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J. Fungi, Volume 6, Issue 1 (March 2020) – 39 articles

Cover Story (view full-size image): Confocal Scanning Fluorescence Microscopy: Green fluorescence represents P. brasiliensis yeast cells coated with F-1.4 monoclonal antibody followed by Alexa Fluor 488-labeled goat anti-mouse IgG. Blue Fluorescence represents Calcofluor-White Stain dying P. brasiliensis cell wall polysaccharides polymers. View this paper.
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Open AccessArticle
Frequency of Invasive Fungal Disease in Adults: Experience of a Specialized Laboratory in Medellín, Colombia (2009–2015)
J. Fungi 2020, 6(1), 39; https://doi.org/10.3390/jof6010039 - 20 Mar 2020
Cited by 2 | Viewed by 1155
Abstract
Invasive fungal diseases (IFD) contribute significantly to worldwide morbidity and mortality, but their frequency is not well-described in some countries. The present work describes the frequency of IFD in a specialized laboratory in Colombia. A retrospective, descriptive study was implemented between March 2009 [...] Read more.
Invasive fungal diseases (IFD) contribute significantly to worldwide morbidity and mortality, but their frequency is not well-described in some countries. The present work describes the frequency of IFD in a specialized laboratory in Colombia. A retrospective, descriptive study was implemented between March 2009 and December 2015. Results: 13,071 patients with clinical suspicion of IFD were referred during the study period, from which 33,516 biological samples were processed and analyzed using 14 laboratory methods. Diagnosis was confirmed in 1425 patients (11%), distributed according to the mycoses of interest analyzed here: histoplasmosis in 641/11,756 patients (6%), aspergillosis in 331/10,985 patients (3%), cryptococcosis in 239/8172 patients (3%), pneumocystosis in 111/1651 patients (7%), paracoccidioidomycosis in 60/10,178 patients (0.6%), and invasive candidiasis in 48/7525 patients (0.6%). From the first year of the study period to the last year, there was a 53% increase in the number of cases of IFD diagnosed. Our laboratory experienced a high frequency of IFD diagnosis, possibly attributable to the availability of a greater range of diagnostic tools. Frequency of IFD in this study was atypical compared with other studies, probably as a result of the single laboratory-site analysis. This demonstrates that implementing educational strategies helps to create a high index of clinical suspicion, while the availability and utilization of appropriate diagnostic assays assure greater reliability in identification of these cases. Full article
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Open AccessArticle
Morphological Characterization and Genetic Diversity of Rice Blast Fungus, Pyricularia oryzae, from Thailand Using ISSR and SRAP Markers
J. Fungi 2020, 6(1), 38; https://doi.org/10.3390/jof6010038 - 19 Mar 2020
Cited by 3 | Viewed by 1774
Abstract
Rice blast disease is caused by the ascomycete fungus Pyricularia oryzae and is one of the most destructive rice diseases in the world. The objectives of this study were investigating various fungal morphological characteristics and performing a phylogenetic analysis. Inter-simple sequence repeat (ISSR) [...] Read more.
Rice blast disease is caused by the ascomycete fungus Pyricularia oryzae and is one of the most destructive rice diseases in the world. The objectives of this study were investigating various fungal morphological characteristics and performing a phylogenetic analysis. Inter-simple sequence repeat (ISSR) and sequence-related amplified polymorphism (SRAP) markers were used to examine the genetic variation of 59 rice blast fungus strains, including 57 strains collected from different fields in Thailand and two reference strains, 70-15 and Guy11. All isolates used in this study were determined to be P. oryzae by internal transcribed spacer (ITS) sequence confirmation. A total of 14 ISSR primers and 17 pairs of SRAP primers, which produced clear and polymorphic bands, were selected for assessing genetic diversity. A total of 123 polymorphic bands were generated. The similarity index value for the strains ranged from 0.25 to 0.95. The results showed that the blast fungus population in Thailand has both morphological and genetic variations. A high level of genetic variation, or genome adaptation, is one of the fungal mechanisms that could overcome host resistance to avoid host recognition. Results from this research study could bring substantial benefits and ultimately help to understand the blast fungal pathogen genome and the population structure in Thai blast fungus. Full article
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Open AccessArticle
Genome Sequence Analysis of Auricularia heimuer Combined with Genetic Linkage Map
J. Fungi 2020, 6(1), 37; https://doi.org/10.3390/jof6010037 - 16 Mar 2020
Viewed by 810
Abstract
Auricularia heimuer is one of the most popular edible fungi in China. In this study, the whole genome of A. heimuer was sequenced on the Illumina HiSeq X system and compared with other mushrooms genomes. As a wood-rotting fungus, a total of 509 [...] Read more.
Auricularia heimuer is one of the most popular edible fungi in China. In this study, the whole genome of A. heimuer was sequenced on the Illumina HiSeq X system and compared with other mushrooms genomes. As a wood-rotting fungus, a total of 509 carbohydrate-active enzymes (CAZymes) were annotated in order to explore its potential capabilities on wood degradation. The glycoside hydrolases (GH) family genes in the A. heimuer genome were more abundant than the genes in the other 11 mushrooms genomes. The A. heimuer genome contained 102 genes encoding class III, IV, and V ethanol dehydrogenases. Evolutionary analysis based on 562 orthologous single-copy genes from 15 mushrooms showed that Auricularia formed an early independent branch of Agaricomycetes. The mating-type locus of A. heimuer was located on linkage group 8 by genetic linkage analysis. By combining the genome sequence analysis with the genetic linkage map, the mating-type locus of A. heimuer was located on scaffold45 and consisted of two subunits, α and β. Each subunit consisted of a pair of homeodomain mating-type protein genes HD1 and HD2. The mapping revealed conserved synteny at the whole mating-type loci and mirror symmetry relations near the β subunit between A. heimuer and Exidia glandulosa. This study proposed the potential for the bioethanol production by consolidated bioprocessing of A. heimuer. It will promote understanding of the lignocellulose degradation system and facilitate more efficient conversion of the agricultural wastes used for mushroom cultivation. It also will advance the research on the fruiting body development and evolution of A. heimuer. Full article
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Open AccessArticle
Baseline Chest Computed Tomography as Standard of Care in High-Risk Hematology Patients
J. Fungi 2020, 6(1), 36; https://doi.org/10.3390/jof6010036 - 13 Mar 2020
Cited by 2 | Viewed by 1382
Abstract
Baseline chest computed tomography (BCT) in high-risk hematology patients allows for the early diagnosis of invasive pulmonary aspergillosis (IPA). The distribution of BCT implementation in hematology departments and impact on outcome is unknown. A web-based questionnaire was designed. International scientific bodies were invited. [...] Read more.
