269 results on '"Christina A, Cuomo"'
Search Results
2. A secondary mechanism of action for triazole antifungals in Aspergillus fumigatus mediated by hmg1
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Jeffrey M. Rybak, Jinhong Xie, Adela Martin-Vicente, Xabier Guruceaga, Harrison I. Thorn, Ashley V. Nywening, Wenbo Ge, Ana C. O. Souza, Amol C. Shetty, Carrie McCracken, Vincent M. Bruno, Josie E. Parker, Steven L. Kelly, Hannah M. Snell, Christina A. Cuomo, P. David Rogers, and Jarrod R. Fortwendel
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Science - Abstract
Abstract Triazole antifungals function as ergosterol biosynthesis inhibitors and are frontline therapy for invasive fungal infections, such as invasive aspergillosis. The primary mechanism of action of triazoles is through the specific inhibition of a cytochrome P450 14-α-sterol demethylase enzyme, Cyp51A/B, resulting in depletion of cellular ergosterol. Here, we uncover a clinically relevant secondary mechanism of action for triazoles within the ergosterol biosynthesis pathway. We provide evidence that triazole-mediated inhibition of Cyp51A/B activity generates sterol intermediate perturbations that are likely decoded by the sterol sensing functions of HMG-CoA reductase and Insulin-Induced Gene orthologs as increased pathway activity. This, in turn, results in negative feedback regulation of HMG-CoA reductase, the rate-limiting step of sterol biosynthesis. We also provide evidence that HMG-CoA reductase sterol sensing domain mutations previously identified as generating resistance in clinical isolates of Aspergillus fumigatus partially disrupt this triazole-induced feedback. Therefore, our data point to a secondary mechanism of action for the triazoles: induction of HMG-CoA reductase negative feedback for downregulation of ergosterol biosynthesis pathway activity. Abrogation of this feedback through acquired mutations in the HMG-CoA reductase sterol sensing domain diminishes triazole antifungal activity against fungal pathogens and underpins HMG-CoA reductase-mediated resistance.
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- 2024
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3. Comparative genomics of the closely related fungal genera Cryptococcus and Kwoniella reveals karyotype dynamics and suggests evolutionary mechanisms of pathogenesis.
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Marco A Coelho, Márcia David-Palma, Terrance Shea, Katharine Bowers, Sage McGinley-Smith, Arman W Mohammad, Andreas Gnirke, Andrey M Yurkov, Minou Nowrousian, Sheng Sun, Christina A Cuomo, and Joseph Heitman
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Biology (General) ,QH301-705.5 - Abstract
In exploring the evolutionary trajectories of both pathogenesis and karyotype dynamics in fungi, we conducted a large-scale comparative genomic analysis spanning the Cryptococcus genus, encompassing both global human fungal pathogens and nonpathogenic species, and related species from the sister genus Kwoniella. Chromosome-level genome assemblies were generated for multiple species, covering virtually all known diversity within these genera. Although Cryptococcus and Kwoniella have comparable genome sizes (about 19.2 and 22.9 Mb) and similar gene content, hinting at preadaptive pathogenic potential, our analysis found evidence of gene gain (via horizontal gene transfer) and gene loss in pathogenic Cryptococcus species, which might represent evolutionary signatures of pathogenic development. Genome analysis also revealed a significant variation in chromosome number and structure between the 2 genera. By combining synteny analysis and experimental centromere validation, we found that most Cryptococcus species have 14 chromosomes, whereas most Kwoniella species have fewer (11, 8, 5, or even as few as 3). Reduced chromosome number in Kwoniella is associated with formation of giant chromosomes (up to 18 Mb) through repeated chromosome fusion events, each marked by a pericentric inversion and centromere loss. While similar chromosome inversion-fusion patterns were observed in all Kwoniella species with fewer than 14 chromosomes, no such pattern was detected in Cryptococcus. Instead, Cryptococcus species with less than 14 chromosomes showed reductions primarily through rearrangements associated with the loss of repeat-rich centromeres. Additionally, Cryptococcus genomes exhibited frequent interchromosomal translocations, including intercentromeric recombination facilitated by transposons shared between centromeres. Overall, our findings advance our understanding of genetic changes possibly associated with pathogenicity in Cryptococcus and provide a foundation to elucidate mechanisms of centromere loss and chromosome fusion driving distinct karyotypes in closely related fungal species, including prominent global human pathogens.
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- 2024
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4. 2024 Acknowledgment of Microbiology Spectrum Reviewing Editors
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Christina A. Cuomo
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Microbiology ,QR1-502 - Published
- 2024
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5. More evidence of Impact Factor Mania
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Patrick D. Schloss and Christina A. Cuomo
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Microbiology ,QR1-502 - Published
- 2023
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6. 2023 Acknowledgment of Microbiology Spectrum Ad Hoc Reviewers
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Christina A. Cuomo
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Microbiology ,QR1-502 - Published
- 2023
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7. The importance of antimicrobial resistance in medical mycology
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Neil A. R. Gow, Carolyn Johnson, Judith Berman, Alix T. Coste, Christina A. Cuomo, David S. Perlin, Tihana Bicanic, Thomas S. Harrison, Nathan Wiederhold, Mike Bromley, Tom Chiller, and Keegan Edgar
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Science - Abstract
The impact of fungal infections on human health has been exacerbated by the rise of antifungal drug resistance. In this Review, the authors outline the problem of antifungal resistance and suggest how this growing threat might be mitigated.
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- 2022
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8. Opening Up Editorial Boards
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Christina A. Cuomo
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editorial board ,open application ,Microbiology ,QR1-502 - Published
- 2023
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9. Inter-species geographic signatures for tracing horizontal gene transfer and long-term persistence of carbapenem resistance
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Rauf Salamzade, Abigail L. Manson, Bruce J. Walker, Thea Brennan-Krohn, Colin J. Worby, Peijun Ma, Lorrie L. He, Terrance P. Shea, James Qu, Sinéad B. Chapman, Whitney Howe, Sarah K. Young, Jenna I. Wurster, Mary L. Delaney, Sanjat Kanjilal, Andrew B. Onderdonk, Cassiana E. Bittencourt, Gabrielle M. Gussin, Diane Kim, Ellena M. Peterson, Mary Jane Ferraro, David C. Hooper, Erica S. Shenoy, Christina A. Cuomo, Lisa A. Cosimi, Susan S. Huang, James E. Kirby, Virginia M. Pierce, Roby P. Bhattacharyya, and Ashlee M. Earl
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Medicine ,Genetics ,QH426-470 - Abstract
Abstract Background Carbapenem-resistant Enterobacterales (CRE) are an urgent global health threat. Inferring the dynamics of local CRE dissemination is currently limited by our inability to confidently trace the spread of resistance determinants to unrelated bacterial hosts. Whole-genome sequence comparison is useful for identifying CRE clonal transmission and outbreaks, but high-frequency horizontal gene transfer (HGT) of carbapenem resistance genes and subsequent genome rearrangement complicate tracing the local persistence and mobilization of these genes across organisms. Methods To overcome this limitation, we developed a new approach to identify recent HGT of large, near-identical plasmid segments across species boundaries, which also allowed us to overcome technical challenges with genome assembly. We applied this to complete and near-complete genome assemblies to examine the local spread of CRE in a systematic, prospective collection of all CRE, as well as time- and species-matched carbapenem-susceptible Enterobacterales, isolated from patients from four US hospitals over nearly 5 years. Results Our CRE collection comprised a diverse range of species, lineages, and carbapenem resistance mechanisms, many of which were encoded on a variety of promiscuous plasmid types. We found and quantified rearrangement, persistence, and repeated transfer of plasmid segments, including those harboring carbapenemases, between organisms over multiple years. Some plasmid segments were found to be strongly associated with specific locales, thus representing geographic signatures that make it possible to trace recent and localized HGT events. Functional analysis of these signatures revealed genes commonly found in plasmids of nosocomial pathogens, such as functions required for plasmid retention and spread, as well survival against a variety of antibiotic and antiseptics common to the hospital environment. Conclusions Collectively, the framework we developed provides a clearer, high-resolution picture of the epidemiology of antibiotic resistance importation, spread, and persistence in patients and healthcare networks.
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- 2022
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10. Diversity, multifaceted evolution, and facultative saprotrophism in the European Batrachochytrium salamandrivorans epidemic
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Moira Kelly, Frank Pasmans, Jose F. Muñoz, Terrance P. Shea, Salvador Carranza, Christina A. Cuomo, and An Martel
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Science - Abstract
B. salamandrivorans (Bsal) is a fungus of amphibians that has been implicated in the collapse of salamander populations. Here, the authors sequence nine Bsal isolates from six epidemic sites and describe variation in genome size and composition.
