scholarly journals Adaptation to the dietary sugar D-tagatose via genome instability in polyploid Candida albicans cells

2021 ◽  
Author(s):  
Gregory J Thomson ◽  
Pallavi Kakade ◽  
Matthew P Hirakawa ◽  
Iuliana V Ene ◽  
Richard J Bennett
Keyword(s):  
Candida Albicans ◽  
Genome Instability ◽  
Carbon Sources ◽  
Metabolic Adaptation ◽  
Chromosome Loss ◽  
Tetraploid Cell ◽  
Parasexual Cycle ◽  
Chromosomal Changes ◽  
Opportunistic Fungal Pathogen ◽  
Diploid Cells

Abstract The opportunistic fungal pathogen Candida albicans undergoes an unusual parasexual cycle wherein diploid cells mate to form tetraploid cells that can generate genetically diverse progeny via a non-meiotic program of chromosome loss. The genetic diversity afforded by parasex impacts clinically relevant features including drug resistance and virulence, and yet the factors influencing genome instability in C. albicans are not well defined. To understand how environmental cues impact genome instability, we monitored ploidy change following tetraploid cell growth in a panel of different carbon sources. We found that growth in one carbon source, D-tagatose, led to high levels of genomic instability and chromosome loss in tetraploid cells. This sugar is a stereoisomer of L-sorbose which was previously shown to promote karyotypic changes in C. albicans. However, while expression of the SOU1 gene enabled utilization of L-sorbose, overexpression of this gene did not promote growth in D-tagatose, indicating differences in assimilation of the two sugars. In addition, genome sequencing of multiple progeny recovered from D-tagatose cultures revealed increased relative copy numbers of chromosome 4, suggestive of chromosome-level regulation of D-tagatose metabolism. Together, these studies identify a novel environmental cue that induces genome instability in C. albicans, and further implicate chromosomal changes in supporting metabolic adaptation in this species.

scholarly journals Parasexuality and Ploidy Change in Candida tropicalis

2013 ◽  
Vol 12 (12) ◽  
pp. 1629-1640 ◽  
Author(s):  
Riyad N. H. Seervai ◽  
Stephen K. Jones ◽  
Matthew P. Hirakawa ◽  
Allison M. Porman ◽  
Richard J. Bennett
Keyword(s):  
Sexual Reproduction ◽  
Candida Tropicalis ◽  
Culture Conditions ◽  
Sexual Cycle ◽  
Chromosome Loss ◽  
Parasexual Cycle ◽  
Content Type ◽  
Ploidy Changes ◽  
Diploid Cells

ABSTRACTCandidaspecies exhibit a variety of ploidy states and modes of sexual reproduction. Most species possess the requisite genes for sexual reproduction, recombination, and meiosis, yet only a few have been reported to undergo a complete sexual cycle including mating and sporulation.Candida albicans, the most studiedCandidaspecies and a prevalent human fungal pathogen, completes its sexual cycle via a parasexual process of concerted chromosome loss rather than a conventional meiosis. In this study, we examine ploidy changes inCandida tropicalis, a closely related species toC. albicansthat was recently revealed to undergo sexual mating.C. tropicalisdiploid cells mate to form tetraploid cells, and we show that these can be induced to undergo chromosome loss to regenerate diploid forms by growth on sorbose medium. The diploid products are themselves mating competent, thereby establishing a parasexual cycle in this species for the first time. Extended incubation (>120 generations) ofC. tropicalistetraploid cells under rich culture conditions also resulted in instability of the tetraploid form and a gradual reduction in ploidy back to the diploid state. The fitness levels ofC. tropicalisdiploid and tetraploid cells were compared, and diploid cells exhibited increased fitness relative to tetraploid cellsin vitro, despite diploid and tetraploid cells having similar doubling times. Collectively, these experiments demonstrate distinct pathways by which a parasexual cycle can occur inC. tropicalisand indicate that nonmeiotic mechanisms drive ploidy changes in this prevalent human pathogen.