Baseline chest computed tomography (BCT) in high-risk hematology patients allows for the early diagnosis of invasive pulmonary aspergillosis (IPA). The distribution of BCT implementation in hematology departments and impact on outcome is unknown. A web-based questionnaire was designed. International scientific bodies were invited. The estimated numbers of annually treated hematology patients, chest imaging timepoints and techniques, IPA rates, and follow-up imaging were assessed. In total, 142 physicians from 43 countries participated. The specialties included infectious diseases (n = 69; 49%), hematology (n = 68; 48%), and others (n = 41; 29%). BCT was performed in 57% (n = 54) of 92 hospitals. Upon the diagnosis of malignancy or admission, 48% and 24% performed BCT, respectively, and X-ray was performed in 48% and 69%, respectively. BCT was more often used in hematopoietic cell transplantation and in relapsed acute leukemia. European centers performed BCT in 59% and non-European centers in 53%. Median estimated IPA rate was 8% and did not differ between BCT (9%; IQR 5–15%) and non-BCT centers (7%; IQR 5–10%) (p = 0.69). Follow-up computed tomography (CT) for IPA was performed in 98% (n = 90) of centers. In high-risk hematology patients, baseline CT is becoming a standard-of-care. Chest X-ray, while inferior, is still widely used. Randomized, controlled trials are needed to investigate the impact of BCT on patient outcome. Full article
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Open AccessReview
Applying the Host-Microbe Damage Response Framework to Candida Pathogenesis: Current and Prospective Strategies to Reduce Damage
J. Fungi 2020, 6(1), 35; https://doi.org/10.3390/jof6010035 - 11 Mar 2020
Cited by 3 | Viewed by 1259
Abstract
Disease is a complex outcome that can occur as a result of pathogen-mediated damage, host-mediated damage or both. This has led to the revolutionary concept of the damage response framework (DRF) that defines microbial virulence as a function of host immunity. The DRF [...] Read more.
Disease is a complex outcome that can occur as a result of pathogen-mediated damage, host-mediated damage or both. This has led to the revolutionary concept of the damage response framework (DRF) that defines microbial virulence as a function of host immunity. The DRF outlines six scenarios (classes) of host damage or beneficial outcomes, depending on the microbe and the strength of the immune response. Candida albicans is uniquely adapted to its human host and can exist as either a commensal, colonizing various anatomical sites without causing notable damage, or as a pathogen, with the ability to cause a diverse array of diseases, ranging from mucosal to invasive systemic infections that result in varying levels of microbe-mediated and/or host-mediated damage. We recently categorized six different forms of candidiasis (oropharyngeal, hematogenous, intra-abdominal, gastrointestinal, denture stomatitis, and vulvovaginitis) into independent DRF classes, supporting a contemporary view of unique mechanisms of pathogenesis for these Candida infections. In this review, we summarize the evidence for the pathogenesis of these various forms of candidiasis in the context of the DRF with the further intent to provide insights into strategies to achieve a level of host response or outcome otherwise, that limits host damage. Full article
(This article belongs to the Special Issue Pathogenesis of Candidiasis)
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Open AccessReview
Advances in Understanding the Acyl-CoA-Binding Protein in Plants, Mammals, Yeast, and Filamentous Fungi
J. Fungi 2020, 6(1), 34; https://doi.org/10.3390/jof6010034 - 10 Mar 2020
Viewed by 1117
Abstract
Acyl-CoA-binding protein (ACBP) is an important protein with a size of about 10 kDa. It has a high binding affinity for C12–C22 acyl-CoA esters and participates in lipid metabolism. ACBP and its family of proteins have been found in all [...] Read more.
Acyl-CoA-binding protein (ACBP) is an important protein with a size of about 10 kDa. It has a high binding affinity for C12–C22 acyl-CoA esters and participates in lipid metabolism. ACBP and its family of proteins have been found in all eukaryotes and some prokaryotes. Studies have described the function and structure of ACBP family proteins in mammals (such as humans and mice), plants (such as Oryza sativa, Arabidopsis thaliana, and Hevea brasiliensis) and yeast. However, little information on the structure and function of the proteins in filamentous fungi has been reported. This article concentrates on recent advances in the research of the ACBP family proteins in plants and mammals, especially in yeast, filamentous fungi (such as Monascus ruber and Aspergillus oryzae), and fungal pathogens (Aspergillus flavus, Cryptococcus neoformans). Furthermore, we discuss some problems in the field, summarize the binding characteristics of the ACBP family proteins in filamentous fungi and yeast, and consider the future of ACBP development. Full article
(This article belongs to the Special Issue Lipids and Fungal Infectious Diseases)
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Open AccessArticle
Posaconazole Alone and in Combination with Caspofungin for Treatment of Experimental Exserohilum rostratum Meningoencephalitis: Developing New Strategies for Treatment of Phaeohyphomycosis of the Central Nervous System
J. Fungi 2020, 6(1), 33; https://doi.org/10.3390/jof6010033 - 05 Mar 2020
Cited by 2 | Viewed by 846
Abstract
Phaeohyphomycosis of the central nervous system (CNS) is a life-threatening infection associated with severe morbidity. New approaches to treatment of CNS phaeohyphomycosis are critically needed. We therefore studied posaconazole with or without caspofungin for treatment of experimental CNS phaeohyphomycosis caused by Exserohilum rostratum [...] Read more.