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- 2021
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11. 2022 Acknowledgment of Microbiology Spectrum Ad Hoc Reviewers
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Christina A. Cuomo
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Microbiology ,QR1-502 - Published
- 2022
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12. Genomic Variation across a Clinical Cryptococcus Population Linked to Disease Outcome
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Poppy Sephton-Clark, Jennifer L. Tenor, Dena L. Toffaletti, Nancy Meyers, Charles Giamberardino, Síle F. Molloy, Julia R. Palmucci, Adrienne Chan, Tarsizio Chikaonda, Robert Heyderman, Mina Hosseinipour, Newton Kalata, Cecilia Kanyama, Christopher Kukacha, Duncan Lupiya, Henry C. Mwandumba, Thomas Harrison, Tihana Bicanic, John R. Perfect, and Christina A. Cuomo
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Cryptococcus ,GWAS ,aneuploidy ,genome sequencing ,sugar transporters ,virulence ,Microbiology ,QR1-502 - Abstract
ABSTRACT Cryptococcus neoformans is the causative agent of cryptococcosis, a disease with poor patient outcomes that accounts for approximately 180,000 deaths each year. Patient outcomes may be impacted by the underlying genetics of the infecting isolate; however, our current understanding of how genetic diversity contributes to clinical outcomes is limited. Here, we leverage clinical, in vitro growth and genomic data for 284 C. neoformans isolates to identify clinically relevant pathogen variants within a population of clinical isolates from patients with human immunodeficiency virus (HIV)-associated cryptococcosis in Malawi. Through a genome-wide association study (GWAS) approach, we identify variants associated with the fungal burden and the growth rate. We also find both small and large-scale variation, including aneuploidy, associated with alternate growth phenotypes, which may impact the course of infection. Genes impacted by these variants are involved in transcriptional regulation, signal transduction, glycosylation, sugar transport, and glycolysis. We show that growth within the central nervous system (CNS) is reliant upon glycolysis in an animal model and likely impacts patient mortality, as the CNS yeast burden likely modulates patient outcome. Additionally, we find that genes with roles in sugar transport are enriched in regions under selection in specific lineages of this clinical population. Further, we demonstrate that genomic variants in two genes identified by GWAS impact virulence in animal models. Our approach identifies links between the genetic variation in C. neoformans and clinically relevant phenotypes and animal model pathogenesis, thereby shedding light on specific survival mechanisms within the CNS and identifying the pathways involved in yeast persistence. IMPORTANCE Infection outcomes for cryptococcosis, most commonly caused by C. neoformans, are influenced by host immune responses as well as by host and pathogen genetics. Infecting yeast isolates are genetically diverse; however, we lack a deep understanding of how this diversity impacts patient outcomes. To better understand both clinical isolate diversity and how diversity contributes to infection outcomes, we utilize a large collection of clinical C. neoformans samples that were isolated from patients enrolled in a clinical trial across 3 hospitals in Malawi. By combining whole-genome sequence data, clinical data, and in vitro growth data, we utilize genome-wide association approaches to examine the genetic basis of virulence. Genes with significant associations display virulence attributes in both murine and rabbit models, demonstrating that our approach can identify potential links between genetic variants and patho-biologically significant phenotypes.
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- 2022
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13. Editorial: New threats of antibiotic-resistant bacteria and fungi
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Shifeng Huang, Yi-Wei Tang, Christina A. Cuomo, Hui Wang, and Xiaojiong Jia
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antibiotic resistance (ABR) ,multidrug resistance ,CRE ,bacterial resistance ,fungal resistance ,Medicine (General) ,R5-920 - Published
- 2022
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14. First Patient-to-Patient Intrahospital Transmission of Clade I Candida auris in France Revealed after a Two-Month Incubation Period
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Alexandre Alanio, Hannah Marie Snell, Camille Cordier, Marie Desnos-Olivier, Sarah Dellière, Nesrine Aissaoui, Aude Sturny-Leclère, Elodie Da Silva, Cyril Eblé, Martine Rouveau, Micheline Thégat, Widad Zebiche, Matthieu Lafaurie, Blandine Denis, Sophie Touratier, Mourad Benyamina, Emmanuel Dudoignon, Samia Hamane, Christina A. Cuomo, and François Dépret
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Candida auris ,burn ,ICU ,qPCR ,outbreak ,transmission ,Microbiology ,QR1-502 - Abstract
ABSTRACT Candida auris is a recently described emerging pathogen in hospital settings. Five genetic clades have been delineated, with each clade being isolated from specific geographic regions. We here describe the first transmission between 2 patients (P0 and P1) of a clade I C. auris strain imported into our burn intensive care unit from the Middle East. The strains have been investigated with whole-genome sequencing, which validated the high similarity of the genomes between isolates from P0 and P1. We repeatedly screened the two patients and contact patients (i.e., other patients present in the same hospital ward at the time of the first positive sample from P0 or P1; n = 49; 268 tests) with fungal culture and a C. auris-specific quantitative PCR assay to assess transmission patterns. We observed that P1 developed C. auris colonization between 41 and 61 days after potential exposure to P0 contamination, despite three negative screening tests as recommended by our national authorities. This study illustrates that transmission of C. auris between patients can lead to long-term incubation times before the detection of colonization. The recommended screening strategy may not be optimal and should be improved in the light of our findings. IMPORTANCE While large outbreaks of C. auris in hospital settings have been described, few clear cases of direct transmission have been documented. We here investigated the transmission of C. auris clade I between two patients with a 41- to 61-day delay between exposure and the development of colonization. This may lead to changes in the recommendations concerning treatment of C. auris cases, as an incubation period of this length is one of the first to be reported.
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- 2022
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15. Obligate sexual reproduction of a homothallic fungus closely related to the Cryptococcus pathogenic species complex
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Andrew Ryan Passer, Shelly Applen Clancey, Terrance Shea, Márcia David-Palma, Anna Floyd Averette, Teun Boekhout, Betina M Porcel, Minou Nowrousian, Christina A Cuomo, Sheng Sun, Joseph Heitman, and Marco A Coelho
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sexual reproduction ,meiosis ,cryptococcus ,Cryptococcus depauperatus ,homothallism in fungi ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Sexual reproduction is a ubiquitous, ancient eukaryotic trait. While most sexual organisms have to find a mating partner, species as diverse as animals, plants, and fungi have evolved the ability to reproduce sexually without requiring another individual. Here, we uncovered the mechanism of self-compatibility (homothallism) in Cryptococcus depauperatus, a fungal species closely related to the human fungal pathogens Cryptococcus neoformans and Cryptococcus gattii. In contrast to C. neoformans or C. gattii, which grow as a yeast asexually, and produce hyphae, basidia, and infectious spores during sexual reproduction, C. depauperatus grows exclusively as hyphae decorated with basidia and abundant spores, thus continuously engaged in sexual reproduction. Through comparative genomics and analyses of mutants defective in key mating/meiosis genes, we demonstrate the C. depauperatus sexual cycle involves meiosis and that self-compatibility is orchestrated by an unlinked mating receptor (Ste3a) and pheromone ligand (MFα) pair derived from opposite mating types of a heterothallic (self-sterile) ancestor. We identified a putative mating-type (MAT) determining region containing genes phylogenetically aligned with MATa alleles of other species, and a few MATα gene alleles scattered throughout the genome, but no homologs of the mating-type homeodomain genes SXI1 (HD1) and SXI2 (HD2). Comparative analyses suggest a dramatic remodeling of the MAT locus possibly owing to reduced selective constraints to maintain mating-type genes in tight linkage, associated with a transition to self-fertility. Our findings support C. depauperatus as an obligately sexual, homothallic fungus and provide insight into repeated transitions between sexual reproduction modes that have occurred throughout the fungal kingdom.
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- 2022
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16. Best practices on the differential expression analysis of multi-species RNA-seq
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Matthew Chung, Vincent M. Bruno, David A. Rasko, Christina A. Cuomo, José F. Muñoz, Jonathan Livny, Amol C. Shetty, Anup Mahurkar, and Julie C. Dunning Hotopp
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RNA-Seq ,Transcriptomics ,Best practices ,Differential gene expression ,Biology (General) ,QH301-705.5 ,Genetics ,QH426-470 - Abstract
Abstract Advances in transcriptome sequencing allow for simultaneous interrogation of differentially expressed genes from multiple species originating from a single RNA sample, termed dual or multi-species transcriptomics. Compared to single-species differential expression analysis, the design of multi-species differential expression experiments must account for the relative abundances of each organism of interest within the sample, often requiring enrichment methods and yielding differences in total read counts across samples. The analysis of multi-species transcriptomics datasets requires modifications to the alignment, quantification, and downstream analysis steps compared to the single-species analysis pipelines. We describe best practices for multi-species transcriptomics and differential gene expression.