scholarly journals A Suppressor Mutation in the β-Subunit Kis1 Restores Functionality of the SNF1 Complex in Candida albicans snf4 Δ Mutants

mSphere ◽  
2021 ◽  
Author(s):  
Bernardo Ramírez-Zavala ◽  
Austin Mottola ◽  
Ines Krüger ◽  
Joachim Morschhäuser
Keyword(s):  
Candida Albicans ◽  
Protein Kinase ◽  
Carbon Sources ◽  
Metabolic Adaptation ◽  
Β Subunit ◽  
Wild Type ◽  
Pathogenic Yeast ◽  
Α Subunit ◽  
Content Type ◽  
Repressor Proteins

The highly conserved protein kinase SNF1 plays a key role in the metabolic adaptation of the pathogenic yeast Candida albicans , but it is not clear how it regulates its downstream targets in this fungus. We show that the repressor proteins Mig1 and Mig2 are phosphorylated also in cells lacking the catalytic α-subunit Snf1 of the SNF1 complex, but the amounts of both proteins were reduced in wild-type cells when glucose was replaced by alternative carbon sources, pointing to an indirect mechanism of regulation.

scholarly journals N -Acetylglucosamine (GlcNAc)-Inducible Gene GIG2 Is a Novel Component of GlcNAc Metabolism in Candida albicans

2013 ◽  
Vol 13 (1) ◽  
pp. 66-76 ◽  
Author(s):  
Swagata Ghosh ◽  
Kongara Hanumantha Rao ◽  
Neel Sarovar Bhavesh ◽  
Gobardhan Das ◽  
Ved Prakash Dwivedi ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Carbon Sources ◽  
Transcriptional Responses ◽  
Content Type ◽  
Metabolic Intermediates ◽  
Catabolic Genes ◽  
Opportunistic Fungal Pathogen ◽  
Targeted Inhibition ◽  
Mutant Cells ◽  
Insight Into

ABSTRACT Candida albicans is an opportunistic fungal pathogen that resides in the human body as a commensal and can turn pathogenic when the host is immunocompromised. Adaptation of C. albicans to host niche-specific conditions is important for the establishment of pathogenicity, where the ability of C. albicans to utilize multiple carbon sources provides additional flexibility. One alternative sugar is N -acetylglucosamine (GlcNAc), which is now established as an important carbon source for many pathogens and can also act as a signaling molecule. Although GlcNAc catabolism has been well studied in many pathogens, the importance of several enzymes involved in the formation of metabolic intermediates still remains elusive. In this context, microarray analysis was carried out to investigate the transcriptional responses induced by GlcNAc under different conditions. A novel gene that was highly upregulated immediately following the GlcNAc catabolic genes was identified and was named GIG2 (GlcNAc-induced gene 2). This gene is regulated in a manner distinct from that of the GlcNAc-induced genes described previously in that GlcNAc metabolism is essential for its induction. Furthermore, this gene is involved in the metabolism of N -acetylneuraminate (sialic acid), a molecule equally important for initial host-pathogen recognition. Mutant cells showed a considerable decrease in fungal burden in mouse kidneys and were hypersensitive to oxidative stress conditions. Since GIG2 is also present in many other fungal and enterobacterial genomes, targeted inhibition of its activity would offer insight into the treatment of candidiasis and other fungal or enterobacterial infections.

scholarly journals Control of Candida albicans Metabolism and Biofilm Formation by Pseudomonas aeruginosa Phenazines

mBio ◽  
2013 ◽  
Vol 4 (1) ◽  
Author(s):  
Diana K. Morales ◽  
Nora Grahl ◽  
Chinweike Okegbe ◽  
Lars E. P. Dietrich ◽  
Nicholas J. Jacobs ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Candida Albicans ◽  
Biofilm Formation ◽  
Carbon Sources ◽  
Metabolic Effects ◽  
Respiratory Metabolism ◽  
Fermentation Products ◽  
Content Type ◽  
Opportunistic Fungal Pathogen ◽  
Biofilm Development

