Review

Authors: Sónia Silva, Melyssa Negri, Mariana Henriques...

The incidence of infections caused by Candida species (candidosis) has increased considerably over the past three decades, mainly due to the rise of the AIDS epidemic, an increasingly aged population, higher numbers of immunocompromised patients and the more widespread use of indwelling medical devices. Candida albicans is the main cause of candidosis; however, non-C. albicans Candida (NCAC) species such as Candida glabrata, Candida tropicalis and Candida parapsilosis are now frequently identified as human pathogens. The apparent increased emergence of these species as human pathogens can be attributed to improved identification methods and also associated with the degree of diseases of the patients, the interventions that they were subjected and the drugs used. Candida pathogenicity is facilitated by a number of virulence factors, most importantly adherence to host surfaces including medical devices, biofilm formation and secretion of hydrolytic enzymes (e.g. proteases, phospholipases and haemolysins). Furthermore, despite extensive research to identify pathogenic factors in fungi, particularly in C. albicans, relatively little is known about NCAC species. This review provides information on the current state of knowledge on the biology, identification, epidemiology, pathogenicity and antifungal resistance of C. glabrata, C. parapsilosis and C. tropicalis.

Topics: Animals; Antifungal Agents; Candida; Candida glabrata; Candida tropicalis; Candidiasis; Drug Resistance, Fungal; Humans

PubMed: 21569057
DOI: 10.1111/j.1574-6976.2011.00278.x

Review

Authors: K E Pristov, M A Ghannoum

BACKGROUND

Recently there has been an increase in Candida infections worldwide. A handful of species in the genus Candida are opportunistic pathogens and have been known to cause infections in immunocompromised or otherwise impaired hosts. These infections can be superficial, affecting the skin or mucous membrane, or invasive, which can be life-threatening. Azoles and echinocandins are antifungal drugs used globally to treat Candida infections. However, resistance to these antifungal drugs has increased in many of the Candida species, and the effects this has in the clinical setting can be seen.

OBJECTIVES

Here, we discuss the mechanisms that Candida albicans, Candida dubliniensis, Candida glabrata, Candida parapsilosis, Candida tropicalis and Candida auris are implementing to increase resistance to azoles and echinocandins, and how they are affecting clinical, or hospital, settings worldwide.

SOURCES

Different studies and papers describing the mechanisms of antifungal drugs and Candida species evolution to becoming resistant to these drugs were looked at for this review.

CONTENT

We discuss the mechanisms that azoles and echinocandins use against Candida species to treat infections, as well as the evolution of these fungi to become resistant to these drugs, and the effect this has in the clinical settings around the globe.

IMPLICATIONS

Increased resistance to azoles and echinocandins by Candida species is an increasingly serious problem in clinical settings worldwide. Understanding the mechanisms used against antifungal drugs is imperative for patient treatment.

Topics: Antifungal Agents; Azoles; Candida; Candida albicans; Candida glabrata; Drug Resistance, Multiple, Fungal; Echinocandins; Humans; Microbial Sensitivity Tests

PubMed: 30965100
DOI: 10.1016/j.cmi.2019.03.028

Candida glabrata (Nakaseomyces glabrata): A systematic review of clinical and microbiological data from 2011 to 2021 to inform the World Health Organization Fungal Priority Pathogens List.

Authors: Justin Beardsley, Hannah Yejin Kim, Aiken Dao...

Recognising the growing global burden of fungal infections, the World Health Organization (WHO) established an advisory group consisting of experts in fungal diseases to develop a Fungal Priority Pathogen List. Pathogens were ranked based on their research and development needs and perceived public health importance using a series of global surveys and pathogen characteristics derived from systematic reviews. This systematic review evaluates the features and global impact of invasive disease caused by Candida glabrata (Nakaseomyces glabrata). PubMed and Web of Science were searched for studies reporting on mortality, morbidity (hospitalization and disability), drug resistance (including isolates from sterile and non-sterile sites, since these reflect the same organisms causing invasive infections), preventability, yearly incidence, diagnostics, treatability, and distribution/emergence in the last 10 years. Candida glabrata (N. glabrata) causes difficult-to-treat invasive infections, particularly in patients with underlying conditions such as immunodeficiency, diabetes, or those who have received broad-spectrum antibiotics or chemotherapy. Beyond standard infection prevention and control measures, no specific preventative measures have been described. We found that infection is associated with high mortality rates and that there is a lack of data on complications and sequelae. Resistance to azoles is common and well described in echinocandins-in both cases, the resistance rates are increasing. Candida glabrata remains mostly susceptible to amphotericin and flucytosine. However, the incidence of the disease is increasing, both at the population level and as a proportion of all invasive yeast infections, and the increases appear related to the use of antifungal agents.

