Transposon mobilization in the human fungal pathogen Cryptococcus is mutagenic during infection and promotes drug resistance in vitro
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Abstract
Significance: The incidence of infections due to fungal pathogens has dramatically increased in human populations with weakened or suppressed immune systems. Understanding how organisms rapidly adapt during human infection to enhance virulence and evolve drug resistance is important for developing effective treatments. We find that transposon mobilization in the human pathogen Cryptococcus causes genomic mutations in a murine model of infection and promotes resistance to antifungal drugs in vitro. Thermotolerance is a key virulence determinant for pathogenic fungi during the environment-to-host transition, and we demonstrate that a temperature increase is sufficient to trigger transposon mobilization in vitro. The link between temperature stress and transposon-associated mutations may significantly impact adaptation to the host during infection, including the acquisition of drug resistance.
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Transposon-mediated resistance in C. neoformans was mediated by inactivation of Ura3 and Ura5 by movement of the DNA transposon T1 and the retrotransposon TCN12.
“Resistance was mediated by inactivation of the genes encoding the targets of 5-fluoroorotic acid, Ura3 and Ura5, by the movement of the DNA transposon T1 and the retrotransposon TCN12 within the fungal genome38.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [38]
These transposable elements also mediated resistance to rapamycin, FK506 and flucytosine.
“Furthermore, these transposable elements also mediated resistance to rapamycin, FK506 and flucytosine38.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [38]
A 2020 report linked transposons to drug resistance in C. neoformans.
“a 2020 report linked transposons to drug resistance in C. neoformans38.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [38]
Transposon-driven mutagenesis was enhanced in multiple strains at 37 °C compared with 30 °C, suggesting that the body temperature of a mammalian host may amplify this phenomenon.
“transposon-driven mutagenesis was enhanced in multiple strains at 37 °C compared with that at 30 °C, suggesting that the body temperature of a mammalian host may amplify this phenomenon38.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [38]
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Treatment strategies for cryptococcal infection: challenges, advances and future outlook
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- Authors
- Gusa, A., Williams, J. D., Cho, J.-E., Averette, A. F., Sun, S., Shouse, E. M., Heitman, J., Alspaugh, J. A., & Jinks-Robertson, S.
- Affiliations
- Duke Medical Center (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2020-04-17
- Volume
- 117
- Issue
- 18
- Pages
- 9973-9980
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC7211991
- OpenAlex
- W3017284745
- Cited by
- 65
- References
- 56
- Citations by year
- 2026: 14 · 2025: 16 · 2024: 12 · 2023: 7 · 2022: 4 · 2021: 7 · 2020: 5
- FWCI
- 4.12
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | National Institutes of Health (R35GM118077, R21AI133644, 2T32AI052080, 5T32AI052080, R01AI074677)
- HHS | NIH | National Institute of Allergy and Infectious Diseases (RO1 AI50113-15, R37 MERIT AI39115-21)
- Topics
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Keywords
- transposon mobility, Cryptococcus, antifungal resistance, mutagenesis, heat tolerance, temperature stress, host adaptation, virulence, fungal pathogen evolution, mouse infection model, genomic mutations
- MeSH terms
- Animals, Antifungal Agents, Cryptococcus neoformans, Humans, Mycoses, Orotic Acid, Virulence, Mutagenesis, Tacrolimus, Retroelements, Sirolimus, Drug Resistance, Fungal, Mice, Host-Pathogen Interactions
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