ABSTRACTCandida albicanshas developmental programs that govern transitions between yeast and filamentous morphologies and between unattached and biofilm lifestyles. Here, we report that filamentation, intercellular adherence, and biofilm development were inhibited during interactions betweenCandida albicansandPseudomonas aeruginosathrough the action ofP. aeruginosa-produced phenazines. While phenazines are toxic toC. albicansat millimolar concentrations, we found that lower concentrations of any of three different phenazines (pyocyanin, phenazine methosulfate, and phenazine-1-carboxylate) allowed growth but affected the development ofC. albicanswrinkled colony biofilms and inhibited the fungal yeast-to-filament transition. Phenazines impairedC. albicansgrowth on nonfermentable carbon sources and led to increased production of fermentation products (ethanol, glycerol, and acetate) in glucose-containing medium, leading us to propose that phenazines specifically inhibited respiration. Methylene blue, another inhibitor of respiration, also prevented the formation of structured colony biofilms. The inhibition of filamentation and colony wrinkling was not solely due to lowered extracellular pH induced by fermentation. Compared to smooth, unstructured colonies, wrinkled colony biofilms had higher oxygen concentrations within the colony, and wrinkled regions of these colonies had higher levels of respiration. Together, our data suggest that the structure of the fungal biofilm promotes access to oxygen and enhances respiratory metabolism and that the perturbation of respiration by bacterial molecules such as phenazines or compounds with similar activities disrupts these pathways. These findings may suggest new ways to limit fungal biofilms in the context of disease.IMPORTANCEMany of the infections caused byCandida albicans, a major human opportunistic fungal pathogen, involve both morphological transitions and the formation of surface-associated biofilms. Through the study ofC. albicansinteractions with the bacteriumPseudomonas aeruginosa, which often coinfects withC. albicans, we have found thatP. aeruginosa-produced phenazines modulateC. albicansmetabolism and, through these metabolic effects, impact cellular morphology, cell-cell interactions, and biofilm formation. We suggest that the structure ofC. albicansbiofilms promotes access to oxygen and enhances respiratory metabolism and that the perturbation of respiration by phenazines inhibits biofilm development. Our findings not only provide insight into interactions between these species but also provide valuable insights into novel pathways that could lead to the development of new therapies to treatC. albicansinfections.

scholarly journals Candida albicans Hexokinase 2 Challenges the Saccharomyces cerevisiae Moonlight Protein Model

2021 ◽  
Vol 9 (4) ◽  
pp. 848
Author(s):  
Romain Laurian ◽  
Jade Ravent ◽  
Karine Dementhon ◽  
Marc Lemaire ◽  
Alexandre Soulard ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Candida Albicans ◽  
Glucose Repression ◽  
Carbon Sources ◽  
Metabolic Adaptation ◽  
Dual Function ◽  
Pathogenic Yeast ◽  
Hexokinase 2 ◽  
Regulatory Functions ◽  
The Impact

Survival of the pathogenic yeast Candida albicans depends upon assimilation of fermentable and non-fermentable carbon sources detected in host microenvironments. Among the various carbon sources encountered in a human body, glucose is the primary source of energy. Its effective detection, metabolism and prioritization via glucose repression are primordial for the metabolic adaptation of the pathogen. In C. albicans, glucose phosphorylation is mainly performed by the hexokinase 2 (CaHxk2). In addition, in the presence of glucose, CaHxK2 migrates in the nucleus and contributes to the glucose repression signaling pathway. Based on the known dual function of the Saccharomyces cerevisiae hexokinase 2 (ScHxk2), we intended to explore the impact of both enzymatic and regulatory functions of CaHxk2 on virulence, using a site-directed mutagenesis approach. We show that the conserved aspartate residue at position 210, implicated in the interaction with glucose, is essential for enzymatic and glucose repression functions but also for filamentation and virulence in macrophages. Point mutations and deletion into the N-terminal region known to specifically affect glucose repression in ScHxk2 proved to be ineffective in CaHxk2. These results clearly show that enzymatic and regulatory functions of the hexokinase 2 cannot be unlinked in C. albicans.

scholarly journals A ‘parameiosis’ drives depolyploidization and homologous recombination in Candida albicans