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- 2021
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17. Genomic insights into the host specific adaptation of the Pneumocystis genus
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Ousmane H. Cissé, Liang Ma, John P. Dekker, Pavel P. Khil, Jung-Ho Youn, Jason M. Brenchley, Robert Blair, Bapi Pahar, Magali Chabé, Koen K. A. Van Rompay, Rebekah Keesler, Antti Sukura, Vanessa Hirsch, Geetha Kutty, Yueqin Liu, Li Peng, Jie Chen, Jun Song, Christiane Weissenbacher-Lang, Jie Xu, Nathan S. Upham, Jason E. Stajich, Christina A. Cuomo, Melanie T. Cushion, and Joseph A. Kovacs
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Biology (General) ,QH301-705.5 - Abstract
Cissé, Ma et al. utilize genomic data from Pneumocystis species infecting macaques, rabbit, dogs and rats to investigate the molecular basis of host specificity in Pneumocystis. Their analyses provide insight to the specific adaptations enabling the infection of humans by P. jirovecii.
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- 2021
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18. An oxindole efflux inhibitor potentiates azoles and impairs virulence in the fungal pathogen Candida auris
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Kali R. Iyer, Kaddy Camara, Martin Daniel-Ivad, Richard Trilles, Sheila M. Pimentel-Elardo, Jen L. Fossen, Karen Marchillo, Zhongle Liu, Shakti Singh, José F. Muñoz, Sang Hu Kim, John A. Porco, Christina A. Cuomo, Noelle S. Williams, Ashraf S. Ibrahim, John E. Edwards, David R. Andes, Justin R. Nodwell, Lauren E. Brown, Luke Whitesell, Nicole Robbins, and Leah E. Cowen
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Science - Abstract
The fungal pathogen Candida auris is resistant to multiple drugs including the common antifungal fluconazole. Here, Iyer et al. identify a compound that potentiates fluconazole activity against C. auris in vitro and in vivo by inhibiting a major efflux pump and thus increasing intracellular fluconazole accumulation.
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- 2020
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19. Chromosome-Level Genome Assembly of a Human Fungal Pathogen Reveals Synteny among Geographically Distinct Species
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Mark Voorhies, Shirli Cohen, Terrance P. Shea, Semar Petrus, José F. Muñoz, Shane Poplawski, William E. Goldman, Todd P. Michael, Christina A. Cuomo, Anita Sil, and Sinem Beyhan
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Histoplasma capsulatum ,genome assembly ,long-read sequencing ,Microbiology ,QR1-502 - Abstract
ABSTRACT Histoplasma capsulatum, a dimorphic fungal pathogen, is the most common cause of fungal respiratory infections in immunocompetent hosts. Histoplasma is endemic in the Ohio and Mississippi River Valleys in the United States and is also distributed worldwide. Previous studies have revealed at least eight clades, each specific to a geographic location: North American classes 1 and 2 (NAm 1 and NAm 2), Latin American groups A and B (LAm A and LAm B), Eurasian, Netherlands, Australian and African, and an additional distinct lineage (H81) comprised of Panamanian isolates. Previously assembled Histoplasma genomes are highly fragmented, with the highly repetitive G217B (NAm 2) strain, which has been used for most whole-genome-scale transcriptome studies, assembled into over 250 contigs. In this study, we set out to fully assemble the repeat regions and characterize the large-scale genome architecture of Histoplasma species. We resequenced five Histoplasma strains (WU24 [NAm 1], G217B [NAm 2], H88 [African], G186AR [Panama], and G184AR [Panama]) using Oxford Nanopore Technologies long-read sequencing technology. Here, we report chromosomal-level assemblies for all five strains, which exhibit extensive synteny among the geographically distant Histoplasma isolates. The new assemblies revealed that RYP2, a major regulator of morphology and virulence, is duplicated in G186AR. In addition, we mapped previously generated transcriptome data sets onto the newly assembled chromosomes. Our analyses revealed that the expression of transposons and transposon-embedded genes are upregulated in yeast phase compared to mycelial phase in the G217B and H88 strains. This study provides an important resource for fungal researchers and further highlights the importance of chromosomal-level assemblies in analyzing high-throughput data sets. IMPORTANCE Histoplasma species are dimorphic fungi causing significant morbidity and mortality worldwide. These fungi grow as mold in the soil and as budding yeast within the human host. Histoplasma can be isolated from soil in diverse regions, including North America, South America, Africa, and Europe. Phylogenetically distinct species of Histoplasma have been isolated and sequenced. However, for the commonly used strains, genome assemblies have been fragmented, leading to underutilization of genome-scale data. This study provides chromosome-level assemblies of the commonly used Histoplasma strains using long-read sequencing technology. Comparative analysis of these genomes shows largely conserved gene order within the chromosomes. Mapping existing transcriptome data on these new assemblies reveals clustering of transcriptionally coregulated genes. The results of this study highlight the importance of obtaining chromosome-level assemblies in understanding the biology of human fungal pathogens.
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- 2022
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20. Gene Expression of Diverse Cryptococcus Isolates during Infection of the Human Central Nervous System
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Chen-Hsin Yu, Poppy Sephton-Clark, Jennifer L. Tenor, Dena L. Toffaletti, Charles Giamberardino, Miriam Haverkamp, Christina A. Cuomo, and John R. Perfect
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Cryptococcus neoformans ,meningitis ,genes ,transcription ,human disease ,Microbiology ,QR1-502 - Abstract
ABSTRACT Cryptococcus neoformans is a major human central nervous system (CNS) fungal pathogen causing considerable morbidity and mortality. In this study, we provide the widest view to date of the yeast transcriptome directly from the human subarachnoid space and within cerebrospinal fluid (CSF). We captured yeast transcriptomes from C. neoformans of various genotypes in 31 patients with cryptococcal meningoencephalitis as well as several Cryptococcus gattii infections. Using transcriptome sequencing (RNA-seq) analyses, we compared the in vivo yeast transcriptomes to those from other environmental conditions, including in vitro growth on nutritious media or artificial CSF as well as samples collected from rabbit CSF at two time points. We ranked gene expressions and identified genetic patterns and networks across these diverse isolates that reveal an emphasis on carbon metabolism, fatty acid synthesis, transport, cell wall structure, and stress-related gene functions during growth in CSF. The most highly expressed yeast genes in human CSF included those known to be associated with survival or virulence and highlighted several genes encoding hypothetical proteins. From that group, a gene encoding the CMP1 putative glycoprotein (CNAG_06000) was selected for functional studies. This gene was found to impact the virulence of Cryptococcus in both mice and the CNS rabbit model, in agreement with a recent study also showing a role in virulence. This transcriptional analysis strategy provides a view of regulated yeast genes across genetic backgrounds important for human CNS infection and a relevant resource for the study of cryptococcal genes, pathways, and networks linked to human disease. IMPORTANCE Cryptococcus is the most common fungus causing high-morbidity and -mortality human meningitis. This encapsulated yeast has a unique propensity to travel to the central nervous system to produce disease. In this study, we captured transcriptomes of yeasts directly out of the human cerebrospinal fluid, the most concerning site of infection. By comparing the RNA transcript levels with other conditions, we gained insights into how the basic machinery involved in metabolism and environmental responses enable this fungus to cause disease at this body site. This approach was applied to clinical isolates with diverse genotypes to begin to establish a genotype-agnostic understanding of how the yeast responds to stress. Based on these results, future studies can focus on how these genes and their pathways and networks can be targeted with new therapeutics and possibly classify yeasts with bad infection outcomes.
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- 2021
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21. The Relaunch of Microbiology Spectrum
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Christina A. Cuomo
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Microbiology ,QR1-502 - Published
- 2021
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22. Whole-genome sequencing of multiple isolates of Puccinia triticina reveals asexual lineages evolving by recurrent mutations
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John P Fellers, Sharadha Sakthikumar, Fei He, Katie McRell, Guus Bakkeren, Christina A Cuomo, and James A Kolmer
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Genetics ,QH426-470 - Abstract
AbstractThe wheat leaf rust fungus, Puccinia triticinaP. triticinaP. triticinaP. triticinaAegilops speltoidesAe. cylindrica
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- 2021
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23. Coordinated host-pathogen transcriptional dynamics revealed using sorted subpopulations and single macrophages infected with Candida albicans
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José F. Muñoz, Toni Delorey, Christopher B. Ford, Bi Yu Li, Dawn A. Thompson, Reeta P. Rao, and Christina A. Cuomo
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Science - Abstract
The outcomes of the interactions between individual host cells and pathogens are heterogeneous. Here, the authors assess transcriptional variability in both host and pathogen during infection of macrophages with the fungus Candida albicans, using sorted subpopulations and single macrophages.
