Molecular characterization of the silencing complex SIR in Candida glabrata hyperadherent clinical isolates

Leiva-Peláez, Osney; Gutiérrez-Escobedo, Guadalupe; López-Fuentes, Eunice; Cruz-Mora, José; Peñas, Alejandro De Las; Castaño, Irene

doi:10.1016/j.fgb.2018.05.005

Cited by 9 publications

(6 citation statements)

References 57 publications

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“…This strain presents a non-synonymous mutation in SIR4 , a gene involved in subtelomeric silencing and regulation of biofilm formation. A recent study (Leiva-Peláez et al, 2018) has found that SIR3 and SIR4 from several clinical isolates present a larger number of non-synonymous polymorphisms as compared to genes encoding other silencing proteins, and that some such polymorphisms relate to different levels of silencing of target genes. A possible scenario is thus that the observed mutation induces changes in the expressed adhesin genes, leading to lower adherence.…”

Section: Discussionmentioning

confidence: 99%

Genome Comparisons of Candida glabrata Serial Clinical Isolates Reveal Patterns of Genetic Variation in Infecting Clonal Populations

et al. 2019

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Candida glabrata is an opportunistic fungal pathogen that currently ranks as the second most common cause of candidiasis. Although the mechanisms underlying virulence and drug resistance in C. glabrata are now starting to be elucidated, we still lack a good understanding of how this yeast adapts during the course of an infection. Outstanding questions are whether the observed genomic plasticity of C. glabrata plays a role during infection, or what levels of genetic variation exist within an infecting clonal population. To shed light onto the genomic variation within infecting C. glabrata populations, we compared the genomes of 11 pairs and one trio of serial clinical isolates, each obtained from a single patient. Our results provide a catalog of genetic variations existing within clonal infecting isolates, and reveal an enrichment of non-synonymous changes in genes encoding cell-wall proteins. Genetic variation and the presence of non-synonymous mutations and copy number variations accumulated within the host, suggest that clonal populations entail a non-negligible level of genetic variation that may reflect selection processes that occur within the human body. As we show here, these genomic changes can underlie phenotypic differences in traits that are relevant for infection.

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Section: Discussionmentioning

confidence: 99%

Genome Comparisons of Candida glabrata Serial Clinical Isolates Reveal Patterns of Genetic Variation in Infecting Clonal Populations

et al. 2019

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“…In C. glabrata, Leiva-Peláez et al (2018) demonstrated that the expression of several related genes is subjected to subtelomeric silencing. HYR1, EPA1, EPA2, EPA3, EPA4, EPA5, EPA6, and EPA7 genes of C. glabrata undergo subtelomeric silencing due to their loci proximity to a telomere.…”

Section: Genomics Of the Biofilmmentioning

confidence: 99%

Pathogenesis and Clinical Relevance of Candida Biofilms in Vulvovaginal Candidiasis

et al. 2020

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The ability of Candida spp. to form biofilms is crucial for its pathogenicity, and thus, it should be considered an important virulence factor in vulvovaginal candidiasis (VVC) and recurrent VVC (RVVC). Its ability to generate biofilms is multifactorial and is generally believed to depend on the site of infection, species and strain involved, and the microenvironment in which the infection develops. Therefore, both cell surface proteins, such as Hwp1, Als1, and Als2, and the cell wall-related protein, Sun41, play a critical role in the adhesion and virulence of the biofilm. Immunological and pharmacological approaches have identified the NLRP3 inflammasome as a crucial molecular factor contributing to host immunopathology. In this context, we have earlier shown that Candida albicans associated with hyphae-secreted aspartyl proteinases (specifically SAP4-6) contribute to the immunopathology of the disease. Transcriptome profiling has revealed that non-coding transcripts regulate protein synthesis post-transcriptionally, which is important for the growth of Candida spp. Other studies have employed RNA sequencing to identify differences in the 1,245 Candida genes involved in surface and invasive cellular metabolism regulation. In vitro systems allow the simultaneous processing of a large number of samples, making them an ideal screening technique for estimating various physicochemical parameters, testing the activity of antimicrobial agents, and analyzing genes involved in biofilm formation and regulation ( in situ ) in specific strains. Murine VVC models are used to study C. albicans infection, especially in trials of novel treatments and to understand the cause(s) for resistance to conventional therapeutics. This review on the clinical relevance of Candida biofilms in VVC focuses on important advances in its genomics, transcriptomics, and proteomics. Moreover, recent experiments on the influence of biofilm formation on VVC or RVVC pathogenesis in laboratory animals have been discussed. A clear elucidation of one of the pathogenesis mechanisms employed by Candida biofilms in vulvovaginal candidiasis and its applications in clinical practice represents the most significant contribution of this manuscript.

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“…Expression of subtelomeric genes (adhesins) have been shown to be much higher in CBS138 strains than in BG2 strains (Halliwell et al 2012; Vale-Silva et al 2016). CBS138 strains express a variant of Sir3, part of the SIR complex that establishes heterochromatin and silences the expression of subtelomeric adhesin genes (De Las Penas et al 2003; Orta-Zavalza et al 2013), containing multiple amino-acid substitutions that have been shown to disrupt subtelomeric gene silencing (Leiva-Pelaez et al 2018; Martinez-Jimenez et al 2013). Because transposon accessibility to DNA is highly sensitive to chromatin compaction (Gangadharan et al 2010; Levitan et al 2020), our Tn-seq findings suggest CBS138 strains may dysregulate expression of adhesin genes at most subtelomeres through an inability to maintain compacted heterochromatin.…”

Section: Resultsmentioning

confidence: 99%

Tn-seq of theCandida glabratareference strain CBS138 reveals epigenetic plasticity, structural variation, and intrinsic mechanisms of resistance to micafungin

Nickels,

Gale,

Harrington

et al. 2024

Preprint

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glabratais an opportunistic pathogen that can resist common antifungals and rapidly acquire multidrug resistance. A large amount of genetic variation exists between isolates, which complicates generalizations. Portable Tn-seq methods can efficiently provide genome-wide information on strain differences and genetic mechanisms. Using theHermestransposon, the CBS138 reference strain and a commonly studied derivative termed 2001 were subjected to Tn-seq in control conditions and after exposure to varying doses of the clinical antifungal micafungin. The approach revealed large differences between these strains, including a 131 kb tandem duplication and a variety of fitness differences. Additionally, both strains exhibited up to 1000-fold increased transposon accessibility in subtelomeric regions relative to the BG2 strain, indicative of open subtelomeric chromatin in these isolates and large epigenetic variation within the species. Unexpectedly, the Pdr1 transcription factor conferred resistance to micafungin through targets other thanCDR1. Other micafungin resistance pathways were also revealed including mannosyltransferase activity and biosynthesis of the lipid precursor sphingosine, the drugging of which by SDZ 90-215 or myriocin enhanced the potency of micafunginin vitro. These findings provide insights into complexity of theC. glabrataspecies as well as strategies for improving antifungal efficacy.

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Molecular characterization of the silencing complex SIR in Candida glabrata hyperadherent clinical isolates

Cited by 9 publications

References 57 publications

Genome Comparisons of Candida glabrata Serial Clinical Isolates Reveal Patterns of Genetic Variation in Infecting Clonal Populations

Genome Comparisons of Candida glabrata Serial Clinical Isolates Reveal Patterns of Genetic Variation in Infecting Clonal Populations

Pathogenesis and Clinical Relevance of Candida Biofilms in Vulvovaginal Candidiasis

Tn-seq of theCandida glabratareference strain CBS138 reveals epigenetic plasticity, structural variation, and intrinsic mechanisms of resistance to micafungin

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