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Matthew Z. Anderson ◽  
Gregory J. Thomson ◽  
Matthew P. Hirakawa ◽  
Richard J. Bennett
Keyword(s):  
Candida Albicans ◽  
Mammalian Cells ◽  
Strand Break ◽  
Chromosome Loss ◽  
Recombination Rates ◽  
Human Fungal Pathogen ◽  
Dna Double Strand Break ◽  
Extant Species ◽  
Specific Factors ◽  
Diploid Cells

Abstract Meiosis is a conserved tenet of sexual reproduction in eukaryotes, yet this program is seemingly absent from many extant species. In the human fungal pathogen Candida albicans, mating of diploid cells generates tetraploid products that return to the diploid state via a non-meiotic process of depolyploidization known as concerted chromosome loss (CCL). Here, we report that recombination rates are more than three orders of magnitude higher during CCL than during normal mitotic growth. Furthermore, two conserved ‘meiosis-specific’ factors play central roles in CCL as SPO11 mediates DNA double-strand break formation while both SPO11 and REC8 regulate chromosome stability and promote inter-homolog recombination. Unexpectedly, SPO11 also promotes DNA repair and recombination during normal mitotic divisions. These results indicate that C. albicans CCL represents a ‘parameiosis’ that blurs the conventional boundaries between mitosis and meiosis. They also reveal parallels with depolyploidization in mammalian cells and provide potential insights into the evolution of meiosis.

scholarly journals Host-Induced Genome Instability Rapidly Generates Phenotypic Variation across Candida albicans Strains and Ploidy States

mSphere ◽  
2020 ◽  
Vol 5 (3) ◽  
Author(s):  
Amanda C. Smith ◽  
Meleah A. Hickman
Keyword(s):  
Genetic Variation ◽  
Candida Albicans ◽  
Genome Size ◽  
Genetic Background ◽  
Genome Instability ◽  
Content Type ◽  
Host Environment ◽  
Genomic Changes ◽  
Opportunistic Fungal Pathogen

ABSTRACT Candida albicans is an opportunistic fungal pathogen of humans that is typically diploid yet has a highly labile genome tolerant of large-scale perturbations including chromosomal aneuploidy and loss-of-heterozygosity events. The ability to rapidly generate genetic variation is crucial for C. albicans to adapt to changing or stressful environments, like those encountered in the host. Genetic variation occurs via stress-induced mutagenesis or can be generated through its parasexual cycle, in which tetraploids arise via diploid mating or stress-induced mitotic defects and undergo nonmeiotic ploidy reduction. However, it remains largely unknown how genetic background contributes to C. albicans genome instability in vitro or in the host environment. Here, we tested how genetic background, ploidy, and the host environment impacts C. albicans genome stability. We found that host association induced both loss-of-heterozygosity events and genome size changes, regardless of genetic background or ploidy. However, the magnitude and types of genome changes varied across C. albicans strain background and ploidy state. We then assessed if host-induced genomic changes resulted in fitness consequences on growth rate and nonlethal virulence phenotypes and found that many host-derived isolates significantly changed relative to their parental strain. Interestingly, diploid host-associated C. albicans predominantly decreased host reproductive fitness, whereas tetraploid host-associated C. albicans increased host reproductive fitness. Together, these results are important for understanding how host-induced genomic changes in C. albicans alter its relationship with the host. IMPORTANCE Candida albicans is an opportunistic fungal pathogen of humans. The ability to generate genetic variation is essential for adaptation and is a strategy that C. albicans and other fungal pathogens use to change their genome size. Stressful environments, including the host, induce C. albicans genome instability. Here, we investigated how C. albicans genetic background and ploidy state impact genome instability, both in vitro and in a host environment. We show that the host environment induces genome instability, but the magnitude depends on C. albicans genetic background. Furthermore, we show that tetraploid C. albicans is highly unstable in host environments and rapidly reduces in genome size. These reductions in genome size often resulted in reduced virulence. In contrast, diploid C. albicans displayed modest host-induced genome size changes, yet these frequently resulted in increased virulence. Such studies are essential for understanding how opportunistic pathogens respond and potentially adapt to the host environment.

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