5-fluorocytosine resistance is associated with hypermutation and alterations in capsule biosynthesis in Cryptococcus

Billmyre, R. Blake; Clancey, Shelly Applen; Li, Lucy X.; Doering, Tamara L.; Heitman, Joseph

doi:10.1038/s41467-019-13890-z

Cited by 93 publications

(98 citation statements)

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“…The combination of antifungal drugs amphotericin B and 5FC is an effective treatment for cryptococcosis (26). The 5FC resistance in fungi can result from inactivation of FCY1 (a cytosine deaminase), FCY2 (a cytosine permease), or FUR1 (a uracil phosphoribosyltransferase) (27,28). Mutation in UXS1, a capsule biosynthesis enzyme, was additionally identified as causative of 5FC resistance in Cryptococcus deuterogattii (28).…”

Section: Resultsmentioning

confidence: 99%

“…The 5FC resistance in fungi can result from inactivation of FCY1 (a cytosine deaminase), FCY2 (a cytosine permease), or FUR1 (a uracil phosphoribosyltransferase) (27,28). Mutation in UXS1, a capsule biosynthesis enzyme, was additionally identified as causative of 5FC resistance in Cryptococcus deuterogattii (28). In a screening of independent 5FC-resistant XL280 mutants obtained in vitro, we identified T1 and TCN12 insertions in the UXS1 gene (SI Appendix, Fig.…”

Section: Resultsmentioning

confidence: 99%

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Transposon mobilization in the human fungal pathogen Cryptococcus is mutagenic during infection and promotes drug resistance in vitro

Gusa

Williams

Cho

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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When transitioning from the environment, pathogenic microorganisms must adapt rapidly to survive in hostile host conditions. This is especially true for environmental fungi that cause opportunistic infections in immunocompromised patients since these microbes are not well adapted human pathogens. Cryptococcus species are yeastlike fungi that cause lethal infections, especially in HIV-infected patients. Using Cryptococcus deneoformans in a murine model of infection, we examined contributors to drug resistance and demonstrated that transposon mutagenesis drives the development of 5-fluoroorotic acid (5FOA) resistance. Inactivation of target genes URA3 or URA5 primarily reflected the insertion of two transposable elements (TEs): the T1 DNA transposon and the TCN12 retrotransposon. Consistent with in vivo results, increased rates of mutagenesis and resistance to 5FOA and the antifungal drugs rapamycin/FK506 (rap/FK506) and 5-fluorocytosine (5FC) were found when Cryptococcus was incubated at 37° compared to 30° in vitro, a condition that mimics the temperature shift that occurs during the environment-to-host transition. Inactivation of the RNA interference (RNAi) pathway, which suppresses TE movement in many organisms, was not sufficient to elevate TE movement at 30° to the level observed at 37°. We propose that temperature-dependent TE mobilization in Cryptococcus is an important mechanism that enhances microbial adaptation and promotes pathogenesis and drug resistance in the human host.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Transposon mobilization in the human fungal pathogen Cryptococcus is mutagenic during infection and promotes drug resistance in vitro

Gusa

Williams

Cho

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Defects in the mismatch repair protein Msh2 are especially prevalent and typically produce single base pair insertions or deletions in homopolymeric nucleotide runs 9 , 44 . These isolates display higher rates of genomic evolution at the nucleotide level and have the ability to more rapidly adapt to novel stressors in vitro , including the ability to develop de novo resistance to antifungal drugs in vitro 9 , 39 – 42 , 45 . Incompatibilities in the mismatch repair components Mlh1 and Pms1 have also been reported to contribute to hypermutation in S. cerevisiae laboratory strains 46 , 47 .…”

