Special Issue "Candida Albicans Infections"

A special issue of Pathogens (ISSN 2076-0817).

Deadline for manuscript submissions: closed (30 June 2015).

Special Issue Editor

Prof. Dr. Sarah Gaffen
E-Mail Website
Guest Editor
Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
Interests: mechanisms of IL-17 receptor signal transduction; role of IL-17 in immunity to oral Candida albicans infections

Special Issue Information

Dear Colleagues,

Immune responses to fungi remain poorly understood, and research in this field has lagged behind that of other microorganisms. To date, there are still no available vaccines or effective immunomodulatory strategies to prevent or treat fungal infections. The impact of fungal pathogens was highlighted in a 2012 outbreak of tainted epidural steroids, which affected almost 700 patients and caused 45 deaths (www.cdc.gov). Studies in the past few years have identified several common—but previously unappreciated—principles that appear to apply broadly to fungal immunity; in particular, the use of C-type lectin receptors (CLRs) as pattern recognition receptors (PRRs) and the importance of Th17-based responses to fungi. The most common fungal infections in humans are caused by Candida albicans, a commensal fungus that colonizes the mouth, skin and other mucosa of most healthy adults. The principles of immunity (CLRs, IL-17) defined for Candida have been found to apply to many other fungi as well, making studies of this organism an appealing model for understanding immunity to fungal pathogens more broadly. For this Special Issue of Pathogens, we invite you to submit a review article related to the microbial pathogenesis of Candida species, and we look forward to your contribution.

Prof. Dr. Sarah Gaffen
Guest Editor

Manuscript Submission Information

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Keywords

  • Candida albicans
  • fungal immunology
  • T cells
  • innate immunity
  • animal models
  • C-type lectin receptors

Published Papers (11 papers)

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Research

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Open AccessArticle
Candida albicans Shed Msb2 and Host Mucins Affect the Candidacidal Activity of Salivary Hst 5
Pathogens 2015, 4(4), 752-763; https://doi.org/10.3390/pathogens4040752 - 30 Oct 2015
Cited by 4
Abstract
Salivary Histatin 5 (Hst 5) is an antimicrobial peptide that exhibits potent antifungal activity towards Candida albicans, the causative agent of oral candidiasis. However, it exhibits limited activity in vivo, largely due to inactivation by salivary components of both host and [...] Read more.
Salivary Histatin 5 (Hst 5) is an antimicrobial peptide that exhibits potent antifungal activity towards Candida albicans, the causative agent of oral candidiasis. However, it exhibits limited activity in vivo, largely due to inactivation by salivary components of both host and pathogen origin. Proteins secreted by C. albicans during infection such as secreted aspartyl proteases (Saps) and shed mucin Msb2 can reduce Hst 5 activity; and human salivary mucins, while suggested to protect Hst 5 from proteolytic degradation, can entrap peptides into mucin gels, thereby reducing bioavailability. We show here that Sap6 that is secreted during hyphal growth reduces Hst 5 activity, most likely a result of proteolytic degradation of Hst 5 since this effect is abrogated with heat inactivated Sap 6. We further show that just like C. albicans shedding Msb2, mammalian mucins, fetuin and porcine gut mucin (that is related to salivary mucins), also reduce Hst 5 activity. However, we identify mucin-like protein-induced changes in C. albicans cell morphology and aggregation patterns, suggesting that the effect of such proteins on Hst 5 cannot be interpreted independently of their effect on yeast cells. Full article
(This article belongs to the Special Issue Candida Albicans Infections)
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Open AccessArticle
Coordination of Candida albicans Invasion and Infection Functions by Phosphoglycerol Phosphatase Rhr2
Pathogens 2015, 4(3), 573-589; https://doi.org/10.3390/pathogens4030573 - 24 Jul 2015
Cited by 7
Abstract
The Candida albicans RHR2 gene, which specifies a glycerol biosynthetic enzyme, is required for biofilm formation in vitro and in vivo. Prior studies indicate that RHR2 is ultimately required for expression of adhesin genes, such as ALS1. In fact, RHR2 is unnecessary [...] Read more.
The Candida albicans RHR2 gene, which specifies a glycerol biosynthetic enzyme, is required for biofilm formation in vitro and in vivo. Prior studies indicate that RHR2 is ultimately required for expression of adhesin genes, such as ALS1. In fact, RHR2 is unnecessary for biofilm formation when ALS1 is overexpressed from an RHR2-independent promoter. Here, we describe two additional biological processes that depend upon RHR2: invasion into an abiotic substrate and pathogenicity in an abdominal infection model. We report here that abiotic substrate invasion occurs concomitantly with biofilm formation, and a screen of transcription factor mutants indicates that biofilm and hyphal formation ability correlates with invasion ability. However, analysis presented here of the rhr2Δ/Δ mutant separates biofilm formation and invasion. We found that an rhr2Δ/Δ mutant forms a biofilm upon overexpression of the adhesin gene ALS1 or the transcription factor genes BRG1 or UME6. However, the biofilm-forming strains do not invade the substrate. These results indicate that RHR2 has an adhesin-independent role in substrate invasion, and mathematical modeling argues that RHR2 is required to generate turgor. Previous studies have shown that abdominal infection by C. albicans has two aspects: infection of abdominal organs and persistence in abscesses. We report here that an rhr2Δ/Δ mutant is defective in both of these infection phenotypes. We find here that overexpression of ALS1 in the mutant restores infection of organs, but does not improve persistence in abscesses. Therefore, RHR2 has an adhesin-independent role in abdominal infection, just as it does in substrate invasion. This report suggests that RHR2, through glycerol synthesis, coordinates adherence with host- or substrate-interaction activities that enable proliferation of the C. albicans population. Full article
(This article belongs to the Special Issue Candida Albicans Infections)
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Open AccessArticle
TLR-2 Signaling Promotes IL-17A Production in CD4+CD25+Foxp3+ Regulatory Cells during Oropharyngeal Candidiasis
Pathogens 2015, 4(1), 90-110; https://doi.org/10.3390/pathogens4010090 - 17 Mar 2015
Cited by 13
Abstract
Recent studies show that CD4+CD25+Foxp3+ regulatory cells (Tregs) produce effector cytokines under inflammatory conditions. However, the direct role of microbial agents that serve as toll-like receptor (TLR) ligands in the induction of effector cytokines in T [...] Read more.
Recent studies show that CD4+CD25+Foxp3+ regulatory cells (Tregs) produce effector cytokines under inflammatory conditions. However, the direct role of microbial agents that serve as toll-like receptor (TLR) ligands in the induction of effector cytokines in Tregs is less clear. Here we show that CD4+Foxp3+Tregs produce the effector cytokine IL-17A during oropharyngeal candidiasis (OPC) and inflammatory bowel disease in a TLR-2/Myd88 signaling dependent manner. TLR-2 ligands promote proliferation in Tregs in the presence and absence of TCR signals and inflammatory cytokines in vitro. The proliferation is directly dependent on TLR-2 expression in Tregs. Consistent with this, Tlr2−/− mice harbor fewer thymically derived Tregs and peripheral Tregs under homeostatic conditions in vivo. However, under Th17 inducing conditions, IL-6 and TLR-2 signaling both in Tregs as well as antigen presenting cells (APC) are critical for maximal ROR-γt and IL-17A up-regulation in Foxp3+ Tregs. The minimal and transient loss of Foxp3 expression and suppressive properties are due to the presence of IL-6 in the milieu, but not the direct effect of TLR-2 signaling in Tregs. Taken together, our data reveal that TLR-2 signaling promotes not only proliferation, but also IL-17A in Tregs, depending on the cytokine milieu. These IL-17A producing Tregs may be relevant in mucosal infections and inflammation. Full article
(This article belongs to the Special Issue Candida Albicans Infections)
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Review