Phaeohyphomycosis of the central nervous system (CNS) is a life-threatening infection associated with severe morbidity. New approaches to treatment of CNS phaeohyphomycosis are critically needed. We therefore studied posaconazole with or without caspofungin for treatment of experimental CNS phaeohyphomycosis caused by Exserohilum rostratum. Each clinical isolate of E. rostratum isolate was inoculated intracisternally with 1.0 × 106 microconidia to fully anesthetized New Zealand White rabbits. Profound persistent neutropenia and immunosuppression were established and maintained using cytarabine and methylprednisolone, respectively. Study groups consisted of posaconazole suspension administered as oral formulation at 10 (PSC10) or 20 (PSC20) mg/kg, caspofungin (CFG) at 2 mg/kg intravenously (IV), combinations of PSC10+CFG or PSC20+CFG, and untreated controls (UC). Posaconazole produced a significant reduction of residual fungal burden of E. rostratum in cerebrum, cerebellum, spinal cord, and paravertebral muscle (p < 0.01), in comparison to UC. The combination of PSC10+CFG and PSC20+CFG achieved full clearance of residual fungal burden from cerebrum, while only PSC20+CFG treated rabbits demonstrated clearance from cerebellum, spinal cord, and paravertebral muscle (p < 0.01). These data correlated with the significant reduction of CSF (1→3)-β-d-glucan levels in rabbits treated with PSC20 and PSC20+CFG in comparison to those of UC (p < 0.05). Posaconazole alone or in combination with caspofungin demonstrated significant antifungal efficacy in the treatment of experimental E. rostratum meningoencephalitis and warrants further study for treatment of CNS phaeohyphomycosis. Full article
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Open AccessReview
SUMOylation in Human Pathogenic Fungi: Role in Physiology and Virulence
J. Fungi 2020, 6(1), 32; https://doi.org/10.3390/jof6010032 - 04 Mar 2020
Cited by 2 | Viewed by 1515
Abstract
The small ubiquitin-related modifier (SUMO) protein is an important component of the post-translational protein modification systems in eukaryotic cells. It is known to modify hundreds of proteins involved in diverse cellular processes, ranging from nuclear pore dynamics to signal transduction pathways. Owing to [...] Read more.
The small ubiquitin-related modifier (SUMO) protein is an important component of the post-translational protein modification systems in eukaryotic cells. It is known to modify hundreds of proteins involved in diverse cellular processes, ranging from nuclear pore dynamics to signal transduction pathways. Owing to its reversible nature, the SUMO-conjugation of proteins (SUMOylation) holds a prominent place among mechanisms that regulate the functions of a wide array of cellular proteins. The dysfunctional SUMOylation system has been associated with many human diseases, including neurodegenerative and autoimmune disorders. Furthermore, the non-pathogenic yeast Saccharomyces cerevisiae has served as an excellent model to advance our understanding of enzymes involved in SUMOylation and proteins modified by SUMOylation. Taking advantage of the tools and knowledge obtained from the S. cerevisiae SUMOylation system, research on fungal SUMOylation is beginning to gather pace, and new insights into the role of SUMOylation in the pathobiology of medically important fungi are emerging. Here, we summarize the known information on components of the SUMOylation machinery, and consequences of overexpression or deletion of these components in the human pathogenic fungi, with major focus on two prevalent Candida bloodstream pathogens, C. albicans and C. glabrata. Additionally, we have identified SUMOylation components, through in silico analysis, in four medically relevant fungi, and compared their sequence similarity with S. cerevisiae counterparts. SUMOylation modulates the virulence of C. albicans and C. glabrata, while it is required for conidia production in Aspergillus nidulans and A. flavus. In addition to highlighting these recent developments, we discuss how SUMOylation fine tunes the expression of virulence factors, and influences survival of fungal cells under diverse stresses in vitro and in the mammalian host. Full article
(This article belongs to the Special Issue Epigenetic Regulation of Fungal Virulence)
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Open AccessReview
Immunotherapy against Systemic Fungal Infections Based on Monoclonal Antibodies
J. Fungi 2020, 6(1), 31; https://doi.org/10.3390/jof6010031 - 29 Feb 2020
Cited by 8 | Viewed by 1593
Abstract
The increasing incidence in systemic fungal infections in humans has increased focus for the development of fungal vaccines and use of monoclonal antibodies. Invasive mycoses are generally difficult to treat, as most occur in vulnerable individuals, with compromised innate and adaptive immune responses. [...] Read more.
The increasing incidence in systemic fungal infections in humans has increased focus for the development of fungal vaccines and use of monoclonal antibodies. Invasive mycoses are generally difficult to treat, as most occur in vulnerable individuals, with compromised innate and adaptive immune responses. Mortality rates in the setting of our current antifungal drugs remain excessively high. Moreover, systemic mycoses require prolonged durations of antifungal treatment and side effects frequently occur, particularly drug-induced liver and/or kidney injury. The use of monoclonal antibodies with or without concomitant administration of antifungal drugs emerges as a potentially efficient treatment modality to improve outcomes and reduce chemotherapy toxicities. In this review, we focus on the use of monoclonal antibodies with experimental evidence on the reduction of fungal burden and prolongation of survival in in vivo disease models. Presently, there are no licensed monoclonal antibodies for use in the treatment of systemic mycoses, although the potential of such a vaccine is very high as indicated by the substantial promising results from several experimental models. Full article
(This article belongs to the Special Issue Antifungal Immunity and Fungal Vaccine Development)
Open AccessReview
Candida auris: A Decade of Understanding of an Enigmatic Pathogenic Yeast
J. Fungi 2020, 6(1), 30; https://doi.org/10.3390/jof6010030 - 26 Feb 2020
Cited by 14 | Viewed by 2115
Abstract
Candida auris is an enigmatic yeast that continues to stimulate interest within the mycology community due its rapid and simultaneous emergence of distinct clades. In the last decade, almost 400 manuscripts have contributed to our understanding of this pathogenic yeast. With dynamic epidemiology, [...] Read more.
Candida auris is an enigmatic yeast that continues to stimulate interest within the mycology community due its rapid and simultaneous emergence of distinct clades. In the last decade, almost 400 manuscripts have contributed to our understanding of this pathogenic yeast. With dynamic epidemiology, elevated resistance levels and an indication of conserved and unique pathogenic traits, it is unsurprising that it continues to cause clinical concern. This mini-review aims to summarise some of the key attributes of this remarkable pathogenic yeast. Full article
(This article belongs to the Special Issue Pathogenesis of Candidiasis)
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Open AccessArticle
Effects of Seedling Age on Colonization Patterns of Citrus limon Plants by Endophytic Beauveria bassiana and Metarhizium anisopliae and Their Influence on Seedlings Growth
J. Fungi 2020, 6(1), 29; https://doi.org/10.3390/jof6010029 - 25 Feb 2020
Cited by 3 | Viewed by 1081
Abstract
The inoculation methods, the fungal strains, and several other factors are known to influent the success of fungal entomopathogens colonization in plants. The physiological status of the plant could also be another determinant. In the present study, the ability of three strains of [...] Read more.