Section: Small-scale Evolution Of Fungal Genomesmentioning

confidence: 99%

Advances in understanding the evolution of fungal genome architecture

2020

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Diversity within the fungal kingdom is evident from the wide range of morphologies fungi display as well as the various ecological roles and industrial purposes they serve. Technological advances, particularly in long-read sequencing, coupled with the increasing efficiency and decreasing costs across sequencing platforms have enabled robust characterization of fungal genomes. These sequencing efforts continue to reveal the rampant diversity in fungi at the genome level. Here, we discuss studies that have furthered our understanding of fungal genetic diversity and genomic evolution. These studies revealed the presence of both small-scale and large-scale genomic changes. In fungi, research has recently focused on many small-scale changes, such as how hypermutation and allelic transmission impact genome evolution as well as how and why a few specific genomic regions are more susceptible to rapid evolution than others. High-throughput sequencing of a diverse set of fungal genomes has also illuminated the frequency, mechanisms, and impacts of large-scale changes, which include chromosome structural variation and changes in chromosome number, such as aneuploidy, polyploidy, and the presence of supernumerary chromosomes. The studies discussed herein have provided great insight into how the architecture of the fungal genome varies within species and across the kingdom and how modern fungi may have evolved from the last common fungal ancestor and might also pave the way for understanding how genomic diversity has evolved in all domains of life.

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“…The combination of antifungal drugs amphotericin B and 5FC is an effective treatment for cryptococcosis (26). 5FC-resistance in fungi can result from inactivation of FCY1 (a cytosine deaminase), FCY2 (a cytosine permease) or FUR1 (a uracil phosphoribosyltransferase) (27,28).…”

Section: Temperature-dependent Te Mobilization In Vitromentioning

confidence: 99%

“…Mutation in UXS1, a capsule biosynthesis enzyme, was additionally identified as causative of 5FC-resistance in C. deuterogattii (28). In a screening of independent 5FC-resistant XL280 mutants obtained in vitro, we identified T1 and TCN12 insertions in the UXS1 gene (SI Appendix, Fig.…”

Section: Temperature-dependent Te Mobilization In Vitromentioning

confidence: 99%

Transposon mobilization in the human fungal pathogenCryptococcus deneoformansis mutagenic during infection and promotes drug resistancein vitro

Gusa

Williams

Cho

et al. 2020

Preprint

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ABSTRACTWhen transitioning from the environment, pathogenic microorganisms must adapt rapidly to survive in hostile host conditions. This is especially true for environmental fungi that cause opportunistic infections in immunocompromised patients since these microbes are not well adapted human pathogens. Cryptococcus species are yeast-like fungi that cause lethal infections, especially in HIV-infected patients. Using Cryptococcus deneoformans in a murine model of infection, we examined contributors to drug resistance and demonstrated that transposon mutagenesis drives the development of 5-fluoroorotic acid (5FOA) resistance. Inactivation of target genes URA3 or URA5 primarily reflected the insertion of two transposable elements (TEs): the T1 DNA transposon and the TCN12 retrotransposon. Consistent with in vivo results, increased rates of mutagenesis and resistance to 5FOA and the antifungal drugs rapamycin/FK506 and 5-fluorocytosine (5FC) were found when Cryptococcus was incubated at 37° compared to 30° in vitro, a condition that mimics the temperature shift that occurs during the environment-to-host transition. Inactivation of the RNAi pathway, which suppresses TE movement in many organisms, was not sufficient to elevate TE movement at 30° to the level observed at 37°. We propose that temperature-dependent TE mobilization in Cryptococcus is an important mechanism that enhances microbial adaptation and promotes pathogenesis and drug resistance in the human host.SIGNIFICANCE STATEMENTThe incidence of infections due to fungal pathogens has dramatically increased in the past few decades with similar increases in human populations with weakened or suppressed immune systems. Understanding the mechanisms by which 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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5-fluorocytosine resistance is associated with hypermutation and alterations in capsule biosynthesis in Cryptococcus

Cited by 93 publications

References 53 publications

Transposon mobilization in the human fungal pathogen Cryptococcus is mutagenic during infection and promotes drug resistance in vitro

Transposon mobilization in the human fungal pathogen Cryptococcus is mutagenic during infection and promotes drug resistance in vitro

Advances in understanding the evolution of fungal genome architecture

Transposon mobilization in the human fungal pathogenCryptococcus deneoformansis mutagenic during infection and promotes drug resistancein vitro

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