Adaptation to Fluconazole via Aneuploidy Enables Cross-Adaptation to Amphotericin B and Flucytosine in Cryptococcus neoformans

Yang, Feng; Gritsenko, Vladimir; Lü, Hui; Zhen, Cheng; Berman, Judith; Jiang, Yuanying

doi:10.1128/spectrum.00723-21

Cited by 26 publications

(34 citation statements)

References 28 publications

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“…Aneuploidy of Chromosome 1 of an isolate (YQJ185) from an HIV-infected patient was tested. Previous studies proved the correlation between the formation of aneuploidy of Chromosome 1 and excessive doses of fluconazole ( Stone et al, 2019 ; Yang F. et al, 2021 ). In addition, we also revealed a point mutation of ERG11 (G484S) ( Rodero et al, 2003 ; Gago et al, 2017 ).…”

Section: Discussionmentioning

confidence: 95%

“…According to previous studies, cryptococcal resistance to fluconazole could be caused by point mutations of ERG11 (G1785C, G1855A, and G1855T) ( Rodero et al, 2003 ; Bosco-Borgeat et al, 2016 ; Gago et al, 2017 ; Selb et al, 2019 ), overexpression of ERG11 , overexpression of AFR1 , and aneuploidy formation. Acquisition of aneuploidies in C. neoformans can mediate increased MIC values to fluconazole and further enable cross-adaptation to other antifungal drugs ( Yang F. et al, 2021 ). Mutations of FCY1 , FCY2 , and FUR1 were the most common 5-fluorocytosine resistance mechanism of cryptococcus ( Vu et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

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Molecular Epidemiology and Antifungal Resistance of Cryptococcus neoformans From Human Immunodeficiency Virus-Negative and Human Immunodeficiency Virus-Positive Patients in Eastern China

Zhou

Zhu

et al. 2022

Front. Microbiol.

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Cryptococcosis is an opportunistic and potentially lethal infection caused by Cryptococcus neoformans and Cryptococcus gattii complex, which affects both immunocompromised and immunocompetent people, and it has become a major public health concern worldwide. In this study, we characterized the molecular epidemiology and antifungal susceptibility of 133 C. neoformans isolates from East China Invasive Fungal Infection Group (ECIFIG), 2017–2020. Isolates were identified to species level by matrix-assisted laser desorption ionization-time of flight mass spectrometry and confirmed by IGS1 sequencing. Whole-genome sequencing (WGS) was conducted on three multidrug-resistant isolates. Among the 133 strains, 61 (45.86%) were isolated from HIV-positive patients and 72 (54.16%) were isolated from HIV-negative patients. In total, C. neoformans var. grubii accounted for 97.74% (130/133), while C. neoformans var. neoformans was rare (2.06%, 3/133). The strains were further classified into nine sequence types (STs) dominated by ST5 (90.23%, 120/133) with low genetic diversity. No association was observed between STs and HIV status. All strains were wild type to voriconazole, while high antifungal minimal inhibitory concentrations (MICs) above the epidemiological cutoff values (ECVs) were observed in C. neoformans strains, and more than half of isolates were non-wild-type to amphotericin B (89.15%, 109/133). Eight isolates were resistant to fluconazole, and eight isolates were non-wild type to 5-fluorocytosine. Furthermore, WGS has verified the novel mutations of FUR1 in 5-fluorocytosine-resistant strains. In one isolate, aneuploidy of chromosome 1 with G484S mutation of ERG11 was observed, inducing high-level resistance (MIC: 32 μg/ml) to fluconazole. In general, our data showed that there was no significant difference between HIV-positive and HIV-negative patients on STs, and we elucidate the resistant mechanisms of C. neoformans from different perspectives. It is important for clinical therapy and drug usage in the future.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Molecular Epidemiology and Antifungal Resistance of Cryptococcus neoformans From Human Immunodeficiency Virus-Negative and Human Immunodeficiency Virus-Positive Patients in Eastern China

Zhou

Zhu

et al. 2022

Front. Microbiol.