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- 2019
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24. Genomic insights into multidrug-resistance, mating and virulence in Candida auris and related emerging species
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José F. Muñoz, Lalitha Gade, Nancy A. Chow, Vladimir N. Loparev, Phalasy Juieng, Elizabeth L. Berkow, Rhys A. Farrer, Anastasia P. Litvintseva, and Christina A. Cuomo
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Science - Abstract
Candida auris is an emergent fungal pathogen that is resistant to multiple antifungals. Here, Muñoz et al. analyse genomic sequences for isolates from each of the four major C. auris clades and for three related species, and identify genetic features associated with virulence, antifungal resistance and mating.
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- 2018
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25. Multimodal analysis of the <scp>COVID</scp> ‐19‐associated mucormycosis outbreak in Delhi, India indicates the convergence of clinical and environmental risk factors
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Anuradha Chowdhary, Nitesh Gupta, Sebastian Wurster, Raj Kumar, Jason T. Mohabir, Shashidhar Tatavarthy, Vikas Mittal, Preeti Rani, Purabi Barman, Neelam Sachdeva, Ashutosh Singh, Brijesh Sharma, Ying Jiang, Christina A. Cuomo, and Dimitrios P. Kontoyiannis
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Infectious Diseases ,Dermatology ,General Medicine - Published
- 2023
26. Genome-Wide Analysis of Experimentally Evolved Candida auris Reveals Multiple Novel Mechanisms of Multidrug Resistance
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Hans Carolus, Siebe Pierson, José F. Muñoz, Ana Subotić, Rita B. Cruz, Christina A. Cuomo, and Patrick Van Dijck
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Microbiology ,QR1-502 - Abstract
Candida aurisC. auris
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- 2021
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27. Amoeba Predation of Cryptococcus neoformans Results in Pleiotropic Changes to Traits Associated with Virulence
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Man Shun Fu, Livia C. Liporagi-Lopes, Samuel R. dos Santos, Jennifer L. Tenor, John R. Perfect, Christina A. Cuomo, and Arturo Casadevall
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Microbiology ,QR1-502 - Abstract
Cryptococcus neoformansC. neoformans
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- 2021
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28. Editorial: Genomic Characterization of Emerging Human Fungal Pathogens
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Bridget M. Barker, Christina A. Cuomo, and Nelesh P. Govender
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Candida ,black fungi ,Aspergillus ,Mucoralesi ,Coccidioides ,Paracoccidioides ,Genetics ,QH426-470 - Published
- 2021
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29. Mutations in TAC1B: a Novel Genetic Determinant of Clinical Fluconazole Resistance in Candida auris
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Jeffrey M. Rybak, José F. Muñoz, Katherine S. Barker, Josie E. Parker, Brooke D. Esquivel, Elizabeth L. Berkow, Shawn R. Lockhart, Lalitha Gade, Glen E. Palmer, Theodore C. White, Steve L. Kelly, Christina A. Cuomo, and P. David Rogers
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Candida ,triazole ,resistance ,efflux ,CRISPR ,WGS ,Microbiology ,QR1-502 - Abstract
ABSTRACT Candida auris has emerged as a multidrug-resistant pathogen of great clinical concern. Approximately 90% of clinical C. auris isolates are resistant to fluconazole, the most commonly prescribed antifungal agent, and yet it remains unknown what mechanisms underpin this fluconazole resistance. To identify novel mechanisms contributing to fluconazole resistance in C. auris, fluconazole-susceptible C. auris clinical isolate AR0387 was passaged in media supplemented with fluconazole to generate derivative strains which had acquired increased fluconazole resistance in vitro. Comparative analyses of comprehensive sterol profiles, [3H]fluconazole uptake, sequencing of C. auris genes homologous to genes known to contribute to fluconazole resistance in other species of Candida, and relative expression levels of C. auris ERG11, CDR1, and MDR1 were performed. All fluconazole-evolved derivative strains were found to have acquired mutations in the zinc-cluster transcription factor-encoding gene TAC1B and to show a corresponding increase in CDR1 expression relative to the parental clinical isolate, AR0387. Mutations in TAC1B were also identified in a set of 304 globally distributed C. auris clinical isolates representing each of the four major clades. Introduction of the most common mutation found among fluconazole-resistant clinical isolates of C. auris into fluconazole-susceptible isolate AR0387 was confirmed to increase fluconazole resistance by 8-fold, and the correction of the same mutation in a fluconazole-resistant isolate, AR0390, decreased fluconazole MIC by 16-fold. Taken together, these data demonstrate that C. auris can rapidly acquire resistance to fluconazole in vitro and that mutations in TAC1B significantly contribute to clinical fluconazole resistance. IMPORTANCE Candida auris is an emerging multidrug-resistant pathogen of global concern, known to be responsible for outbreaks on six continents and to be commonly resistant to antifungals. While the vast majority of clinical C. auris isolates are highly resistant to fluconazole, an essential part of the available antifungal arsenal, very little is known about the mechanisms contributing to resistance. In this work, we show that mutations in the transcription factor TAC1B significantly contribute to clinical fluconazole resistance. These studies demonstrated that mutations in TAC1B can arise rapidly in vitro upon exposure to fluconazole and that a multitude of resistance-associated TAC1B mutations are present among the majority of fluconazole-resistant C. auris isolates from a global collection and appear specific to a subset of lineages or clades. Thus, identification of this novel genetic determinant of resistance significantly adds to the understanding of clinical antifungal resistance in C. auris.
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- 2020
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30. Threats Posed by the Fungal Kingdom to Humans, Wildlife, and Agriculture
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Matthew C. Fisher, Sarah J. Gurr, Christina A. Cuomo, David S. Blehert, Hailing Jin, Eva H. Stukenbrock, Jason E. Stajich, Regine Kahmann, Charles Boone, David W. Denning, Neil A. R. Gow, Bruce S. Klein, James W. Kronstad, Donald C. Sheppard, John W. Taylor, Gerard D. Wright, Joseph Heitman, Arturo Casadevall, and Leah E. Cowen
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antifungal resistance ,biodiversity ,food security ,fungal pathogens ,global health ,medical mycology ,Microbiology ,QR1-502 - Abstract
ABSTRACT The fungal kingdom includes at least 6 million eukaryotic species and is remarkable with respect to its profound impact on global health, biodiversity, ecology, agriculture, manufacturing, and biomedical research. Approximately 625 fungal species have been reported to infect vertebrates, 200 of which can be human associated, either as commensals and members of our microbiome or as pathogens that cause infectious diseases. These organisms pose a growing threat to human health with the global increase in the incidence of invasive fungal infections, prevalence of fungal allergy, and the evolution of fungal pathogens resistant to some or all current classes of antifungals. More broadly, there has been an unprecedented and worldwide emergence of fungal pathogens affecting animal and plant biodiversity. Approximately 8,000 species of fungi and Oomycetes are associated with plant disease. Indeed, across agriculture, such fungal diseases of plants include new devastating epidemics of trees and jeopardize food security worldwide by causing epidemics in staple and commodity crops that feed billions. Further, ingestion of mycotoxins contributes to ill health and causes cancer. Coordinated international research efforts, enhanced technology translation, and greater policy outreach by scientists are needed to more fully understand the biology and drivers that underlie the emergence of fungal diseases and to mitigate against their impacts. Here, we focus on poignant examples of emerging fungal threats in each of three areas: human health, wildlife biodiversity, and food security.
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- 2020
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31. Understanding the Emergence of Multidrug-Resistant Candida: Using Whole-Genome Sequencing to Describe the Population Structure of Candida haemulonii Species Complex
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Lalitha Gade, Jose F. Muñoz, Mili Sheth, Darlene Wagner, Elizabeth L. Berkow, Kaitlin Forsberg, Brendan R. Jackson, Ruben Ramos-Castro, Patricia Escandón, Maribel Dolande, Ronen Ben-Ami, Andrés Espinosa-Bode, Diego H. Caceres, Shawn R. Lockhart, Christina A. Cuomo, and Anastasia P. Litvintseva
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Candida ,haemulonii ,duobushaemulonii ,pseudohaemulonii ,vulturna ,Genetics ,QH426-470 - Abstract
The recent emergence of a multidrug-resistant yeast, Candida auris, has drawn attention to the closely related species from the Candida haemulonii complex that include C. haemulonii, Candida duobushaemulonii, Candida pseudohaemulonii, and the recently identified Candida vulturna. Here, we used antifungal susceptibility testing and whole-genome sequencing (WGS) to investigate drug resistance and genetic diversity among isolates of C. haemulonii complex from different geographic areas in order to assess population structure and the extent of clonality among strains. Although most isolates of all four species were genetically distinct, we detected evidence of the in-hospital transmission of C. haemulonii and C. duobushaemulonii in one hospital in Panama, indicating that these species are also capable of causing outbreaks in healthcare settings. We also detected evidence of the rising azole resistance among isolates of C. haemulonii and C. duobushaemulonii in Colombia, Panama, and Venezuela linked to substitutions in ERG11 gene as well as amplification of this gene in C. haemulonii in isolates in Colombia suggesting the presence of evolutionary pressure for developing azole resistance in this region. Our results demonstrate that these species need to be monitored as possible causes of outbreaks of invasive infection.
