Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, WI 53706, USA
Adi Perevitsky
Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
Fang Yun Lim
Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, WI 53706, USA
Yana Shadkchan
Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
Benjamin P. Knox
Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, WI 53706, USA
Julio A. Landero Figueora
University of Cincinnati/Agilent Technologies Metallomics Center of the Americas, Department of Chemistry, University of Cincinnati, Cincinnati, OH 45221, USA
Tsokyi Choera
Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, WI 53706, USA
Mengyao Niu
Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, WI 53706, USA
Andrew J. Steinberger
Department of Bacteriology, University of Wisconsin, Madison, WI 53706, USA
Marcel Wüthrich
Department of Pediatrics, University of Wisconsin, Madison, WI 53706, USA
Rachel A. Idol
Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA
Bruce S. Klein
Department 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, USA
Mary C. Dinauer
Department 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, USA
Anna Huttenlocher
Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, WI 53706, USA; Department of Pediatrics, University of Wisconsin, Madison, WI 53706, USA
Nir Osherov
Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; Corresponding author
Nancy P. Keller
Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, WI 53706, USA; Department of Bacteriology, University of Wisconsin, Madison, WI 53706, USA; Corresponding author
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
