Genomic variation in C. albicans.

B L Wickes; R Petter

Home/Archive/PubMed

PubMed · 9504060

Genomic variation in C. albicans.

B L Wickes·R Petter

View original source ↗Export metadata ↓

Abstract

Candida albicans displays many types of variation which affect a broad spectrum of phenotypes. Among them are antigenic, chromosomal, morphologic, and biochemical variation. The ability to modulate many phenotypes is clearly an important factor in the success of this fungus as a pathogen and variation at the genomic level may be the common denominator among the different systems. Genomic variation in C. albicans has been studied by many researchers and a number of different mechanisms have been identified. Among them are ploidy fluctuations, which allow the organism to cycle from 2n chromosome number to 4n or higher; translocation, which has been demonstrated to involve many different chromosomes and affects many phenotypes including virulence; mitotic recombination, which has been demonstrated to increase resistance to certain drugs; and nondisjunction, which has been shown to have morphological consequences. The number and diversity of these mechanisms combine to make C. albicans a highly successful organism. Although normally a commensal of humans, when invasive, C. albicans can inhabit almost any site in the body. It is not known what governs the transition of C. albicans from a commensal to pathogenic invader, however, variation at the genomic level likely plays a role. One possible consequence of variation is the generation of atypical strains, further expanding the documented phenotypic plasticity of this organism. The exposure of patients to cytotoxic drugs during treatment of such diseases as AIDS or cancer increases the selective pressure and has exacerbated both the frequency and degree of variability observed in C. albicans. The molecular analysis of genomic variation in C. albicans is proving to be a fertile area of research and future investigations can only be expected to add to the mechanisms documented in this review.

Explore related subjects

Candida albicans Genetic Variation Genome, Fungal Journal Article Review

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

B L Wickes, R Petter. 1996. Genomic variation in C. albicans.. https://pubmed.ncbi.nlm.nih.gov/9504060/

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related citations

PubMed2026

Analysis of the genome of a Pseudomonas monsensis isolate that produces the antifungal dipeptide maculosin.

Candida species have been attributed to causing ~647,000 deaths annually. Candida albicans has been identified by the WHO as a priority pathogen for targeted antifungal drug development. To this end, we have screened microbial strains from the public outreach project Swab and Send for anti-Candida activity. This process identified Pseudomonas sp. SS1954.14, which displayed potent activity against C. albicans, both on agar and in a cell-free supernatant assay. Whole-genome sequence analysis identified this strain as Pseudomonas monsensis. It contains several biosynthetic gene clusters, suggesting that it can produce hydrogen cyanide, lokisin, pyoverdine and colicin/carocin, which may contribute to the observed antifungal activity. However, an active compound was separated by preparative high-performance liquid chromatography and identified through high-resolution mass spectrometry as maculosin [cyclo(Pro-Tyr)]. This cyclic dipeptide has previously been found to possess antifungal activity, but the exact biosynthetic mechanism remains undetermined. Reporting this genome alongside the associated evidence of maculosin production represents a valuable resource for biosynthetic investigations.

Candida albicans↗

PubMed2026

The catheterized urinary tract selects for MRR1-mediated efflux and fluconazole resistance in Candida albicans biofilms.

