Comparative Genome Analysis and Gene Finding in Candida Species Using CGOB

Maguire, Sarah; ÓhÉigeartaigh, Seán S.; Byrne, Kevin; Schröder, Markus; Ó’Gaora, Peadar; Wolfe, Kenneth H.; Butler, Geraldine

doi:10.1093/molbev/mst042

Cited by 116 publications

(127 citation statements)

References 64 publications

(95 reference statements)

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“…Among the haploid species, C. lusitaniae, although relatively rare clinically, is nonetheless much more common than M. guilliermondii, which in turn is more common than D. hansenii (25). Thus, we sought to add to the existing bioinformatics comparisons based on genome sequence and predicted protein content (17,26,27) by understanding the phenotypic differences that may contribute to virulence in these species.…”

Section: Resultsmentioning

confidence: 99%

Characterization of Virulence-Related Phenotypes in Candida Species of the CUG Clade

Priest

Lorenz

2015

Eukaryot Cell

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bCandida species cause a variety of mucosal and invasive infections and are, collectively, the most important human fungal pathogens in the developed world. The majority of these infections result from a few related species within the "CUG clade," so named because they use a nonstandard translation for that codon. Some members of the CUG clade, such as Candida albicans, present significant clinical problems, whereas others, such as Candida (Meyerozyma) guilliermondii, are uncommon in patients. The differences in incidence rates are imperfectly correlated with virulence in animal models of infection, but comparative analyses that might provide an explanation for why some species are effective pathogens and others are not have been rare or incomplete. To better understand the phenotypic basis for these differences, we characterized eight CUG clade species-C. albicans, C. dubliniensis, C. tropicalis, C. parapsilosis, Clavispora lusitaniae, M. guilliermondii, Debaryomyces hansenii, and Lodderomyces elongisporus-for host-relevant phenotypes, including nutrient utilization, stress tolerance, morphogenesis, interactions with phagocytes, and biofilm formation. Two species deviated from expectations based on animal studies and human incidence. C. dubliniensis was quite robust, grouping in nearly all assays with the most virulent species, C. albicans and C. tropicalis, whereas C. parapsilosis was substantially less fit than might be expected from its clinical importance. These findings confirm the utility of in vitro measures of virulence and provide insight into the evolution of virulence in the CUG clade. Candida species are the most important fungal pathogens of humans and are collectively responsible for a vast number of infections. These range from superficial mucosal infections such as vulvovaginal candidiasis, and oropharyngeal thrush, to lifethreatening infections such as disseminated hematogenous and invasive candidiasis. These latter infections have steadily increased in incidence in the last 30 years and are associated with a stubbornly high mortality rate as a result of the underlying immunodeficiency of the patients and inadequate diagnostics and treatments (1).Of the approximately 150 species in the genus, 95% of infections are caused by just four species: C. albicans, C. tropicalis, C. parapsilosis, and C. glabrata (2-4). C. albicans is the dominant species, representing about half of disseminated disease and an even greater percentage of mucosal infections. Other clinically relevant species include Clavispora lusitaniae (anamorph: Candida lusitaniae), M. guilliermondii (anamorph: Candida guilliermondii), C. krusei, and C. dubliniensis, while D. hansenii (synonym: Candida famata) and Lodderomyces elongisporus are subjects of rare clinical reports. Because the genus Candida is polyphyletic, a better sense of evolutionary relationships comes in the "CUG clade," a grouping of species that use an alternative genetic code in which that codon specifies serine rather than leucine (5, 6). The CUG clade encompasses ...

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Section: Resultsmentioning

confidence: 99%

Characterization of Virulence-Related Phenotypes in Candida Species of the CUG Clade

Priest

Lorenz

2015

Eukaryot Cell

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“…The Fungal Orthogroups tool within the Candida Genome Database was used to identify orthologs and paralogs of ZCFs ( Figure 1, B and C). To evaluate selective pressure on ZCF15 and ZCF29, the most closely related gene in C. dubliniensis was mapped using the Candida Gene Order Browser (Maguire et al 2013); C. tropicalis orthologs were not used, as rates of synonymous substitution appear saturated (d S . 6 for both genes).…”

Section: Zcf Sequence Analysismentioning

confidence: 99%

Zinc Cluster Transcription Factors Alter Virulence in Candida albicans

et al. 2017

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Almost all humans are colonized with Candida albicans. However, in immunocompromised individuals, this benign commensal organism becomes a serious, life-threatening pathogen. Here, we describe and analyze the regulatory networks that modulate innate responses in the host niches. We identified Zcf15 and Zcf29, two Zinc Cluster transcription Factors (ZCF) that are required for C. albicans virulence. Previous sequence analysis of clinical C. albicans isolates from immunocompromised patients indicates that both ZCF genes diverged during clonal evolution. Using in vivo animal models, ex vivo cell culture methods, and in vitro sensitivity assays, we demonstrate that knockout mutants of both ZCF15 and ZCF29 are hypersensitive to reactive oxygen species (ROS), suggesting they help neutralize the host-derived ROS produced by phagocytes, as well as establish a sustained infection in vivo. Transcriptomic analysis of mutants under resting conditions where cells were not experiencing oxidative stress revealed a large network that control macro and micronutrient homeostasis, which likely contributes to overall pathogen fitness in host niches. Under oxidative stress, both transcription factors regulate a separate set of genes involved in detoxification of ROS and down-regulating ribosome biogenesis. ChIP-seq analysis, which reveals vastly different binding partners for each transcription factor (TF) before and after oxidative stress, further confirms these results. Furthermore, the absence of a dominant binding motif likely facilitates their mobility, and supports the notion that they represent a recent expansion of the ZCF family in the pathogenic Candida species. Our analyses provide a framework for understanding new aspects of the interface between C. albicans and host defense response, and extends our understanding of how complex cell behaviors are linked to the evolution of TFs.

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“…Many Candida species belong to the CTG (or CUG) clade, in which the CTG codon codes for serine, rather than leucine (Table 1) (Santos et al 1993). The CTG clade includes many of the most important pathogens (C. albicans, C. tropicalis, and C. parapsilosis) as well as rarer causes of disease (Candida dubliniensis, Candida guilliermondii, and Candida lusitaniae) (Fitzpatrick et al 2006(Fitzpatrick et al , 2010Maguire et al 2013). Some of the species are always, or mostly, diploid (Table 1).…”

Section: Classification Of Candida Species: the Ctg Clade And Beyondmentioning

confidence: 99%

“…For example, comparing the genomes of six species in the CTG clade led to the identification of 91 novel ORFs in C. albicans . A more detailed analysis uncovered more than 1500 previously unannotated ORFs in 13 genomes (Maguire et al 2013) (Fig. 2).…”

Section: Concluding Remarks: the Future Of Genomics In Candidamentioning

confidence: 99%