Topics: Candida glabrata; Humans; Drug Resistance, Fungal; Antifungal Agents; World Health Organization; Candidiasis; Global Health; Incidence

PubMed: 38935913
DOI: 10.1093/mmy/myae041

Review

Authors: Khadija M Ahmad, Janez Kokošar, Xiaoxian Guo...

The yeast pathogen Candida glabrata is the second most frequent cause of Candida infections. However, from the phylogenetic point of view, C. glabrata is much closer to Saccharomyces cerevisiae than to Candida albicans. Apparently, this yeast has relatively recently changed its life style and become a successful opportunistic pathogen. Recently, several C. glabrata sister species, among them clinical and environmental isolates, have had their genomes characterized. Also, hundreds of C. glabrata clinical isolates have been characterized for their genomes. These isolates display enormous genomic plasticity. The number and size of chromosomes vary drastically, as well as intra- and interchromosomal segmental duplications occur frequently. The observed genome alterations could affect phenotypic properties and thus help to adapt to the highly variable and harsh habitats this yeast finds in different human patients and their tissues. Further genome sequencing of pathogenic isolates will provide a valuable tool to understand the mechanisms behind genome dynamics and help to elucidate the genes contributing to the virulence potential.

Topics: Adaptation, Biological; Candida glabrata; Gene Order; Gene Rearrangement; Genome, Fungal; Genomic Structural Variation

PubMed: 24528571
DOI: 10.1111/1567-1364.12145

Review

Authors: Sascha Brunke, Bernhard Hube

Candida albicans and C. glabrata are the two most common pathogenic yeasts of humans, yet they are phylogenetically, genetically and phenotypically very different. In this review, we compare and contrast the strategies of C. albicans and C. glabrata to attach to and invade into the host, obtain nutrients and evade the host immune response. Although their strategies share some basic concepts, they differ greatly in their outcome. While C. albicans follows an aggressive strategy to subvert the host response and to obtain nutrients for its survival, C. glabrata seems to have evolved a strategy which is based on stealth, evasion and persistence, without causing severe damage in murine models. However, both fungi are successful as commensals and as pathogens of humans. Understanding these strategies will help in finding novel ways to fight Candida, and fungal infections in general.

Topics: Candida albicans; Candida glabrata; Candidiasis; Cell Adhesion; Host-Pathogen Interactions; Humans; Phylogeny

PubMed: 23253282
DOI: 10.1111/cmi.12091

Authors: Jane Usher, Gabriela F Ribeiro, Delma S Childers...

Reference strains improve reproducibility by standardizing observations and methodology, which has ultimately led to important insights into fungal pathogenesis. However, recent investigations have highlighted significant genotypic and phenotypic heterogeneity across isolates that influence genetic circuitry and virulence within a species. Candida glabrata is the second leading cause of candidiasis, a life-threatening infection, and undergoes extensive karyotype and phenotypic changes in response to stress. Much of the work conducted on this pathogen has focused on two sequenced strains, CBS138 (ATCC 2001) and BG2. Few studies have compared these strains in detail, but key differences include mating type and altered patterns of expression of EPA adhesins. In fact, most C. glabrata isolates and BG2 are , while CBS138 is . However, it is not known if other phenotypic differences between these strains play a role in our understanding of C. glabrata pathogenesis. Thus, we set out to characterize metabolic, cell wall, and host-interaction attributes for CBS138 and BG2. We found that BG2 utilized a broader range of nitrogen sources and had reduced cell wall size and carbohydrate exposure than CBS138, which we hypothesized results in differences in innate immune interactions and virulence. We observed that, although both strains were phagocytosed to a similar extent, BG2 replicated to higher numbers in macrophages and was more virulent during Galleria mellonella infection than CBS138 in a dose-dependent manner. Interestingly, deletion of , a major nutrient sensor, did not affect virulence in G. mellonella for BG2, but significantly enhanced larval killing in the CBS138 background compared to the parent strain. Understanding these fundamental differences in metabolism and host interactions will allow more robust conclusions to be drawn in future studies of C. glabrata pathogenesis. Reference strains provide essential insights into the mechanisms underlying virulence in fungal pathogens. However, recent studies in Candida albicans and other species have revealed significant genotypic and phenotypic diversity within clinical isolates that are challenging paradigms regarding key virulence factors and their regulation. Candida glabrata is the second leading cause of candidiasis, and many studies use BG2 or CBS138 for their investigations. Therefore, we aimed to characterize important virulence-related phenotypes for both strains that might alter conclusions about C. glabrata pathogenesis. Our study provides context for metabolic and cell wall changes and how these may influence host interaction phenotypes. Understanding these differences is necessary to support robust conclusions about how virulence factors may function in these and other very different strain backgrounds.