The inoculation methods, the fungal strains, and several other factors are known to influent the success of fungal entomopathogens colonization in plants. The physiological status of the plant could also be another determinant. In the present study, the ability of three strains of Beauveria bassiana and one strain of Metarhizium anisopliae to successfully colonize Citrus limon plants and the influence of seedling age on endophytic colonization success was examined. Three, 4, and 6 months old seedlings were inoculated with 10 mL of 1 × 108 conidial·mL−1 suspensions of each of the four fungal strains via foliar spraying. All fungal strains successfully colonized citrus seedlings and were sustained up to 2 months in colonized plants irrespective of the seedling age, with differences in the mean percentage colonization recorded at various post-inoculation periods among the fungal strains. The highest percent endophytic fungi recovery rate was recorded in the 3 months old seedlings, where fungal mycelia of inoculated fungi were successfully re-isolated from 65.6% of the untreated newly developed leaf and stem tissues. One strain of B. bassiana, BB Fafu-12, significantly improved seedling height and leaf number. The study demonstrates the influence of seedling age on B. bassiana and M. anisopliae successful colonization in the citrus plant. Full article
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Open AccessReview
Aspiring Antifungals: Review of Current Antifungal Pipeline Developments
J. Fungi 2020, 6(1), 28; https://doi.org/10.3390/jof6010028 - 25 Feb 2020
Cited by 25 | Viewed by 3087
Abstract
Invasive fungal infections are associated with significant morbidity and mortality, and their management is restricted to a variety of agents from five established classes of antifungal medication. In practice, existing antifungal agents are often constrained by dose-limiting toxicities, drug interactions, and the routes [...] Read more.
Invasive fungal infections are associated with significant morbidity and mortality, and their management is restricted to a variety of agents from five established classes of antifungal medication. In practice, existing antifungal agents are often constrained by dose-limiting toxicities, drug interactions, and the routes of administration. An increasing prevalence of invasive fungal infections along with rising rates of resistance and the practical limitations of existing agents has created a demand for the development of new antifungals, particularly those with novel mechanisms of action. This article reviews antifungal agents currently in various stages of clinical development. New additions to existing antifungal classes will be discussed, including SUBA-itraconazole, a highly bioavailable azole, and amphotericin B cochleate, an oral amphotericin formulation, as well as rezafungin, a long-acting echinocandin capable of once-weekly administration. Additionally, novel first-in-class agents such as ibrexafungerp, an oral glucan synthase inhibitor with activity against various resistant fungal isolates, and olorofim, a pyrimidine synthesis inhibitor with a broad spectrum of activity and oral formulation, will be reviewed. Various other innovative antifungal agents and classes, including MGCD290, tetrazoles, and fosmanogepix, will also be examined. Full article
(This article belongs to the Special Issue Antifungal Drug Development: Rearview and the Horizon)
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Open AccessReview
Vulvovaginal Candidiasis: A Current Understanding and Burning Questions
J. Fungi 2020, 6(1), 27; https://doi.org/10.3390/jof6010027 - 25 Feb 2020
Cited by 24 | Viewed by 2986
Abstract
Candida albicans, along with other closely related Candida species, are the primary causative agents of vulvovaginal candidiasis (VVC)—a multifactorial infectious disease of the lower female reproductive tract resulting in pathologic inflammation. Unlike other forms of candidiasis, VVC is a disease of immunocompetent [...] Read more.
Candida albicans, along with other closely related Candida species, are the primary causative agents of vulvovaginal candidiasis (VVC)—a multifactorial infectious disease of the lower female reproductive tract resulting in pathologic inflammation. Unlike other forms of candidiasis, VVC is a disease of immunocompetent and otherwise healthy women, most predominant during their child-bearing years. While VVC is non-lethal, its high global incidence and profound negative impact on quality-of-life necessitates further understanding of the host and fungal factors that drive disease pathogenesis. In this review, we cover the current state of our understanding of the epidemiology, host response, fungal pathogenicity mechanisms, impact of the microbiome, and novel approaches to treatment of this most prevalent human candidal infection. We also offer insight into the latest advancements in the VVC field and identify important questions that still remain. Full article
(This article belongs to the Special Issue Pathogenesis of Candidiasis)
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Open AccessReview
The Role of Secretory Pathways in Candida albicans Pathogenesis
J. Fungi 2020, 6(1), 26; https://doi.org/10.3390/jof6010026 - 24 Feb 2020
Cited by 2 | Viewed by 1618
Abstract
Candida albicans is a fungus that is a commensal organism and a member of the normal human microbiota. It has the ability to transition into an opportunistic invasive pathogen. Attributes that support pathogenesis include secretion of virulence-associated proteins, hyphal formation, and biofilm formation. [...] Read more.
Candida albicans is a fungus that is a commensal organism and a member of the normal human microbiota. It has the ability to transition into an opportunistic invasive pathogen. Attributes that support pathogenesis include secretion of virulence-associated proteins, hyphal formation, and biofilm formation. These processes are supported by secretion, as defined in the broad context of membrane trafficking. In this review, we examine the role of secretory pathways in Candida virulence, with a focus on the model opportunistic fungal pathogen, Candida albicans. Full article
(This article belongs to the Special Issue Pathogenesis of Candidiasis)
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Open AccessReview
Steryl Glycosides in Fungal Pathogenesis: An Understudied Immunomodulatory Adjuvant
J. Fungi 2020, 6(1), 25; https://doi.org/10.3390/jof6010025 - 24 Feb 2020
Cited by 2 | Viewed by 899
Abstract
Invasive fungal infections pose an increasing threat to human hosts, especially in immunocompromised individuals. In response to the increasing morbidity and mortality of fungal infections, numerous groups have shown great strides in uncovering novel treatment options and potential efficacious vaccine candidates for this [...] Read more.