Catheter-associated urinary tract infections (CAUTIs) are the most common nosocomial infection in developed countries, and Candida species are among the most frequently isolated organisms. Despite this, little is known about the biology, host-pathogen interactions, or outcomes of these infections, and this has led to uncertain guidelines for clinical management of Candida CAUTIs. Here, we develop the first physiologically relevant artificial urine medium (AUM) that supports fungal growth in a manner similar to, but more consistent than, human urine samples. We demonstrate that human catheter-associated (CA) clinical isolates of C. albicans exhibit environment-dependent fluconazole resistance: many isolates determined to be susceptible by standard CLSI testing in RPMI (MIC ≤ 2 µg/mL) were fully resistant (MIC ≥ 128 µg/mL) when grown in pooled human urine or AUM, complicating clinical management, which is based on catheter exchange and fluconazole treatment. Transcriptomic profiling of biofilms formed in AUM revealed a remarkably convergent upregulation of efflux and detoxification processes across clinical isolates with diverse biofilm phenotypes. Whole-genome sequencing of the CA isolates identified variant alleles of transcriptional regulators of drug efflux, including MRR1, that have been previously associated with antifungal resistance. A competition assay confirmed that Mrr1 provides a fitness advantage in urine and AUM in a urea-dependent manner. Thus, we show that the urinary environment promotes a unique biofilm differentiation program and selects for adaptations that increase drug resistance and would be predicted to render standard treatment regimens ineffective.IMPORTANCECatheter-associated urinary tract infections are the most common nosocomial infection in the United States, and Candida albicans is one of the most frequently isolated organisms from these infections. Despite this high prevalence, few molecular studies have examined C. albicans biology in the urinary environment, and recommendations for clinical management lack robust evidence. Here, we show that clinical catheter-associated isolates of C. albicans identified as susceptible to fluconazole by standard clinical microbiology testing were resistant when grown in human or artificial urine. We identified transcriptional responses intrinsic to the urinary environment that produce this environment-specific resistance phenotype. Biofilm growth in the urinary environment induces cellular processes for efflux and detoxification. These findings suggest that standard susceptibility testing may not predict fluconazole efficacy in the urinary tract and underscore the need for niche-informed approaches to antifungal management of these common infections.

Candida albicans↗

PubMed2026

Functional analysis of Candida albicans protein kinases identifies Crk1 as a modulator of epithelial cell damage.

UNLABELLED: The commensal and pathogenic lifestyles of the opportunistic fungal pathogen Candida albicans require complex signaling networks regulated by protein kinases. To investigate the role of C. albicans protein kinases at the intestinal epithelial interface, we screened a comprehensive protein kinase deletion library for the capacity of the mutants to damage intestinal epithelial cells (IEC). Mutants showing altered IEC cytotoxicity relative to the wild type were further analyzed for their growth and morphology, focusing on hyper-damaging strains to identify kinases that rather prevent host cell damage. Deletion of CRK1 caused increased IEC-specific damage, despite slower growth, reduced hyphal length, and reduced adhesion as compared to wild-type cells. While tissue invasion levels and the formation of transcellular tunnels of the crk1Δ/Δ mutant were increased, the translocation capacity through the IEC barrier was reduced. Transcriptional and metabolic profiling suggested a role for Crk1 in metabolic adaptation to carbon and nitrogen sources, which was validated by showing that high glucose and amino acids are required for crk1Δ/Δ to cause increased IEC damage. Deletion of CRK1 rendered C. albicans more susceptible to cell wall and membrane stressors, but caused higher resistance to a catalase-specific and histidine biosynthesis inhibitor. This phenotypic pattern of medium- and epithelial cell type-specific cytotoxicity displayed by a C. albicans protein kinase mutant suggests that Crk1 regulates processes linked to carbon and amino acid metabolism that are relevant to interactions with intestinal epithelial cells. IMPORTANCE: Microbial signal transduction pathways regulate adaptation to changing environmental conditions and facilitate the success of many microbes during interactions with their hosts. The fungal pathobiont Candida albicans exists as a harmless commensal on mucosal surfaces of most humans but can also cause superficial and invasive infections under certain circumstances. Both lifestyles require complex signaling networks, predominantly regulated by protein kinases. The C. albicans genome was predicted to encode 108 protein kinases, yet nearly 50% remain uncharacterized. We aimed to dissect the role of C. albicans protein kinases during the transition from commensal to pathogen. We showed that multiple protein kinase genes are involved in epithelial cell damage. Particularly, the protein kinase gene Crk1 was of interest because deletion of CRK1 caused increased damage to intestinal epithelial cells under distinct conditions. Our study links Crk1 with regulation of metabolic processes relevant for commensalism and pathogenicity of C. albicans.

Candida albicans↗