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- 2020
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32. Diversity and Complexity of the Large Surface Protein Family in the Compacted Genomes of Multiple Pneumocystis Species
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Liang Ma, Zehua Chen, Da Wei Huang, Ousmane H. Cissé, Jamie L. Rothenburger, Alice Latinne, Lisa Bishop, Robert Blair, Jason M. Brenchley, Magali Chabé, Xilong Deng, Vanessa Hirsch, Rebekah Keesler, Geetha Kutty, Yueqin Liu, Daniel Margolis, Serge Morand, Bapi Pahar, Li Peng, Koen K. A. Van Rompay, Xiaohong Song, Jun Song, Antti Sukura, Sabrina Thapar, Honghui Wang, Christiane Weissenbacher-Lang, Jie Xu, Chao-Hung Lee, Claire Jardine, Richard A. Lempicki, Melanie T. Cushion, Christina A. Cuomo, and Joseph A. Kovacs
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classification ,conserved domains ,major surface glycoprotein ,phylogenetic analysis ,Pneumocystis ,Microbiology ,QR1-502 - Abstract
ABSTRACT Pneumocystis, a major opportunistic pathogen in patients with a broad range of immunodeficiencies, contains abundant surface proteins encoded by a multicopy gene family, termed the major surface glycoprotein (Msg) gene superfamily. This superfamily has been identified in all Pneumocystis species characterized to date, highlighting its important role in Pneumocystis biology. In this report, through a comprehensive and in-depth characterization of 459 msg genes from 7 Pneumocystis species, we demonstrate, for the first time, the phylogeny and evolution of conserved domains in Msg proteins and provide a detailed description of the classification, unique characteristics, and phylogenetic relatedness of five Msg families. We further describe, for the first time, the relative expression levels of individual msg families in two rodent Pneumocystis species, the substantial variability of the msg repertoires in P. carinii from laboratory and wild rats, and the distinct features of the expression site for the classic msg genes in Pneumocystis from 8 mammalian host species. Our analysis suggests multiple functions for this superfamily rather than just conferring antigenic variation to allow immune evasion as previously believed. This study provides a rich source of information that lays the foundation for the continued experimental exploration of the functions of the Msg superfamily in Pneumocystis biology. IMPORTANCE Pneumocystis continues to be a major cause of disease in humans with immunodeficiency, especially those with HIV/AIDS and organ transplants, and is being seen with increasing frequency worldwide in patients treated with immunodepleting monoclonal antibodies. Annual health care associated with Pneumocystis pneumonia costs ∼$475 million dollars in the United States alone. In addition to causing overt disease in immunodeficient individuals, Pneumocystis can cause subclinical infection or colonization in healthy individuals, which may play an important role in species preservation and disease transmission. Our work sheds new light on the diversity and complexity of the msg superfamily and strongly suggests that the versatility of this superfamily reflects multiple functions, including antigenic variation to allow immune evasion and optimal adaptation to host environmental conditions to promote efficient infection and transmission. These findings are essential to consider in developing new diagnostic and therapeutic strategies.
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- 2020
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33. Tracing the Evolutionary History and Global Expansion of Candida auris Using Population Genomic Analyses
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Nancy A. Chow, José F. Muñoz, Lalitha Gade, Elizabeth L. Berkow, Xiao Li, Rory M. Welsh, Kaitlin Forsberg, Shawn R. Lockhart, Rodney Adam, Alexandre Alanio, Ana Alastruey-Izquierdo, Sahar Althawadi, Ana Belén Araúz, Ronen Ben-Ami, Amrita Bharat, Belinda Calvo, Marie Desnos-Ollivier, Patricia Escandón, Dianne Gardam, Revathi Gunturu, Christopher H. Heath, Oliver Kurzai, Ronny Martin, Anastasia P. Litvintseva, and Christina A. Cuomo
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Candida auris ,antifungal resistance ,emerging species ,genome analysis ,population genetics ,Microbiology ,QR1-502 - Abstract
ABSTRACT Candida auris has emerged globally as a multidrug-resistant yeast that can spread via nosocomial transmission. An initial phylogenetic study of isolates from Japan, India, Pakistan, South Africa, and Venezuela revealed four populations (clades I, II, III, and IV) corresponding to these geographic regions. Since this description, C. auris has been reported in more than 30 additional countries. To trace this global emergence, we compared the genomes of 304 C. auris isolates from 19 countries on six continents. We found that four predominant clades persist across wide geographic locations. We observed phylogeographic mixing in most clades; clade IV, with isolates mainly from South America, demonstrated the strongest phylogeographic substructure. C. auris isolates from two clades with opposite mating types were detected contemporaneously in a single health care facility in Kenya. We estimated a Bayesian molecular clock phylogeny and dated the origin of each clade within the last 360 years; outbreak-causing clusters from clades I, III, and IV originated 36 to 38 years ago. We observed high rates of antifungal resistance in clade I, including four isolates resistant to all three major classes of antifungals. Mutations that contribute to resistance varied between the clades, with Y132F in ERG11 as the most widespread mutation associated with azole resistance and S639P in FKS1 for echinocandin resistance. Copy number variants in ERG11 predominantly appeared in clade III and were associated with fluconazole resistance. These results provide a global context for the phylogeography, population structure, and mechanisms associated with antifungal resistance in C. auris. IMPORTANCE In less than a decade, C. auris has emerged in health care settings worldwide; this species is capable of colonizing skin and causing outbreaks of invasive candidiasis. In contrast to other Candida species, C. auris is unique in its ability to spread via nosocomial transmission and its high rates of drug resistance. As part of the public health response, whole-genome sequencing has played a major role in characterizing transmission dynamics and detecting new C. auris introductions. Through a global collaboration, we assessed genome evolution of isolates of C. auris from 19 countries. Here, we described estimated timing of the expansion of each C. auris clade and of fluconazole resistance, characterized discrete phylogeographic population structure of each clade, and compared genome data to sensitivity measurements to describe how antifungal resistance mechanisms vary across the population. These efforts are critical for a sustained, robust public health response that effectively utilizes molecular epidemiology.
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- 2020
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34. Tracking a Global Threat: a New Genotyping Method for Candida auris
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Christina A. Cuomo and Alexandre Alanio
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Candida auris ,genome analysis ,genotyping ,short tandem repeats ,Microbiology ,QR1-502 - Abstract
ABSTRACT Over the past decade, Candida auris has emerged as an urgent threat to public health. Initially reported from cases of ear infections in Japan and Korea, C. auris has since been detected around the world. While whole-genome sequencing has been extensively used to trace the genetic relationships of the global emergence and local outbreaks, a recent report in mBio describes a targeted genotyping method as a rapid and inexpensive method for classifying C. auris isolates (T. de Groot, Y. Puts, I. Berrio, A. Chowdhary, and J. F. Meis, mBio 11:e02971-19, https://doi.org/10.1128/mBio.02971-19, 2020).
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- 2020
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35. A New Lineage of Cryptococcus gattii (VGV) Discovered in the Central Zambezian Miombo Woodlands
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Rhys A. Farrer, Miwha Chang, Michael J. Davis, Lucy van Dorp, Dong-Hoon Yang, Terrance Shea, Thomas R. Sewell, Wieland Meyer, Francois Balloux, Hannah M. Edwards, Duncan Chanda, Geoffrey Kwenda, Mathieu Vanhove, Yun C. Chang, Christina A. Cuomo, Matthew C. Fisher, and Kyung J. Kwon-Chung
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Cryptococcus ,drug resistance evolution ,genome analysis ,molecular epidemiology ,mycology ,population genetics ,Microbiology ,QR1-502 - Abstract
ABSTRACT We discovered a new lineage of the globally important fungal pathogen Cryptococcus gattii on the basis of analysis of six isolates collected from three locations spanning the Central Miombo Woodlands of Zambia, Africa. All isolates were from environments (middens and tree holes) that are associated with a small mammal, the African hyrax. Phylogenetic and population genetic analyses confirmed that these isolates form a distinct, deeply divergent lineage, which we name VGV. VGV comprises two subclades (A and B) that are capable of causing mild lung infection with negligible neurotropism in mice. Comparing the VGV genome to previously identified lineages of C. gattii revealed a unique suite of genes together with gene loss and inversion events. However, standard URA5 restriction fragment length polymorphism (RFLP) analysis could not distinguish between VGV and VGIV isolates. We therefore developed a new URA5 RFLP method that can reliably identify the newly described lineage. Our work highlights how sampling understudied ecological regions alongside genomic and functional characterization can broaden our understanding of the evolution and ecology of major global pathogens. IMPORTANCE Cryptococcus gattii is an environmental pathogen that causes severe systemic infection in immunocompetent individuals more often than in immunocompromised humans. Over the past 2 decades, researchers have shown that C. gattii falls within four genetically distinct major lineages. By combining field work from an understudied ecological region (the Central Miombo Woodlands of Zambia, Africa), genome sequencing and assemblies, phylogenetic and population genetic analyses, and phenotypic characterization (morphology, histopathological, drug-sensitivity, survival experiments), we discovered a hitherto unknown lineage, which we name VGV (variety gattii five). The discovery of a new lineage from an understudied ecological region has far-reaching implications for the study and understanding of fungal pathogens and diseases they cause.