Invasive fungal infections pose an increasing threat to human hosts, especially in immunocompromised individuals. In response to the increasing morbidity and mortality of fungal infections, numerous groups have shown great strides in uncovering novel treatment options and potential efficacious vaccine candidates for this increasing threat due to the increase in current antifungal resistance. Steryl glycosides are lipid compounds produced by a wide range of organisms, and are largely understudied in the field of pathogenicity, especially to fungal infections. Published works over the years have shown these compounds positively modulating the host immune response. Recent advances, most notably from our lab, have strongly indicated that steryl glycosides have high efficacy in protecting the host against lethal Cryptococcal infection through acting as an immunoadjuvant. This review will summarize the keystone studies on the role of steryl glycosides in the host immune response, as well as elucidate the remaining unknown characteristics and future perspectives of these compounds for the host–fungal interactions. Full article
(This article belongs to the Special Issue Lipids and Fungal Infectious Diseases)
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Open AccessArticle
Cysteine Dioxygenase Enzyme Activity and Gene Expression in the Dimorphic Pathogenic Fungus Histoplasma capsulatum Is in both the Mold and Yeast Morphotypes and Exhibits Substantial Strain Variation
J. Fungi 2020, 6(1), 24; https://doi.org/10.3390/jof6010024 - 13 Feb 2020
Viewed by 719
Abstract
In the dimorphism (mold/yeast) Histoplasma capsulatum (Hc) literature are reports that yeast (the so-called pathogenic form) uniquely expresses a cysteine dioxygenase (CDO, approx. 10,500 dal) activity which the mold morphotype (the so-called saprophytic soil form) does not express (C.F., Kumar et [...] Read more.
In the dimorphism (mold/yeast) Histoplasma capsulatum (Hc) literature are reports that yeast (the so-called pathogenic form) uniquely expresses a cysteine dioxygenase (CDO, approx. 10,500 dal) activity which the mold morphotype (the so-called saprophytic soil form) does not express (C.F., Kumar et al., Biochem 22, 762, 1983). This yeast-specific CDO activity is postulated to play a critical role in the mold-to-yeast shift. A number of years ago, our lab isolated the gene encoding the Hc cysteine dioxygenase (CDO1, Genbank accession AY804144) and noted significant expression in the mold morphotype of several Histoplasma strains and also determined that the predicted protein would be over double the 10,500 dal reported by Kumar et al. Our report demonstrates (in the class 1 Downs strain, the class 2 G271B strain and two Panamanian strains, 184AS and 186AS) that the CDO1 gene is expressed in both the mold and yeast morphotypes and both morphotypes show significant CDO activity. Furthermore, we show via a FLAG-tag analysis that the expressed protein is approximately 24.7 ± 2.4 kd, in agreement with the putative protein sequence (determined from cDNA sequence) which yields 23.8 kd and is consistent with most other eukaryotic CDO enzymes. Additionally, we demonstrate that intracellular cysteine levels are actually significantly higher in the mold form of the two Panamanian strains, 184AS and 186AS, equal in both mold and yeast in the class 1 Downs strain and significantly higher in yeast of the more pathogenic class 2 G217B strain. Full article
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Open AccessReview
An Overview on Conventional and Non-Conventional Therapeutic Approaches for the Treatment of Candidiasis and Underlying Resistance Mechanisms in Clinical Strains
J. Fungi 2020, 6(1), 23; https://doi.org/10.3390/jof6010023 - 10 Feb 2020
Cited by 6 | Viewed by 1031
Abstract
Fungal infections and, in particular, those caused by species of the Candida genus, are growing at an alarming rate and have high associated rates of mortality and morbidity. These infections, generally referred as candidiasis, range from common superficial rushes caused by an overgrowth [...] Read more.
Fungal infections and, in particular, those caused by species of the Candida genus, are growing at an alarming rate and have high associated rates of mortality and morbidity. These infections, generally referred as candidiasis, range from common superficial rushes caused by an overgrowth of the yeasts in mucosal surfaces to life-threatening disseminated mycoses. The success of currently used antifungal drugs to treat candidiasis is being endangered by the continuous emergence of resistant strains, specially among non-albicans Candida species. In this review article, the mechanisms of action of currently used antifungals, with emphasis on the mechanisms of resistance reported in clinical isolates, are reviewed. Novel approaches being taken to successfully inhibit growth of pathogenic Candida species, in particular those based on the exploration of natural or synthetic chemicals or on the activity of live probiotics, are also reviewed. It is expected that these novel approaches, either used alone or in combination with traditional antifungals, may contribute to foster the identification of novel anti-Candida therapies. Full article
(This article belongs to the Special Issue Molecular Diagnostics of Fungal Infections)
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Open AccessReview
Monoclonal Antibodies as Tools to Combat Fungal Infections
J. Fungi 2020, 6(1), 22; https://doi.org/10.3390/jof6010022 - 04 Feb 2020
Cited by 4 | Viewed by 1143
Abstract
Antibodies represent an important element in the adaptive immune response and a major tool to eliminate microbial pathogens. For many bacterial and viral infections, efficient vaccines exist, but not for fungal pathogens. For a long time, antibodies have been assumed to be of [...] Read more.
Antibodies represent an important element in the adaptive immune response and a major tool to eliminate microbial pathogens. For many bacterial and viral infections, efficient vaccines exist, but not for fungal pathogens. For a long time, antibodies have been assumed to be of minor importance for a successful clearance of fungal infections; however this perception has been challenged by a large number of studies over the last three decades. In this review, we focus on the potential therapeutic and prophylactic use of monoclonal antibodies. Since systemic mycoses normally occur in severely immunocompromised patients, a passive immunization using monoclonal antibodies is a promising approach to directly attack the fungal pathogen and/or to activate and strengthen the residual antifungal immune response in these patients. Full article
(This article belongs to the Special Issue Antifungal Immunity and Fungal Vaccine Development)
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Open AccessReview
Contributions of the Biofilm Matrix to Candida Pathogenesis
J. Fungi 2020, 6(1), 21; https://doi.org/10.3390/jof6010021 - 03 Feb 2020
Cited by 14 | Viewed by 1341
Abstract
In healthcare settings, Candida spp. cause invasive disease with high mortality. The overwhelming majority of cases are associated with the use of critically-needed medical devices, such as vascular catheters. On the surface of these indwelling materials, Candida forms resilient, adherent biofilm communities. A [...] Read more.
