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Open AccessArticle

Deletion of the SKO1 Gene in a hog1 Mutant Reverts Virulence in Candida albicans

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J. Fungi 2019, 5(4), 107; https://doi.org/10.3390/jof5040107 - 15 Nov 2019

Cited by 1 | Viewed by 2612

Abstract

Candida albicans displays the ability to adapt to a wide variety of environmental conditions, triggering signaling pathways and transcriptional regulation. Sko1 is a transcription factor that was previously involved in early hypoxic response, cell wall remodeling, and stress response. In the present work, [...] Read more.

Candida albicans displays the ability to adapt to a wide variety of environmental conditions, triggering signaling pathways and transcriptional regulation. Sko1 is a transcription factor that was previously involved in early hypoxic response, cell wall remodeling, and stress response. In the present work, the role of sko1 mutant in in vivo and ex vivo studies was explored. The sko1 mutant behaved as its parental wild type strain regarding the ability to colonize murine intestinal tract, ex vivo adhesion to murine gut epithelium, or systemic virulence. These observations suggest that Sko1 is expendable during commensalism or pathogenesis. Nevertheless, the study of the hog1 sko1 double mutant showed unexpected phenotypes. Previous researches reported that the deletion of the HOG1 gene led to avirulent C. albicans mutant cell, which was, therefore, unable to establish as a commensal in a gastrointestinal murine model. Here, we show that the deletion of sko1 in a hog1 background reverted the virulence of the hog1 mutant in a systemic infection model in Galleria mellonella larvae and slightly improved the ability to colonize the murine gut in a commensalism animal model compared to the hog1 mutant. These results indicate that Sko1 acts as a repressor of virulence related genes, concluding that Sko1 plays a relevant role during commensalism and systemic infection. Full article

(This article belongs to the Special Issue Pathogenesis of Candidiasis)

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Open AccessReview

Multicopper Oxidases in Saccharomyces cerevisiae and Human Pathogenic Fungi

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J. Fungi 2020, 6(2), 56; https://doi.org/10.3390/jof6020056 - 27 Apr 2020

Cited by 3 | Viewed by 2807

Abstract

Multicopper oxidases (MCOs) are produced by microscopic and macroscopic fungal species and are involved in various physiological processes such as morphogenesis, lignin degradation, and defense mechanisms to stress inducing environmental conditions as well as fungal virulence. This review will summarize our current understanding [...] Read more.

Multicopper oxidases (MCOs) are produced by microscopic and macroscopic fungal species and are involved in various physiological processes such as morphogenesis, lignin degradation, and defense mechanisms to stress inducing environmental conditions as well as fungal virulence. This review will summarize our current understanding regarding the functions of MCOs present in Saccharomyces cerevisiae and in different human fungal pathogens. Of the two main MCO groups, the first group of MCOs is involved in iron homoeostasis and the second includes laccases. This review will also discuss their role in the pathogenesis of human fungal pathogens. Full article

(This article belongs to the Special Issue Pathogenesis of Candidiasis)

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Open AccessReview

Phosphate in Virulence of Candida albicans and Candida glabrata

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Julia R. Köhler

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Maikel Acosta-Zaldívar

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Wanjun Qi

J. Fungi 2020, 6(2), 40; https://doi.org/10.3390/jof6020040 - 26 Mar 2020

Cited by 13 | Viewed by 3434

Abstract

Candida species are the most commonly isolated invasive human fungal pathogens. A role for phosphate acquisition in their growth, resistance against host immune cells, and tolerance of important antifungal medications is becoming apparent. Phosphorus is an essential element in vital components of the [...] Read more.

Candida species are the most commonly isolated invasive human fungal pathogens. A role for phosphate acquisition in their growth, resistance against host immune cells, and tolerance of important antifungal medications is becoming apparent. Phosphorus is an essential element in vital components of the cell, including chromosomes and ribosomes. Producing the energy currency of the cell, ATP, requires abundant inorganic phosphate. A comparison of the network of regulators and effectors that controls phosphate acquisition and intracellular distribution, the PHO regulon, between the model yeast Saccharomyces cerevisiae, a plant saprobe, its evolutionarily close relative C. glabrata, and the more distantly related C. albicans, highlights the need to coordinate phosphate homeostasis with adenylate biosynthesis for ATP production. It also suggests that fungi that cope with phosphate starvation as they invade host tissues, may link phosphate acquisition to stress responses as an efficient mechanism of anticipatory regulation. Recent work indicates that connections among the PHO regulon, Target of Rapamycin Complex 1 signaling, oxidative stress management, and cell wall construction are based both in direct signaling links, and in the provision of phosphate for sufficient metabolic intermediates that are substrates in these processes. Fundamental differences in fungal and human phosphate homeostasis may offer novel drug targets. Full article

(This article belongs to the Special Issue Pathogenesis of Candidiasis)

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Open AccessReview

Applying the Host-Microbe Damage Response Framework to Candida Pathogenesis: Current and Prospective Strategies to Reduce Damage

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J. Fungi 2020, 6(1), 35; https://doi.org/10.3390/jof6010035 - 11 Mar 2020

Cited by 5 | Viewed by 4379

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

Candida auris: A Decade of Understanding of an Enigmatic Pathogenic Yeast

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J. Fungi 2020, 6(1), 30; https://doi.org/10.3390/jof6010030 - 26 Feb 2020