Topics: Candida glabrata; Fungal Proteins; Reproducibility of Results; Candidiasis; Phenotype; Virulence Factors

PubMed: 36633405
DOI: 10.1128/spectrum.03724-22

Review

Authors: Hsueh-lui Ho, Ken Haynes

In recent years, there has been a noticeable rise in fungal infections related to non-albicans Candida species, including Candida glabrata which has both intrinsic resistance to and commonly acquired resistance to azole antifungals. Phylogenetically, C. glabrata is more closely related to the mostly non-pathogenic model organism Saccharomyces cerevisiae than to other Candida species. Despite C. glabrata's designation as a pathogen by Wickham in 1957, relatively little is known about its mechanism of virulence. Over the past few years, technology to analyse the molecular basis of infection has developed rapidly, and here we briefly review the major advances in tools and technologies available to explore and investigate the virulence of C. glabrata that have occurred over the past decade.

Topics: Animals; Candida glabrata; Candidiasis; Disease Models, Animal; Genetics, Microbial; Humans; Molecular Biology; Virulence; Virulence Factors

PubMed: 26205243
DOI: 10.1093/femsyr/fov066

Comparative Study

Authors: Elan E Filler, Yaoping Liu, Norma V Solis...

The mechanisms by which resists host defense peptides and caspofungin are incompletely understood. To identify transcriptional regulators that enable to withstand these classes of stressors, a library of 215 transcriptional regulatory deletion mutants was screened for susceptibility to both protamine and caspofungin. We identified eight mutants that had increased susceptibility to both host defense peptides and caspofungin. Of these mutants, six were deleted for genes that were predicted to specify proteins involved in histone modification. These genes were , , , , , and Deletion of , , and also increased susceptibility to mammalian host defense peptides. The Δ and Δ mutants had increased susceptibility to other stressors, such as HO and SDS. In the model of disseminated infection, the Δ and Δ mutants had attenuated virulence, whereas in neutropenic mice, the virulence of the Δ and Δ mutants was decreased. Thus, histone modification plays a central role in enabling to survive host defense peptides and caspofungin, and Ada2 and Rpd3 are essential for the maximal virulence of this organism during disseminated infection.

Topics: Candida glabrata; Fungal Proteins; Gene Deletion; Genetic Variation; Host-Pathogen Interactions; Humans; Mutation; Transcription Factors; Virulence

PubMed: 33318139
DOI: 10.1128/IAI.00146-20

Authors: Oscar Hernández-Carreón, Cesia Hernández-Howell, Grecia Hernández-Hernández...

The most common nosocomial fungal infections are caused by several species of Candida, of which Candida glabrata is the second most frequently isolated species from bloodstream infections. C. glabrata displays relatively high minimal inhibitory concentration values (MIC) to the antifungal fluconazole and is associated with high mortality rates. To decrease mortality rates, the appropriate treatment must be administered promptly. C. glabrata contains in its genome several non-identical copies of species-specific sequences. We designed three pairs of C. glabrata-specific primers for endpoint PCR amplification that align to these species-specific sequences and amplify the different copies in the genome. Using these primers, we developed a fast, sensitive, inexpensive, and highly specific PCR-based method to positively detect C. glabrata DNA in a concentration-dependent manner from mixes of purified genomic DNA of several Candida species, as well as from hemocultures and urine clinical samples. This tool can be used for positive identification of C. glabrata in the clinic.

Topics: Antifungal Agents; Candida glabrata; Candidiasis; DNA Primers; Fluconazole; Humans; Microbial Sensitivity Tests; Polymerase Chain Reaction

PubMed: 34331680
DOI: 10.1007/s42770-021-00584-2

Authors: Javier Coloma, Nayim Gonzalez-Rodriguez, Francisco A Balaguer...

The CST complex is a key player in telomere replication and stability, which in yeast comprises Cdc13, Stn1 and Ten1. While Stn1 and Ten1 are very well conserved across species, Cdc13 does not resemble its mammalian counterpart CTC1 either in sequence or domain organization, and Cdc13 but not CTC1 displays functions independently of the rest of CST. Whereas the structures of human CTC1 and CST have been determined, the molecular organization of Cdc13 remains poorly understood. Here, we dissect the molecular architecture of Candida glabrata Cdc13 and show how it regulates binding to telomeric sequences. Cdc13 forms dimers through the interaction between OB-fold 2 (OB2) domains. Dimerization stimulates binding of OB3 to telomeric sequences, resulting in the unfolding of ssDNA secondary structure. Once bound to DNA, Cdc13 prevents the refolding of ssDNA by mechanisms involving all domains. OB1 also oligomerizes, inducing higher-order complexes of Cdc13 in vitro. OB1 truncation disrupts these complexes, affects ssDNA unfolding and reduces telomere length in C. glabrata. Together, our results reveal the molecular organization of C. glabrata Cdc13 and how this regulates the binding and the structure of DNA, and suggest that yeast species evolved distinct architectures of Cdc13 that share some common principles.

Topics: Humans; Candida glabrata; Telomere-Binding Proteins; Protein Binding; Shelterin Complex; Telomere

PubMed: 36629261
DOI: 10.1093/nar/gkac1261