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- 2019
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36. Cryptococcus neoformans Recovered From Olive Trees (Olea europaea) in Turkey Reveal Allopatry With African and South American Lineages
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Çağri Ergin, Mustafa Şengül, Levent Aksoy, Aylin Döğen, Sheng Sun, Anna F. Averette, Christina A. Cuomo, Seyedmojtaba Seyedmousavi, Joseph Heitman, and Macit Ilkit
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Cryptococcus neoformans ,natural isolates ,Turkey ,genetic diversity ,population ,evolution ,Microbiology ,QR1-502 - Abstract
Cryptococcus species are life-threatening human fungal pathogens that cause cryptococcal meningoencephalitis in both immunocompromised and healthy hosts. The natural environmental niches of Cryptococcus include pigeon (Columba livia) guano, soil, and a variety of tree species such as Eucalyptus camaldulensis, Ceratonia siliqua, Platanus orientalis, and Pinus spp. Genetic and genomic studies of extensive sample collections have provided insights into the population distribution and composition of different Cryptococcus species in geographic regions around the world. However, few such studies examined Cryptococcus in Turkey. We sampled 388 Olea europaea (olive) and 132 E. camaldulensis trees from seven locations in coastal and inland areas of the Aegean region of Anatolian Turkey in September 2016 to investigate the distribution and genetic diversity present in the natural Cryptococcus population. We isolated 84 Cryptococcus neoformans strains (83 MATα and 1 MATa) and 3 Cryptococcus deneoformans strains (all MATα) from 87 (22.4% of surveyed) O. europaea trees; a total of 32 C. neoformans strains were isolated from 32 (24.2%) of the E. camaldulensis trees, all of which were MATα. A statistically significant difference was observed in the frequency of C. neoformans isolation between coastal and inland areas (P < 0.05). Interestingly, the MATaC. neoformans isolate was fertile in laboratory crosses with VNI and VNB MATα tester strains and produced robust hyphae, basidia, and basidiospores, thus suggesting potential sexual reproduction in the natural population. Sequencing analyses of the URA5 gene identified at least five different genotypes among the isolates. Population genetics and genomic analyses revealed that most of the isolates in Turkey belong to the VNBII lineage of C. neoformans, which is predominantly found in southern Africa; these isolates are part of a distinct minor clade within VNBII that includes several isolates from Zambia and Brazil. Our study provides insights into the geographic distribution of different C. neoformans lineages in the Mediterranean region and highlights the need for wider geographic sampling to gain a better understanding of the natural habitats, migration, epidemiology, and evolution of this important human fungal pathogen.
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- 2019
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37. Genomic Understanding of an Infectious Brain Disease from the Desert
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Leandro F. Moreno, Abdalla A. O. Ahmed, Balázs Brankovics, Christina A. Cuomo, Steph B. J. Menken, Saad J. Taj-Aldeen, Hani Faidah, J. Benjamin Stielow, Marcus de M. Teixeira, Francesc X. Prenafeta-Boldú, Vania A. Vicente, and Sybren de Hoog
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black yeast ,comparative genomics ,Chaetothyriales ,cerebral phaeohyphomycosis ,Genetics ,QH426-470 - Abstract
Rhinocladiella mackenziei accounts for the majority of fungal brain infections in the Middle East, and is restricted to the arid climate zone between Saudi Arabia and Pakistan. Neurotropic dissemination caused by this fungus has been reported in immunocompromised, but also immunocompetent individuals. If untreated, the infection is fatal. Outside of humans, the environmental niche of R. mackenziei is unknown, and the fungus has been only cultured from brain biopsies. In this paper, we describe the whole-genome resequencing of two R. mackenziei strains from patients in Saudi Arabia and Qatar. We assessed intraspecies variation and genetic signatures to uncover the genomic basis of the pathogenesis, and potential niche adaptations. We found that the duplicated genes (paralogs) are more susceptible to accumulating significant mutations. Comparative genomics with other filamentous ascomycetes revealed a diverse arsenal of genes likely engaged in pathogenicity, such as the degradation of aromatic compounds and iron acquisition. In addition, intracellular accumulation of trehalose and choline suggests possible adaptations to the conditions of an arid climate region. Specifically, protein family contractions were found, including short-chain dehydrogenase/reductase SDR, the cytochrome P450 (CYP) (E-class), and the G-protein β WD-40 repeat. Gene composition and metabolic potential indicate extremotolerance and hydrocarbon assimilation, suggesting a possible environmental habitat of oil-polluted desert soil.
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- 2018
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38. Pas de deux: An Intricate Dance of Anther Smut and Its Host
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Su San Toh, Zehua Chen, Eric C. Rouchka, David J. Schultz, Christina A. Cuomo, and Michael H. Perlin
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host/pathogen interaction ,anther-smut fungi ,fungal effectors ,Microbotryum ,Silene ,Genetics ,QH426-470 - Abstract
The successful interaction between pathogen/parasite and host requires a delicate balance between fitness of the former and survival of the latter. To optimize fitness a parasite/pathogen must effectively create an environment conducive to reproductive success, while simultaneously avoiding or minimizing detrimental host defense response. The association between Microbotryum lychnidis-dioicae and its host Silene latifolia serves as an excellent model to examine such interactions. This fungus is part of a species complex that infects species of the Caryophyllaceae, replacing pollen with the fungal spores. In the current study, transcriptome analyses of the fungus and its host were conducted during discrete stages of bud development so as to identify changes in fungal gene expression that lead to spore development and to identify changes associated with infection in the host plant. In contrast to early biotrophic phase stages of infection for the fungus, the latter stages involve tissue necrosis and in the case of infected female flowers, further changes in the developmental program in which the ovary aborts and a pseudoanther is produced. Transcriptome analysis via Illumina RNA sequencing revealed enrichment of fungal genes encoding small secreted proteins, with hallmarks of effectors and genes found to be relatively unique to the Microbotryum species complex. Host gene expression analyses also identified interesting sets of genes up-regulated, including those involving stress response, host defense response, and several agamous-like MADS-box genes (AGL61 and AGL80), predicted to interact and be involved in male gametophyte development.
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- 2018
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39. Phenotypic Characterization and Comparative Genomics of the Melanin-Producing Yeast Exophiala lecanii-corni Reveals a Distinct Stress Tolerance Profile and Reduced Ribosomal Genetic Content
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Jillian Romsdahl, Zachary Schultzhaus, Christina A. Cuomo, Hong Dong, Hashanthi Abeyratne-Perera, W. Judson Hervey, and Zheng Wang
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Exophiala lecanii-corni ,black yeast ,melanin biosynthesis ,extremophile ,toluene degradation ,comparative genomics ,Biology (General) ,QH301-705.5 - Abstract
The black yeast Exophiala lecanii-corni of the order Chaetothyriales is notable for its ability to produce abundant quantities of DHN-melanin. While many other Exophiala species are frequent causal agents of human infection, E. lecanii-corni CBS 102400 lacks the thermotolerance requirements that enable pathogenicity, making it appealing for use in targeted functional studies and biotechnological applications. Here, we report the stress tolerance characteristics of E. lecanii-corni, with an emphasis on the influence of melanin on its resistance to various forms of stress. We find that E. lecanii-corni has a distinct stress tolerance profile that includes variation in resistance to temperature, osmotic, and oxidative stress relative to the extremophilic and pathogenic black yeast Exophiala dermatitidis. Notably, the presence of melanin substantially impacts stress resistance in E. lecanii-corni, while this was not found to be the case in E. dermatitidis. The cellular context, therefore, influences the role of melanin in stress protection. In addition, we present a detailed analysis of the E. lecanii-corni genome, revealing key differences in functional genetic content relative to other ascomycetous species, including a significant decrease in abundance of genes encoding ribosomal proteins. In all, this study provides insight into how genetics and physiology may underlie stress tolerance and enhances understanding of the genetic diversity of black yeasts.
