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

Autor: Arastehfar A; Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, 07110, USA., Daneshnia F; Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, 07110, USA.; Institute of Biodiversity and Ecosystem Dynamics (IBED), University of Amsterdam, Amsterdam, 1012 WX, The Netherlands., Cabrera N; Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, 07110, USA., Penalva-Lopez S; Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, 07110, USA., Sarathy J; Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, 07110, USA.; Department of Medical Sciences, Hackensack Meridian School of Medicine, Nutley, NJ, USA., Zimmerman M; Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, 07110, USA.; Department of Medical Sciences, Hackensack Meridian School of Medicine, Nutley, NJ, USA., Shor E; Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, 07110, USA. erika.shor@hmh-cdi.org.; Department of Medical Sciences, Hackensack Meridian School of Medicine, Nutley, NJ, USA. erika.shor@hmh-cdi.org., Perlin DS; Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, 07110, USA. david.perlin@hmh-cdi.org.; Department of Medical Sciences, Hackensack Meridian School of Medicine, Nutley, NJ, USA. david.perlin@hmh-cdi.org.; Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC, 20057, USA. david.perlin@hmh-cdi.org.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Mar 02; Vol. 14 (1), pp. 1183. Date of Electronic Publication: 2023 Mar 02.
DOI: 10.1038/s41467-023-36882-6
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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