In healthcare settings, Candida spp. cause invasive disease with high mortality. The overwhelming majority of cases are associated with the use of critically-needed medical devices, such as vascular catheters. On the surface of these indwelling materials, Candida forms resilient, adherent biofilm communities. A hallmark characteristic of this process is the production of an extracellular matrix, which promotes fungal adhesion and provides protection from external threats. In this review, we highlight the medical relevance of device-associated Candida biofilms and draw attention to the process of Candida-biofilm-matrix production. We provide an update on the current understanding of how biofilm extracellular matrix contributes to pathogenicity, particularly through its roles in the promoting antifungal drug tolerance and immune evasion. Full article
(This article belongs to the Special Issue Pathogenesis of Candidiasis)
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Open AccessArticle
Breakthrough Bloodstream Infections Caused by Echinocandin-Resistant Candida tropicalis: An Emerging Threat to Immunocompromised Patients with Hematological Malignancies
J. Fungi 2020, 6(1), 20; https://doi.org/10.3390/jof6010020 - 31 Jan 2020
Cited by 1 | Viewed by 1171
Abstract
Background. Candida tropicalis is a virulent fungal pathogen for which echinocandins are the primary therapy. Emergence of resistance to echinocandins of C. tropicalis carries potentially ominous therapeutic implications. Methods. We describe herein two patients with breakthrough C. tropicalis fungemia during echinocandin therapy, characterize [...] Read more.
Background. Candida tropicalis is a virulent fungal pathogen for which echinocandins are the primary therapy. Emergence of resistance to echinocandins of C. tropicalis carries potentially ominous therapeutic implications. Methods. We describe herein two patients with breakthrough C. tropicalis fungemia during echinocandin therapy, characterize their molecular mechanism of resistance, and systematically review 13 previously reported cases of echinocandin-resistant C. tropicalis bloodstream infections (BSIs) and other diseases. Results. Among these 15 patients with echinocandin-resistant C. tropicalis infections, the median age was 61 years (ages 28–84 years) and 13 (86%) were immunocompromised. Thirteen (86%) of all patients had a history of pervious or concurrent exposure to echinocandins. Isolates of C. tropicalis from 11 cases, including the two index cases, underwent DNA sequencing of the FKS1 gene for mutations known to confer echinocandin resistance. The amino acid substitution Ser654Pro was shown in four cases, while other FKS1 mutations encoded Ser80S/Pro, Phe641Leu, Phe641Ser, Ser80S/Pro substitutions. These mutational events were not associated with collateral increases in minimum inhibitory concentrations to antifungal triazoles and amphotericin B. Overall mortality in patients with echinocandin-resistant C. tropicalis infections was 40%. Among those six patients who died, two received monotherapy with voriconazole, one was treated with fluconazole, one remained on caspofungin, and two were switched to liposomal amphotericin B. Nine patients (60%) survived after being treated with an antifungal agent other than an echinocandin. Conclusions. Emergence of resistance to echinocandins by C. tropicalis, occurs during antifungal therapy, is associated with high mortality, is mediated by a diverse range of FKS1 mutations, retains in vitro susceptibility to triazoles and amphotericin B, and constitutes an emerging threat to patients with hematological malignancies. Full article
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Open AccessReview
The Squeaky Yeast Gets Greased: The Roles of Host Lipids in the Clearance of Pathogenic Fungi
J. Fungi 2020, 6(1), 19; https://doi.org/10.3390/jof6010019 - 31 Jan 2020
Viewed by 915
Abstract
Fungal infections remain a global health threat with high morbidity and mortality. The human immune system must, therefore, perpetually defend against invasive fungal infections. Phagocytosis is critical for the clearance of fungal pathogens, as this cellular process allows select immune cells to internalize [...] Read more.
Fungal infections remain a global health threat with high morbidity and mortality. The human immune system must, therefore, perpetually defend against invasive fungal infections. Phagocytosis is critical for the clearance of fungal pathogens, as this cellular process allows select immune cells to internalize and destroy invading fungal cells. While much is known about the protein players that enable phagocytosis, the various roles that lipids play during this fundamental innate immune process are still being illuminated. In this review, we describe recent discoveries that shed new light on the mechanisms by which host lipids enable the phagocytic uptake and clearance of fungal pathogens. Full article
(This article belongs to the Special Issue Lipids and Fungal Infectious Diseases)
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Open AccessReview
Blood Aspergillus PCR: The Good, the Bad, and the Ugly
J. Fungi 2020, 6(1), 18; https://doi.org/10.3390/jof6010018 - 27 Jan 2020
Cited by 5 | Viewed by 1389
Abstract
Invasive Aspergillosis (IA) is one of the most common invasive fungal diseases and is accompanied by high morbidity and mortality. In order to maximize patient outcomes and survival, early and rapid diagnosis has been shown to be pivotal. Hence, diagnostic tools aiding and [...] Read more.
Invasive Aspergillosis (IA) is one of the most common invasive fungal diseases and is accompanied by high morbidity and mortality. In order to maximize patient outcomes and survival, early and rapid diagnosis has been shown to be pivotal. Hence, diagnostic tools aiding and improving the diagnostic process are ambitiously searched for. In this context, polymerase chain reaction (PCR) may represent a potential candidate. Its additional value and benefits in diagnosis have been demonstrated and are scientifically established. Nevertheless, standardized and widespread usage is sparse because several factors influence diagnostic quality and need to be considered in order to optimize diagnostic performance and outcome. In the following review, the current role of PCR in the diagnosis of IA is explored, with special focus on the strengths and limitations of PCR in different settings. Full article
(This article belongs to the Special Issue Molecular Diagnostics of Fungal Infections)
Open AccessEditorial
Acknowledgement to Reviewers of Journal of Fungi in 2019
J. Fungi 2020, 6(1), 17; https://doi.org/10.3390/jof6010017 - 21 Jan 2020
Viewed by 598
Abstract
The editorial team greatly appreciates the reviewers who have dedicated their considerable time and expertise to the journal’s rigorous editorial process over the past 12 months, regardless of whether the papers are finally published or not [...] Full article
Open AccessReview
On Commensalism of Candida
J. Fungi 2020, 6(1), 16; https://doi.org/10.3390/jof6010016 - 17 Jan 2020
Cited by 11 | Viewed by 1508
Abstract
Candida species are both opportunistic fungal pathogens and common members of the human mycobiome. Over the years, the main focus of the fungal field has been on understanding the pathogenic potential and disease manifestation of these organisms. Therefore, understanding of their commensal lifestyle, [...] Read more.
