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Drug-Resistant Epimutants Exhibit Organ-Specific Stability and Induction during Murine Infections Caused by the Human Fungal Pathogen Mucor circinelloides
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Abstract
The emerging fungal pathogen Mucor circinelloides causes a severe infection, mucormycosis, which leads to considerable morbidity and mortality. Treatment of Mucor infection is challenging because Mucor is inherently resistant to nearly all clinical antifungal agents. An RNAi-dependent and reversible mechanism of antifungal resistance, epimutation, was recently reported for Mucor . Epimutation has not been studied in vivo , and it was unclear whether it would contribute to antifungal resistance observed clinically. We demonstrate that epimutation can both be induced and reverted after in vivo passage through a mouse; rates of both induction and reversion are higher after brain infection than after infection of other organs (liver, spleen, kidneys, or lungs). Elucidating the roles played by epimutation in drug resistance and infection will improve our understanding of Mucor and other fungal pathogens and may have implications for antifungal treatment.
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“In a systemic mouse model of Mucor infection, epimutation-mediated drug resistance can be rapidly induced and reverted over the course of the infection, and thus represents a potential clinically-relevant factor affecting drug resistance103.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [103]
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“In a systemic mouse model of Mucor infection, epimutation-mediated drug resistance can be rapidly induced and reverted over the course of the infection, and thus represents a potential clinically-relevant factor affecting drug resistance103.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [103]
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Metadata
- Authors
- Chang, Z., & Heitman, J.
- Affiliations
- Duke University (US)
- Corresponding author
- Heitman, Joseph
- Venue
- mBio
- Publisher
- American Society for Microbiology
- Published
- 2019-12-24
- Volume
- 10
- Issue
- 6
- ISSN
- 2150-7511 (ISSN-L)
- 2161-2129
- PMC
- PMC6831780
- OpenAlex
- W2985567791
- Cited by
- 202
- References
- 43
- Citations by year
- 2026: 21 · 2025: 16 · 2024: 22 · 2023: 30 · 2022: 42 · 2021: 39 · 2020: 30 · 2019: 2
- FWCI
- 21.85
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- mBio (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- HHS | National Institutes of Health (AI39115-21, AI50113-15, AI104533-05, AI112595-04)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Infectious Diseases › Fungal Infections and Studies
- Keywords
- Mucor circinelloides, mucormycosis, epimutations, antifungal resistance, brain infection, fungal pathogens
- MeSH terms
- Animals, Antifungal Agents, Disease Models, Animal, Humans, Male, Mice, Inbred BALB C, Mucor, Mucormycosis, Tacrolimus, Sirolimus, Drug Resistance, Fungal, RNA Interference, Epigenesis, Genetic, Mice
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