Cited by 45 | Viewed by 7624

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 AccessReview

Vulvovaginal Candidiasis: A Current Understanding and Burning Questions

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Hubertine M. E. Willems

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J. Fungi 2020, 6(1), 27; https://doi.org/10.3390/jof6010027 - 25 Feb 2020

Cited by 139 | Viewed by 15882

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

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Christiane Rollenhagen

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J. Fungi 2020, 6(1), 26; https://doi.org/10.3390/jof6010026 - 24 Feb 2020

Cited by 13 | Viewed by 5374

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

Contributions of the Biofilm Matrix to Candida Pathogenesis

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Jeniel E. Nett

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David R. Andes

J. Fungi 2020, 6(1), 21; https://doi.org/10.3390/jof6010021 - 03 Feb 2020

Cited by 52 | Viewed by 4644

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 AccessReview

On Commensalism of Candida

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Jesus A. Romo

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Carol A. Kumamoto

J. Fungi 2020, 6(1), 16; https://doi.org/10.3390/jof6010016 - 17 Jan 2020

Cited by 43 | Viewed by 5065

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

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Taissa Vila

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Ahmed S. Sultan

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Daniel Montelongo-Jauregui

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Mary Ann Jabra-Rizk

J. Fungi 2020, 6(1), 15; https://doi.org/10.3390/jof6010015 - 16 Jan 2020

Cited by 165 | Viewed by 23656

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

A Re-Evaluation of the Relationship between Morphology and Pathogenicity in Candida Species

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David Kadosh

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Vasanthakrishna Mundodi

J. Fungi 2020, 6(1), 13; https://doi.org/10.3390/jof6010013 - 13 Jan 2020

Cited by 18 | Viewed by 7091

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

The Impact of Gene Dosage and Heterozygosity on the Diploid Pathobiont Candida albicans

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Shen-Huan Liang

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Richard J. Bennett

J. Fungi 2020, 6(1), 10; https://doi.org/10.3390/jof6010010 - 27 Dec 2019

Cited by 15 | Viewed by 8455

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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Open AccessReview

N-Acetylglucosamine Regulates Morphogenesis and Virulence Pathways in Fungi

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Kyunghun Min

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Shamoon Naseem

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James B. Konopka

J. Fungi 2020, 6(1), 8; https://doi.org/10.3390/jof6010008 - 24 Dec 2019

Cited by 19 | Viewed by 5368

Abstract

N-acetylglucosamine (GlcNAc) is being increasingly recognized for its ability to stimulate cell signaling. This amino sugar is best known as a component of cell wall peptidoglycan in bacteria, cell wall chitin in fungi and parasites, exoskeletons of arthropods, and the extracellular matrix [...] Read more.

N-acetylglucosamine (GlcNAc) is being increasingly recognized for its ability to stimulate cell signaling. This amino sugar is best known as a component of cell wall peptidoglycan in bacteria, cell wall chitin in fungi and parasites, exoskeletons of arthropods, and the extracellular matrix of animal cells. In addition to these structural roles, GlcNAc is now known to stimulate morphological and stress responses in a wide range of organisms. In fungi, the model organisms Saccharomyces cerevisiae and Schizosaccharomyces pombe lack the ability to respond to GlcNAc or catabolize it, so studies with the human pathogen Candida albicans have been providing new insights into the ability of GlcNAc to stimulate cellular responses. GlcNAc potently induces C. albicans to transition from budding to filamentous hyphal growth. It also promotes an epigenetic switch from White to Opaque cells, which differ in morphology, metabolism, and virulence properties. These studies have led to new discoveries, such as the identification of the first eukaryotic GlcNAc transporter. Other results have shown that GlcNAc can induce signaling in C. albicans in two ways. One is to act as a signaling molecule independent of its catabolism, and the other is that its catabolism can cause the alkalinization of the extracellular environment, which provides an additional stimulus to form hyphae. GlcNAc also induces the expression of virulence genes in the C. albicans, indicating it can influence pathogenesis. Therefore, this review will describe the recent advances in understanding the role of GlcNAc signaling pathways in regulating C. albicans morphogenesis and virulence. Full article

(This article belongs to the Special Issue Pathogenesis of Candidiasis)

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Open AccessReview

Candida spp./Bacteria Mixed Biofilms

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Maria Elisa Rodrigues

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Fernanda Gomes

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Célia F. Rodrigues

J. Fungi 2020, 6(1), 5; https://doi.org/10.3390/jof6010005 - 20 Dec 2019

Cited by 68 | Viewed by 7149

Abstract

The ability to form biofilms is a common feature of microorganisms, such as bacteria or fungi. These consortiums can colonize a variety of surfaces, such as host tissues, dentures, and catheters, resulting in infections highly resistant to drugs, when compared with their planktonic [...] Read more.

The ability to form biofilms is a common feature of microorganisms, such as bacteria or fungi. These consortiums can colonize a variety of surfaces, such as host tissues, dentures, and catheters, resulting in infections highly resistant to drugs, when compared with their planktonic counterparts. This refractory effect is particularly critical in polymicrobial biofilms involving both fungi and bacteria. This review emphasizes Candida spp.-bacteria biofilms, the epidemiology of this community, the challenges in the eradication of such biofilms, and the most relevant treatments. Full article

(This article belongs to the Special Issue Pathogenesis of Candidiasis)

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