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“…Laboratory studies have emphasized the fitness cost incurred by aneuploids when grown in the absence of obvious stresses, although the price of aneuploidy differs depending on the aneuploid chromosomes 47 ; the fitness cost is also more evident in the disomic collection, which must be maintained under G418 selection 1 , than in the induced-meiosis strains, which were selected for aneuploid stability 2 . In aneuploids, extra DNA needs to be synthesized, more mRNAs are transcribed and subsequently translated 49 .…”

Section: Discussionmentioning

confidence: 99%

“…Similar examples of "salvage by aneuploidy'' in Sc include rescue of a myosin gene deficiency 43 , or tunicamycin-induced ER stress that can be countered by chromosome II aneuploidy 44 . In pathogenic fungi such as Candida albicans or Cryptococcus neoformans, specific aneuploidies can increase antifungal resistance or tolerance and can drive cross-adaptation to different antifungal drug classes or to antifungals and chemotherapeutics [45][46][47][48] . The increased survival of aneuploid cells under stress conditions is often dependent on one or more key stress response genes that are encoded on the aneuploid chromosome, thus acting through an increased gene dosage, although the slower growth rates of some aneuploids and other general aneuploidy-associated features might confer benefits as well 14 .…”

Section: Discussionmentioning

confidence: 99%

The natural diversity of the yeast proteome reveals chromosome-wide dosage compensation in aneuploids

Muenzner

Trébulle

Agostini

et al. 2022

Preprint

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Aneuploidy, an imbalance in chromosome copy numbers, causes genetic disorders, and drives cancer progression, drug tolerance, and antimicrobial resistance. While aneuploidy can confer stress resistance, it is not well understood how cells overcome the fitness burden caused by aberrant chromosomal copy numbers. Studies using both systematically generated and natural aneuploid yeasts triggered an intense debate about the role of dosage compensation, concluding that aneuploidy is transmitted to the transcriptome and proteome without significant buffering at the chromosome-wide level, and is, at least in lab strains, associated with significant fitness costs. Conversely, systematic sequencing and phenotyping of large collections of natural isolates revealed that aneuploidy is frequent and has few - if any - fitness costs in nature. To address these discrepant findings at the proteomic level, we developed a platform that yields highly precise proteomic measurements across large numbers of genetically diverse samples, and applied it to natural isolates collected as part of the 1011 genomes project. For 613 of the isolates, we were able to match the proteomes to their corresponding transcriptomes and genomes, subsequently quantifying the effect of aneuploidy on gene expression by comparing 95 aneuploid with 518 euploid strains. We find, as in previous studies, that aneuploid gene dosage is not buffered chromosome-wide at the transcriptome level. Importantly, in the proteome, we detect an attenuation of aneuploidy by about 25% below the aneuploid gene dosage in natural yeast isolates. Furthermore, this chromosome-wide dosage compensation is associated with the ubiquitin-proteasome system (UPS), which is expressed at higher levels and has increased activity across natural aneuploid strains. Thus, through systematic exploration of the species-wide diversity of the yeast proteome, we shed light on a long-standing debate about the biology of aneuploids, revealing that aneuploidy tolerance is mediated through chromosome-wide dosage compensation at the proteome level.

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“…The cross-adaptation may occur because alleles of two adaptor genes are located on the same chromosome [ 20 ]. In fluconazole-resistant Cryptococcus neoformans isolates, those with disomy of chromosome 1 (chr1) are adapted to flucytosine (5FC), and those with disomy of both chr1 and chr4 exhibit cross-tolerance to AMB and 5FC [ 29 ].…”

Section: Antifungal Resistances Mediated By Aneuploidymentioning

confidence: 99%

Genomic Variation-Mediating Fluconazole Resistance in Yeast

Wang

Cai

et al. 2022

Biomolecules

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Fungal infections pose a serious and growing threat to public health. These infections can be treated with antifungal drugs by killing hazardous fungi in the body. However, the resistance can develop over time when fungi are exposed to antifungal drugs by generating genomic variations, including mutation, aneuploidy, and loss of heterozygosity. The variations could reduce the binding affinity of a drug to its target or block the pathway through which drugs exert their activity. Here, we review genomic variation-mediating fluconazole resistance in the yeast Candida, with the hope of highlighting the functional consequences of genomic variations for the antifungal resistance.

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Adaptation to Fluconazole via Aneuploidy Enables Cross-Adaptation to Amphotericin B and Flucytosine in Cryptococcus neoformans

Cited by 26 publications

References 28 publications

Molecular Epidemiology and Antifungal Resistance of Cryptococcus neoformans From Human Immunodeficiency Virus-Negative and Human Immunodeficiency Virus-Positive Patients in Eastern China

Molecular Epidemiology and Antifungal Resistance of Cryptococcus neoformans From Human Immunodeficiency Virus-Negative and Human Immunodeficiency Virus-Positive Patients in Eastern China

The natural diversity of the yeast proteome reveals chromosome-wide dosage compensation in aneuploids

Genomic Variation-Mediating Fluconazole Resistance in Yeast

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