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- 2021
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40. Diagnostic Allele-Specific PCR for the Identification of Candida auris Clades
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Hans Carolus, Stef Jacobs, Celia Lobo Romero, Quinten Deparis, Christina A. Cuomo, Jacques F. Meis, and Patrick Van Dijck
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Candida auris ,diagnostics ,clades ,PCR ,Biology (General) ,QH301-705.5 - Abstract
Candida auris is an opportunistic pathogenic yeast that emerged worldwide during the past decade. This fungal pathogen poses a significant public health threat due to common multidrug resistance (MDR), alarming hospital outbreaks, and frequent misidentification. Genomic analyses have identified five distinct clades that are linked to five geographic areas of origin and characterized by differences in several phenotypic traits such as virulence and drug resistance. Typing of C. auris strains and the identification of clades can be a powerful tool in molecular epidemiology and might be of clinical importance by estimating outbreak and MDR potential. As C. auris has caused global outbreaks, including in low-income countries, typing C. auris strains quickly and inexpensively is highly valuable. We report five allele-specific polymerase chain reaction (AS-PCR) assays for the identification of C. auris and each of the five described clades of C. auris based on conserved mutations in the internal transcribed spacer (ITS) rDNA region and a clade-specific gene cluster. This PCR method provides a fast, cheap, sequencing-free diagnostic tool for the identification of C. auris, C. auris clades, and potentially, the discovery of new clades.
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- 2021
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41. Impact of pathogen genetics on clinical phenotypes in a population of Talaromyces marneffei from Vietnam
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Poppy Sephton-Clark, Thu Nguyen, Ngo Thi Hoa, Philip Ashton, H. Rogier van Doorn, Vo Trieu Ly, Thuy Le, and Christina A. Cuomo
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Genetics ,Article - Abstract
Talaromycosis, a severe and invasive fungal infection caused byTalaromyces marneffei, is difficult to treat and impacts those living in endemic regions of southeast Asia, India, and China. While 30% of infections result in mortality, our understanding of the genetic basis of pathogenesis for this fungus is limited. To address this, we apply population genomics and genome wide association study approaches to a cohort of 336T. marneffeiisolates collected from patients who enrolled in the Itraconazole versus Amphotericin B for Talaromycosis (IVAP) trial in Vietnam. We find that isolates from northern and southern Vietnam form two distinct geographical clades, with isolates from southern Vietnam associated with increased disease severity. Leveraging longitudinal isolates, we identify multiple instances of disease relapse linked to unrelated strains, highlighting the potential for multi-strain infections. In more frequent cases of persistent talaromycosis caused by the same strain, we identify variants arising over the course of patient infections that impact genes predicted to function in the regulation of gene expression and secondary metabolite production. By combining genetic variant data with patient metadata for all 336 isolates, we identify pathogen variants significantly associated with multiple clinical phenotypes. In addition, we identify genes and genomic regions under selection across both clades, highlighting loci undergoing rapid evolution, potentially in response to external pressures. With this combination of approaches, we identify links between pathogen genetics and patient outcomes and identify genomic regions that are altered duringT. marneffeiinfection, providing an initial view of how pathogen genetics affects disease outcomes.
- Published
- 2023
42. Whole Genome Sequence of the Heterozygous Clinical Isolate Candida krusei 81-B-5
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Christina A. Cuomo, Terrance Shea, Bo Yang, Reeta Rao, and Anja Forche
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Candida krusei ,81-B-5 ,heterozygosity ,LOH ,mating type locus ,transporters ,Genome Report ,Genetics ,QH426-470 - Abstract
Candida krusei is a diploid, heterozygous yeast that is an opportunistic fungal pathogen in immunocompromised patients. This species also is utilized for fermenting cocoa beans during chocolate production. One major concern in the clinical setting is the innate resistance of this species to the most commonly used antifungal drug fluconazole. Here, we report a high-quality genome sequence and assembly for the first clinical isolate of C. krusei, strain 81-B-5, into 11 scaffolds generated with PacBio sequencing technology. Gene annotation and comparative analysis revealed a unique profile of transporters that could play a role in drug resistance or adaptation to different environments. In addition, we show that, while 82% of the genome is highly heterozygous, a 2.0 Mb region of the largest scaffold has undergone loss of heterozygosity. This genome will serve as a reference for further genetic studies of this pathogen.
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- 2017
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43. Genomic innovations linked to infection strategies across emerging pathogenic chytrid fungi
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Rhys A. Farrer, An Martel, Elin Verbrugghe, Amr Abouelleil, Richard Ducatelle, Joyce E. Longcore, Timothy Y. James, Frank Pasmans, Matthew C. Fisher, and Christina A. Cuomo
- Subjects
Science - Abstract
Batrachochytrium dendrobatidis and B. salamandrivoransare both important pathogens of amphibians, but they differ in their host ranges, infection strategies, and host immune responses. Here, Farrer and colleagues compare their genomes and transcriptomes to identify the genetic basis of these differences.
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- 2017
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44. Comparative Analysis Highlights Variable Genome Content of Wheat Rusts and Divergence of the Mating Loci
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Christina A. Cuomo, Guus Bakkeren, Hala Badr Khalil, Vinay Panwar, David Joly, Rob Linning, Sharadha Sakthikumar, Xiao Song, Xian Adiconis, Lin Fan, Jonathan M. Goldberg, Joshua Z. Levin, Sarah Young, Qiandong Zeng, Yehoshua Anikster, Myron Bruce, Meinan Wang, Chuntao Yin, Brent McCallum, Les J. Szabo, Scot Hulbert, Xianming Chen, and John P. Fellers
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Puccinia ,genome comparisons ,effectors ,mating-type genes ,sexual stage ,Genetics ,QH426-470 - Abstract
Three members of the Puccinia genus, Puccinia triticina (Pt), P. striiformis f.sp. tritici (Pst), and P. graminis f.sp. tritici (Pgt), cause the most common and often most significant foliar diseases of wheat. While similar in biology and life cycle, each species is uniquely adapted and specialized. The genomes of Pt and Pst were sequenced and compared to that of Pgt to identify common and distinguishing gene content, to determine gene variation among wheat rust pathogens, other rust fungi, and basidiomycetes, and to identify genes of significance for infection. Pt had the largest genome of the three, estimated at 135 Mb with expansion due to mobile elements and repeats encompassing 50.9% of contig bases; in comparison, repeats occupy 31.5% for Pst and 36.5% for Pgt. We find all three genomes are highly heterozygous, with Pst [5.97 single nucleotide polymorphisms (SNPs)/kb] nearly twice the level detected in Pt (2.57 SNPs/kb) and that previously reported for Pgt. Of 1358 predicted effectors in Pt, 784 were found expressed across diverse life cycle stages including the sexual stage. Comparison to related fungi highlighted the expansion of gene families involved in transcriptional regulation and nucleotide binding, protein modification, and carbohydrate degradation enzymes. Two allelic homeodomain pairs, HD1 and HD2, were identified in each dikaryotic Puccinia species along with three pheromone receptor (STE3) mating-type genes, two of which are likely representing allelic specificities. The HD proteins were active in a heterologous Ustilago maydis mating assay and host-induced gene silencing (HIGS) of the HD and STE3 alleles reduced wheat host infection.
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- 2017
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45. In vivo emergence of high-level resistance during treatment reveals the first identified mechanism of amphotericin B resistance in Candida auris
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Jeffrey M. Rybak, Katherine S. Barker, José F. Muñoz, Josie E. Parker, Suhail Ahmad, Eiman Mokaddas, Aneesa Abdullah, Rehab S. Elhagracy, Steve L. Kelly, Christina A. Cuomo, and P. David Rogers
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Microbiology (medical) ,Sterols ,Antifungal Agents ,Infectious Diseases ,Amphotericin B ,Humans ,Microbial Sensitivity Tests ,General Medicine ,Candida auris ,Article - Abstract
OBJECTIVE: Candida auris has emerged as a health-care-associated and multidrug-resistant fungal pathogen of great clinical concern. As many as 50% of C. auris clinical isolates are reported to be resistant to amphotericin B, but no mechanisms contributing to this resistance have been identified. Here we describe a clinical case in which high-level amphotericin B resistance was acquired in vivo during therapy and undertake molecular and genetic studies to identify and characterize the genetic determinant of resistance. METHODS: Whole-genome sequencing was performed on four C. auris isolates obtained from a single patient case. Cas9-mediated genetic manipulations were then used to generate mutant strains harbouring mutations of interest, and these strains were subsequently subjected to amphotericin B susceptibility testing and comprehensive sterol profiling. RESULTS: A novel mutation in the C. auris sterol-methyltransferase gene ERG6 was found to be associated with amphotericin B resistance, and this mutation alone conferred a >32-fold increase in amphotericin B resistance. Comprehensive sterol profiling revealed an abrogation of ergosterol biosynthesis and a corresponding accumulation of cholesta-type sterols in isolates and strains harbouring the clinically derived ERG6 mutation. CONCLUSIONS: Together these findings definitively demonstrate mutations in C. auris ERG6 as the first identified mechanism of clinical amphotericin B resistance in C. auris and represent a significant step forward in the understanding of antifungal resistance in this emerging public health threat.
