Cited by 23Antifungal resistance and susceptibilityTrace Elements in Healthinterferon and immune responses

Type I Interferons Ameliorate Zinc Intoxication of Candida glabrata by Macrophages and Promote Fungal Immune Evasion

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Riedelberger, Michael, Penninger, Philipp, Tscherner, Michael, Hadriga, Bernhard, Brunnhofer, Carina, Jenull, Sabrina, Stoiber, Anton, Bourgeois, Christelle +7 more·2020·iScience

Abstract

Host and fungal pathogens compete for metal ion acquisition during infectious processes, but molecular mechanisms remain largely unknown. Here, we show that type I interferons (IFNs-I) dysregulate zinc homeostasis in macrophages, which employ metallothionein-mediated zinc intoxication of pathogens as fungicidal response. However, Candida glabrata can escape immune surveillance by sequestering zinc into vacuoles. Interestingly, zinc-loading is inhibited by IFNs-I, because a Janus kinase 1 (JAK1)-dependent suppression of zinc homeostasis affects zinc distribution in macrophages as well as generation of reactive oxygen species (ROS). In addition, systemic fungal infections elicit IFN-I responses that suppress splenic zinc homeostasis, thereby altering macrophage zinc pools that otherwise exert fungicidal actions. Thus, IFN-I signaling inadvertently increases fungal fitness both in vitro and in vivo during fungal infections. Our data reveal an as yet unrecognized role for zinc intoxication in antifungal immunity and suggest that interfering with host zinc homeostasis may offer therapeutic options to treat invasive fungal infections.

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Authors
Riedelberger, M., Penninger, P., Tscherner, M., Hadriga, B., Brunnhofer, C., Jenull, S., Stoiber, A., Bourgeois, C., Petryshyn, A., Glaser, W., Limbeck, A., Lynes, M. A., Schabbauer, G., Weiss, G., & Kuchler, K.
Affiliations
  • Max Perutz Labs (AT)
  • TU Wien (AT)
  • University of Connecticut (US)
  • Medical University of Vienna (AT)
  • Innsbruck Medical University (AT)
Corresponding author
Kuchler, Karl
Venue
iScience
Publisher
Elsevier BV
Published
2020-05
Volume
23
Issue
5
Pages
101121
ISSN
2589-0042 (ISSN-L)
OpenAlex
W3023176160
Cited by
23
References
152
Citations by year
2026: 2 · 2025: 1 · 2024: 7 · 2023: 3 · 2022: 2 · 2021: 6 · 2020: 2
FWCI
0.43
Type
journal article
Language
en
Open access
Locations
  • iScience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • FP7 Health
  • Christian Doppler Forschungsgesellschaft
  • Austrian Science Fund (FWF-I3319-B22)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
  • Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
Keywords
type I interferon, Candida glabrata, macrophages, zinc homeostasis, metallothionein, fungal immune evasion, reactive oxygen species, antifungal immunity, invasive fungal infections

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