary C. Dinauer Anna Huttenlocher Nir Osherov Nancy P. Keller Aspergillus fumigatus Copper Export Machinery and Reactive Oxygen Intermediate Defense Counter Host Copper-Mediated Oxidative Antimicrobial Offense Cell Reports |
| author_facet |
Philipp Wiemann Adi Perevitsky Fang Yun Lim Yana Shadkchan Benjamin P. Knox Julio A. Landero Figueora Tsokyi Choera Mengyao Niu Andrew J. Steinberger Marcel Wüthrich Rachel A. Idol Bruce S. Klein Mary C. Dinauer Anna Huttenlocher Nir Osherov Nancy P. Keller |
| author_sort |
Philipp Wiemann |
| title |
Aspergillus fumigatus Copper Export Machinery and Reactive Oxygen Intermediate Defense Counter Host Copper-Mediated Oxidative Antimicrobial Offense |
| title_short |
Aspergillus fumigatus Copper Export Machinery and Reactive Oxygen Intermediate Defense Counter Host Copper-Mediated Oxidative Antimicrobial Offense |
| title_full |
Aspergillus fumigatus Copper Export Machinery and Reactive Oxygen Intermediate Defense Counter Host Copper-Mediated Oxidative Antimicrobial Offense |
| title_fullStr |
Aspergillus fumigatus Copper Export Machinery and Reactive Oxygen Intermediate Defense Counter Host Copper-Mediated Oxidative Antimicrobial Offense |
| title_full_unstemmed |
Aspergillus fumigatus Copper Export Machinery and Reactive Oxygen Intermediate Defense Counter Host Copper-Mediated Oxidative Antimicrobial Offense |
| title_sort |
aspergillus fumigatus copper export machinery and reactive oxygen intermediate defense counter host copper-mediated oxidative antimicrobial offense |
| publisher |
Elsevier |
| series |
Cell Reports |
| issn |
2211-1247 |
| publishDate |
2017-05-01 |
| description |
Summary: 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. : Wiemann et al. find that Aspergillus fumigatus employs the copper-sensing transcription factor AceA to express the copper exporter CrpA as a defense mechanism against macrophages. Copper and reactive oxygen intermediate attack and defense are inextricably connected on the side of both host and pathogen during infection. Keywords: ATP7A, CrpA, AtfA, CTR1, CGD, ROI, ROS, PHOX, Aspergillus fumigatus, copper |
| url |
http://www.sciencedirect.com/science/article/pii/S2211124717304941 |
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doaj-153c382f8c2f412281161132bf7a71b62020-11-25T02:13:27ZengElsevierCell Reports2211-12472017-05-0119510081021Aspergillus fumigatus Copper Export Machinery and Reactive Oxygen Intermediate Defense Counter Host Copper-Mediated Oxidative Antimicrobial OffensePhilipp Wiemann0Adi Perevitsky1Fang Yun Lim2Yana Shadkchan3Benjamin P. Knox4Julio A. Landero Figueora5Tsokyi Choera6Mengyao Niu7Andrew J. Steinberger8Marcel Wüthrich9Rachel A. Idol10Bruce S. Klein11Mary C. Dinauer12Anna Huttenlocher13Nir Osherov14Nancy P. Keller15Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, WI 53706, USADepartment of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 6997801, IsraelDepartment of Medical Microbiology and Immunology, University of Wisconsin, Madison, WI 53706, USADepartment of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 6997801, IsraelDepartment of Medical Microbiology and Immunology, University of Wisconsin, Madison, WI 53706, USAUniversity of Cincinnati/Agilent Technologies Metallomics Center of the Americas, Department of Chemistry, University of Cincinnati, Cincinnati, OH 45221, USADepartment of Medical Microbiology and Immunology, University of Wisconsin, Madison, WI 53706, USADepartment of Medical Microbiology and Immunology, University of Wisconsin, Madison, WI 53706, USADepartment of Bacteriology, University of Wisconsin, Madison, WI 53706, USADepartment of Pediatrics, University of Wisconsin, Madison, WI 53706, USADepartment of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USADepartment of Medical Microbiology and Immunology, University of Wisconsin, Madison, WI 53706, USA; Department of Pediatrics, University of Wisconsin, Madison, WI 53706, USA; Department of Medicine, University of Wisconsin, Madison, WI 53706, USADepartment of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USADepartment of Medical Microbiology and Immunology, University of Wisconsin, Madison, WI 53706, USA; Department of Pediatrics, University of Wisconsin, Madison, WI 53706, USADepartment of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; Corresponding authorDepartment of Medical Microbiology and Immunology, University of Wisconsin, Madison, WI 53706, USA; Department of Bacteriology, University of Wisconsin, Madison, WI 53706, USA; Corresponding authorSummary: 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. : Wiemann et al. find that Aspergillus fumigatus employs the copper-sensing transcription factor AceA to express the copper exporter CrpA as a defense mechanism against macrophages. Copper and reactive oxygen intermediate attack and defense are inextricably connected on the side of both host and pathogen during infection. Keywords: ATP7A, CrpA, AtfA, CTR1, CGD, ROI, ROS, PHOX, Aspergillus fumigatus, copperhttp://www.sciencedirect.com/science/article/pii/S2211124717304941 |