Candida species are both opportunistic fungal pathogens and common members of the human mycobiome. Over the years, the main focus of the fungal field has been on understanding the pathogenic potential and disease manifestation of these organisms. Therefore, understanding of their commensal lifestyle, interactions with host epithelial barriers, and initial transition into pathogenesis is less developed. In this review, we will describe the current knowledge on the commensal lifestyle of these fungi, how they are able to adhere to and colonize host epithelial surfaces, compete with other members of the microbiota, and interact with the host immune response, as well as their transition into opportunistic pathogens by invading the gastrointestinal epithelium. Full article
(This article belongs to the Special Issue Pathogenesis of Candidiasis)
Open AccessReview
Oral Candidiasis: A Disease of Opportunity
J. Fungi 2020, 6(1), 15; https://doi.org/10.3390/jof6010015 - 16 Jan 2020
Cited by 26 | Viewed by 3974
Abstract
Oral candidiasis, commonly referred to as “thrush,” is an opportunistic fungal infection that commonly affects the oral mucosa. The main causative agent, Candida albicans, is a highly versatile commensal organism that is well adapted to its human host; however, changes in the [...] Read more.
Oral candidiasis, commonly referred to as “thrush,” is an opportunistic fungal infection that commonly affects the oral mucosa. The main causative agent, Candida albicans, is a highly versatile commensal organism that is well adapted to its human host; however, changes in the host microenvironment can promote the transition from one of commensalism to pathogen. This transition is heavily reliant on an impressive repertoire of virulence factors, most notably cell surface adhesins, proteolytic enzymes, morphologic switching, and the development of drug resistance. In the oral cavity, the co-adhesion of C. albicans with bacteria is crucial for its persistence, and a wide range of synergistic interactions with various oral species were described to enhance colonization in the host. As a frequent colonizer of the oral mucosa, the host immune response in the oral cavity is oriented toward a more tolerogenic state and, therefore, local innate immune defenses play a central role in maintaining Candida in its commensal state. Specifically, in addition to preventing Candida adherence to epithelial cells, saliva is enriched with anti-candidal peptides, considered to be part of the host innate immunity. The T helper 17 (Th17)-type adaptive immune response is mainly involved in mucosal host defenses, controlling initial growth of Candida and inhibiting subsequent tissue invasion. Animal models, most notably the mouse model of oropharyngeal candidiasis and the rat model of denture stomatitis, are instrumental in our understanding of Candida virulence factors and the factors leading to host susceptibility to infections. Given the continuing rise in development of resistance to the limited number of traditional antifungal agents, novel therapeutic strategies are directed toward identifying bioactive compounds that target pathogenic mechanisms to prevent C. albicans transition from harmless commensal to pathogen. Full article
(This article belongs to the Special Issue Pathogenesis of Candidiasis)
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Open AccessReview
Unraveling How Candida albicans Forms Sexual Biofilms
J. Fungi 2020, 6(1), 14; https://doi.org/10.3390/jof6010014 - 15 Jan 2020
Cited by 4 | Viewed by 1901
Abstract
Biofilms, structured and densely packed communities of microbial cells attached to surfaces, are considered to be the natural growth state for a vast majority of microorganisms. The ability to form biofilms is an important virulence factor for most pathogens, including the opportunistic human [...] Read more.
Biofilms, structured and densely packed communities of microbial cells attached to surfaces, are considered to be the natural growth state for a vast majority of microorganisms. The ability to form biofilms is an important virulence factor for most pathogens, including the opportunistic human fungal pathogen Candida albicans. C. albicans is one of the most prevalent fungal species of the human microbiota that asymptomatically colonizes healthy individuals. However, C. albicans can also cause severe and life-threatening infections when host conditions permit (e.g., through alterations in the host immune system, pH, and resident microbiota). Like many other pathogens, this ability to cause infections depends, in part, on the ability to form biofilms. Once formed, C. albicans biofilms are often resistant to antifungal agents and the host immune response, and can act as reservoirs to maintain persistent infections as well as to seed new infections in a host. The majority of C. albicans clinical isolates are heterozygous (a/α) at the mating type-like (MTL) locus, which defines Candida mating types, and are capable of forming robust biofilms when cultured in vitro. These “conventional” biofilms, formed by MTL-heterozygous (a/α) cells, have been the primary focus of C. albicans biofilm research to date. Recent work in the field, however, has uncovered novel mechanisms through which biofilms are generated by C. albicans cells that are homozygous or hemizygous (a/a, a/Δ, α/α, or α/Δ) at the MTL locus. In these studies, the addition of pheromones of the opposite mating type can induce the formation of specialized “sexual” biofilms, either through the addition of synthetic peptide pheromones to the culture, or in response to co-culturing of cells of the opposite mating types. Although sexual biofilms are generally less robust than conventional biofilms, they could serve as a protective niche to support genetic exchange between mating-competent cells, and thus may represent an adaptive mechanism to increase population diversity in dynamic environments. Although conventional and sexual biofilms appear functionally distinct, both types of biofilms are structurally similar, containing yeast, pseudohyphal, and hyphal cells surrounded by an extracellular matrix. Despite their structural similarities, conventional and sexual biofilms appear to be governed by distinct transcriptional networks and signaling pathways, suggesting that they may be adapted for, and responsive to, distinct environmental conditions. Here we review sexual biofilms and compare and contrast them to conventional biofilms of C. albicans. Full article
(This article belongs to the Special Issue Fungal Biofilms 2020)
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Open AccessReview
A Re-Evaluation of the Relationship between Morphology and Pathogenicity in Candida Species
J. Fungi 2020, 6(1), 13; https://doi.org/10.3390/jof6010013 - 13 Jan 2020
Cited by 2 | Viewed by 1518
Abstract
Many pathogenic Candida species possess the ability to undergo a reversible morphological transition from yeast to filamentous cells. In Candida albicans, the most frequently isolated human fungal pathogen, multiple lines of evidence strongly suggest that this transition is associated with virulence and [...] Read more.
