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Macrophage internalization creates a multidrug-tolerant fungal persister reservoir and facilitates the emergence of drug resistance

Author

Listed:
  • Amir Arastehfar

    (Hackensack Meridian Health)

  • Farnaz Daneshnia

    (Hackensack Meridian Health
    University of Amsterdam)

  • Nathaly Cabrera

    (Hackensack Meridian Health)

  • Suyapa Penalva-Lopez

    (Hackensack Meridian Health)

  • Jansy Sarathy

    (Hackensack Meridian Health
    Hackensack Meridian School of Medicine)

  • Matthew Zimmerman

    (Hackensack Meridian Health
    Hackensack Meridian School of Medicine)

  • Erika Shor

    (Hackensack Meridian Health
    Hackensack Meridian School of Medicine)

  • David S. Perlin

    (Hackensack Meridian Health
    Hackensack Meridian School of Medicine
    Georgetown University Lombardi Comprehensive Cancer Center)

Abstract

Candida glabrata is a major fungal pathogen notable for causing recalcitrant infections, rapid emergence of drug-resistant strains, and its ability to survive and proliferate within macrophages. Resembling bacterial persisters, a subset of genetically drug-susceptible C. glabrata cells can survive lethal exposure to the fungicidal echinocandin drugs. Herein, we show that macrophage internalization induces cidal drug tolerance in C. glabrata, expanding the persister reservoir from which echinocandin-resistant mutants emerge. We show that this drug tolerance is associated with non-proliferation and is triggered by macrophage-induced oxidative stress, and that deletion of genes involved in reactive oxygen species detoxification significantly increases the emergence of echinocandin-resistant mutants. Finally, we show that the fungicidal drug amphotericin B can kill intracellular C. glabrata echinocandin persisters, reducing emergence of resistance. Our study supports the hypothesis that intra-macrophage C. glabrata is a reservoir of recalcitrant/drug-resistant infections, and that drug alternating strategies can be developed to eliminate this reservoir.

Suggested Citation

  • Amir Arastehfar & Farnaz Daneshnia & Nathaly Cabrera & Suyapa Penalva-Lopez & Jansy Sarathy & Matthew Zimmerman & Erika Shor & David S. Perlin, 2023. "Macrophage internalization creates a multidrug-tolerant fungal persister reservoir and facilitates the emergence of drug resistance," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36882-6
    DOI: 10.1038/s41467-023-36882-6
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    References listed on IDEAS

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    1. Erica J. Zheng & Ian W. Andrews & Alexandra T. Grote & Abigail L. Manson & Miguel A. Alcantar & Ashlee M. Earl & James J. Collins, 2022. "Modulating the evolutionary trajectory of tolerance using antibiotics with different metabolic dependencies," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    2. Frédéric Peyrusson & Hugo Varet & Tiep Khac Nguyen & Rachel Legendre & Odile Sismeiro & Jean-Yves Coppée & Christiane Wolz & Tanel Tenson & Françoise Van Bambeke, 2020. "Intracellular Staphylococcus aureus persisters upon antibiotic exposure," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    3. Alexander Rosenberg & Iuliana V. Ene & Maayan Bibi & Shiri Zakin & Ella Shtifman Segal & Naomi Ziv & Alon M. Dahan & Arnaldo Lopes Colombo & Richard J. Bennett & Judith Berman, 2018. "Antifungal tolerance is a subpopulation effect distinct from resistance and is associated with persistent candidemia," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    4. Madhumitha Nandakumar & Carl Nathan & Kyu Y. Rhee, 2014. "Isocitrate lyase mediates broad antibiotic tolerance in Mycobacterium tuberculosis," Nature Communications, Nature, vol. 5(1), pages 1-10, September.
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