- Published
- 2022
46. Emergomyces: The global rise of new dimorphic fungal pathogens.
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Ilan S Schwartz, Nelesh P Govender, Lynne Sigler, Yanping Jiang, Tsidiso G Maphanga, Barbra Toplis, Alfred Botha, Karolina Dukik, J Claire Hoving, Jose F Muñoz, Sybren de Hoog, Christina A Cuomo, Robert Colebunders, and Chris Kenyon
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Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Published
- 2019
- Full Text
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47. Genetic and Genomic Analyses Reveal Boundaries between Species Closely Related to Cryptococcus Pathogens
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Andrew Ryan Passer, Marco A. Coelho, Robert Blake Billmyre, Minou Nowrousian, Moritz Mittelbach, Andrey M. Yurkov, Anna Floyd Averette, Christina A. Cuomo, Sheng Sun, and Joseph Heitman
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chromosomal rearrangements ,fungi ,genome analysis ,reproductive isolation ,speciation ,Microbiology ,QR1-502 - Abstract
ABSTRACT Speciation is a central mechanism of biological diversification. While speciation is well studied in plants and animals, in comparison, relatively little is known about speciation in fungi. One fungal model is the Cryptococcus genus, which is best known for the pathogenic Cryptococcus neoformans/Cryptococcus gattii species complex that causes >200,000 new human infections annually. Elucidation of how these species evolved into important human-pathogenic species remains challenging and can be advanced by studying the most closely related nonpathogenic species, Cryptococcus amylolentus and Tsuchiyaea wingfieldii. However, these species have only four known isolates, and available data were insufficient to determine species boundaries within this group. By analyzing full-length chromosome assemblies, we reappraised the phylogenetic relationships of the four available strains, confirmed the genetic separation of C. amylolentus and T. wingfieldii (now Cryptococcus wingfieldii), and revealed an additional cryptic species, for which the name Cryptococcus floricola is proposed. The genomes of the three species are ∼6% divergent and exhibit significant chromosomal rearrangements, including inversions and a reciprocal translocation that involved intercentromeric ectopic recombination, which together likely impose significant barriers to genetic exchange. Using genetic crosses, we show that while C. wingfieldii cannot interbreed with any of the other strains, C. floricola can still undergo sexual reproduction with C. amylolentus. However, most of the resulting spores were inviable or sterile or showed reduced recombination during meiosis, indicating that intrinsic postzygotic barriers had been established. Our study and genomic data will foster additional studies addressing fungal speciation and transitions between nonpathogenic and pathogenic Cryptococcus lineages. IMPORTANCE The evolutionary drivers of speciation are critical to our understanding of how new pathogens arise from nonpathogenic lineages and adapt to new environments. Here we focus on the Cryptococcus amylolentus species complex, a nonpathogenic fungal lineage closely related to the human-pathogenic Cryptococcus neoformans/Cryptococcus gattii complex. Using genetic and genomic analyses, we reexamined the species boundaries of four available isolates within the C. amylolentus complex and revealed three genetically isolated species. Their genomes are ∼6% divergent and exhibit chromosome rearrangements, including translocations and small-scale inversions. Although two of the species (C. amylolentus and newly described C. floricola) were still able to interbreed, the resulting hybrid progeny were usually inviable or sterile, indicating that barriers to reproduction had already been established. These results advance our understanding of speciation in fungi and highlight the power of genomics in assisting our ability to correctly identify and discriminate fungal species.
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- 2019
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48. Erratum for Kim et al., 'Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance'
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Sang Hu Kim, Kali R. Iyer, Lakhansing Pardeshi, José F. Muñoz, Nicole Robbins, Christina A. Cuomo, Koon Ho Wong, and Leah E. Cowen
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Microbiology ,QR1-502 - Published
- 2019
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49. Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance
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Sang Hu Kim, Kali R. Iyer, Lakhansing Pardeshi, José F. Muñoz, Nicole Robbins, Christina A. Cuomo, Koon Ho Wong, and Leah E. Cowen
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antifungal drug resistance ,Candida albicans ,Candida auris ,Cdr1 ,developmental program ,emerging pathogen ,Microbiology ,QR1-502 - Abstract
ABSTRACT Candida auris is an emerging fungal pathogen and a serious global health threat as the majority of clinical isolates display elevated resistance to currently available antifungal drugs. Despite the increased prevalence of C. auris infections, the mechanisms governing drug resistance remain largely elusive. In diverse fungi, the evolution of drug resistance is enabled by the essential molecular chaperone Hsp90, which stabilizes key regulators of cellular responses to drug-induced stress. Hsp90 also orchestrates temperature-dependent morphogenesis in Candida albicans, a key virulence trait. However, the role of Hsp90 in the pathobiology of C. auris remains unknown. In order to study regulatory functions of Hsp90 in C. auris, we placed HSP90 under the control of a doxycycline-repressible promoter to enable transcriptional repression. We found that Hsp90 is essential for growth in C. auris and that it enables tolerance of clinical isolates with respect to the azoles, which inhibit biosynthesis of the membrane sterol ergosterol. High-level azole resistance was independent of Hsp90 but dependent on the ABC transporter CDR1, deletion of which resulted in abrogated resistance. Strikingly, we discovered that C. auris undergoes a morphogenetic transition from yeast to filamentous growth in response to HSP90 depletion or cell cycle arrest but not in response to other cues that induce C. albicans filamentation. Finally, we observed that this developmental transition is associated with global transcriptional changes, including the induction of cell wall-related genes. Overall, this report provides a novel insight into mechanisms of drug tolerance and resistance in C. auris and describes a developmental transition in response to perturbation of a core regulator of protein homeostasis. IMPORTANCE Fungal pathogens pose a serious threat to public health. Candida auris is an emerging fungal pathogen that is often resistant to commonly used antifungal drugs. However, the mechanisms governing drug resistance and virulence in this organism remain largely unexplored. In this study, we adapted a conditional expression system to modulate the transcription of an essential gene, HSP90, which regulates antifungal resistance and virulence in diverse fungal pathogens. We showed that Hsp90 is essential for growth in C. auris and is important for tolerance of the clinically important azole antifungals, which block ergosterol biosynthesis. Further, we established that the Cdr1 efflux transporter regulates azole resistance. Finally, we discovered that C. auris transitions from yeast to filamentous growth in response to Hsp90 inhibition, accompanied by global transcriptional remodeling. Overall, this work provides a novel insight into mechanisms regulating azole resistance in C. auris and uncovers a distinct developmental program regulated by Hsp90.
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- 2019
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50. Antagonistic paralogs control a switch between growth and pathogen resistance in C. elegans.
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Kirthi C Reddy, Tal Dror, Ryan S Underwood, Guled A Osman, Corrina R Elder, Christopher A Desjardins, Christina A Cuomo, Michalis Barkoulas, and Emily R Troemel
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Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Abstract
Immune genes are under intense, pathogen-induced pressure, which causes these genes to diversify over evolutionary time and become species-specific. Through a forward genetic screen we recently described a C. elegans-specific gene called pals-22 to be a repressor of "Intracellular Pathogen Response" or IPR genes. Here we describe pals-25, which, like pals-22, is a species-specific gene of unknown biochemical function. We identified pals-25 in a screen for suppression of pals-22 mutant phenotypes and found that mutations in pals-25 suppress all known phenotypes caused by mutations in pals-22. These phenotypes include increased IPR gene expression, thermotolerance, and immunity against natural pathogens, including Nematocida parisii microsporidia and the Orsay virus. Mutations in pals-25 also reverse the reduced lifespan and slowed growth of pals-22 mutants. Transcriptome analysis indicates that pals-22 and pals-25 control expression of genes induced not only by natural pathogens of the intestine, but also by natural pathogens of the epidermis. Indeed, in an independent forward genetic screen we identified pals-22 as a repressor and pals-25 as an activator of epidermal defense gene expression. In summary, the species-specific pals-22 and pals-25 genes act as a switch to regulate a program of gene expression, growth, and defense against diverse natural pathogens in C. elegans.
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- 2019
- Full Text
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