Many pathogenic Candida species possess the ability to undergo a reversible morphological transition from yeast to filamentous cells. In Candida albicans, the most frequently isolated human fungal pathogen, multiple lines of evidence strongly suggest that this transition is associated with virulence and pathogenicity. While it has generally been assumed that non-albicans Candida species (NACS) are less pathogenic than C. albicans, in part, because they do not filament as well, definitive evidence is lacking. Interestingly, however, a recent study suggests that filamentation of NACS is associated with reduced, rather than increased, pathogenicity. These findings, in turn, challenge conventional views and suggest that there are fundamental evolutionary differences in the morphology–pathogenicity relationship in C. albicans vs. NACS. The findings also raise many new and intriguing questions and open new avenues for future research, which are discussed. Full article
(This article belongs to the Special Issue Pathogenesis of Candidiasis)
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Open AccessReview
Detecting Azole-Antifungal Resistance in Aspergillus fumigatus by Pyrosequencing
J. Fungi 2020, 6(1), 12; https://doi.org/10.3390/jof6010012 - 10 Jan 2020
Cited by 7 | Viewed by 2104
Abstract
Guidelines on the diagnosis and management of Aspergillus disease recommend a multi-test approach including CT scans, culture, fungal biomarker tests, microscopy and fungal PCR. The first-line treatment of confirmed invasive aspergillosis (IA) consists of drugs in the azole family; however, the emergence of [...] Read more.
Guidelines on the diagnosis and management of Aspergillus disease recommend a multi-test approach including CT scans, culture, fungal biomarker tests, microscopy and fungal PCR. The first-line treatment of confirmed invasive aspergillosis (IA) consists of drugs in the azole family; however, the emergence of azole-resistant isolates has negatively impacted the management of IA. Failure to detect azole-resistance dramatically increases the mortality rates of azole-treated patients. Despite drug susceptibility tests not being routinely performed currently, we suggest including resistance testing whilst diagnosing Aspergillus disease. Multiple tools, including DNA sequencing, are available to screen for drug-resistant Aspergillus in clinical samples. This is particularly beneficial as a large proportion of IA samples are culture negative, consequently impeding susceptibility testing through conventional methods. Pyrosequencing is a promising in-house DNA sequencing method that can rapidly screen for genetic hotspots associated with antifungal resistance. Pyrosequencing outperforms other susceptibility testing methods due to its fast turnaround time, accurate detection of polymorphisms within critical genes, including simultaneous detection of wild type and mutated sequences, and—most importantly—it is not limited to specific genes nor fungal species. Here we review current diagnostic methods and highlight the potential of pyrosequencing to aid in a diagnosis complete with a resistance profile to improve clinical outcomes. Full article
(This article belongs to the Special Issue Molecular Diagnostics of Fungal Infections)
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Open AccessBrief Report
Molecular Detection of Aspergillus: Application of a Real-Time PCR Multiplex Assay in Tissue Samples
J. Fungi 2020, 6(1), 11; https://doi.org/10.3390/jof6010011 - 10 Jan 2020
Cited by 3 | Viewed by 1026
Abstract
Diagnosis of invasive fungal infections is complex, and the lack of standardization of molecular methods is still a challenge. Several methods are available for the diagnosis of invasive aspergillosis, but their effectiveness will depend on the studied population, the patients’ comorbidities, and the [...] Read more.
Diagnosis of invasive fungal infections is complex, and the lack of standardization of molecular methods is still a challenge. Several methods are available for the diagnosis of invasive aspergillosis, but their effectiveness will depend on the studied population, the patients’ comorbidities, and the use of mold active prophylaxis, among others. The ability to determine the identity of the infecting Aspergillus species, and to detect mutations conferring specific resistance patterns directly from DNA extracted from the biological product, is an advantage of nucleic acid testing compared with antigen-based assays. In this study, we present laboratory cases where the diagnosis of aspergillosis was performed using a real-time multiplex PCR for the detection of Aspergillus DNA in tissue samples, showing its usefulness as one more tool in the diagnosis of aspergillosis in tissue samples. Aspergillus real-time multiplex PCR was also used to detect azole-resistance in some cases. In the majority of the PCR positive cases, cultures remained negative after 60 days. The PCR assay directed to Aspergillus gave positive signals for Aspergillus fumigatus sensu stricto. Results were confirmed by panfungal PCR, followed by sequencing, revealing 100% homology with Aspergillus fumigatus sensu stricto. Mutations conferring azole resistance were not detected. Full article
(This article belongs to the Special Issue Molecular Diagnostics of Fungal Infections)
Open AccessReview
The Impact of Gene Dosage and Heterozygosity on the Diploid Pathobiont Candida albicans
J. Fungi 2020, 6(1), 10; https://doi.org/10.3390/jof6010010 - 27 Dec 2019
Cited by 4 | Viewed by 1666
Abstract
Candida albicans is a fungal species that can colonize multiple niches in the human host where it can grow either as a commensal or as an opportunistic pathogen. The genome of C. albicans has long been of considerable interest, given that it is [...] Read more.
Candida albicans is a fungal species that can colonize multiple niches in the human host where it can grow either as a commensal or as an opportunistic pathogen. The genome of C. albicans has long been of considerable interest, given that it is highly plastic and can undergo a wide variety of alterations. These changes play a fundamental role in determining C. albicans traits and have been shown to enable adaptation both to the host and to antifungal drugs. C. albicans isolates contain a heterozygous diploid genome that displays variation from the level of single nucleotides to largescale rearrangements and aneuploidy. The heterozygous nature of the genome is now increasingly recognized as being central to C. albicans biology, as the relative fitness of isolates has been shown to correlate with higher levels of overall heterozygosity. Moreover, loss of heterozygosity (LOH) events can arise frequently, either at single polymorphisms or at a chromosomal level, and both can alter the behavior of C. albicans cells during infection or can modulate drug resistance. In this review, we examine genome plasticity in this pathobiont focusing on how gene dosage variation and loss of heterozygosity events can arise and how these modulate C. albicans behavior. Full article
(This article belongs to the Special Issue Pathogenesis of Candidiasis)
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