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Open AccessReview
The Role of Autophagy-Related Proteins in Candida albicans Infections
Pathogens 2016, 5(2), 34; https://doi.org/10.3390/pathogens5020034 - 29 Mar 2016
Cited by 10
Abstract
Autophagy plays an important role in maintaining cell homeostasis by providing nutrients during periods of starvation and removing damaged organelles from the cytoplasm. A marker in the autophagic process is the reversible conjugation of LC3, a membrane scaffolding protein, to double membrane autophagosomes. [...] Read more.
Autophagy plays an important role in maintaining cell homeostasis by providing nutrients during periods of starvation and removing damaged organelles from the cytoplasm. A marker in the autophagic process is the reversible conjugation of LC3, a membrane scaffolding protein, to double membrane autophagosomes. Recently, a role for LC3 in the elimination of pathogenic bacteria and fungi, including Candida albicans (C. albicans), was demonstrated, but these organisms reside in single membrane phagosomes. This process is distinct from autophagy and is termed LC3-associated phagocytosis (LAP). This review will detail the hallmarks of LAP that distinguish it from classical autophagy and review the role of autophagy proteins in host response to C. albicans and other pathogenic fungi. Full article
(This article belongs to the Special Issue Candida Albicans Infections)
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Open AccessReview
How Chemotherapy Increases the Risk of Systemic Candidiasis in Cancer Patients: Current Paradigm and Future Directions
Pathogens 2016, 5(1), 6; https://doi.org/10.3390/pathogens5010006 - 15 Jan 2016
Cited by 16
Abstract
Candida albicans is a fungal commensal and a major colonizer of the human skin, as well as of the gastrointestinal and genitourinary tracts. It is also one of the leading causes of opportunistic microbial infections in cancer patients, often presenting in a life-threatening, [...] Read more.
Candida albicans is a fungal commensal and a major colonizer of the human skin, as well as of the gastrointestinal and genitourinary tracts. It is also one of the leading causes of opportunistic microbial infections in cancer patients, often presenting in a life-threatening, systemic form. Increased susceptibility to such infections in cancer patients is attributed primarily to chemotherapy-induced depression of innate immune cells and weakened epithelial barriers, which are the body’s first-line defenses against fungal infections. Moreover, classical chemotherapeutic agents also have a detrimental effect on components of the adaptive immune system, which further play important roles in the antifungal response. In this review, we discuss the current paradigm regarding the mechanisms behind the increased risk of systemic candidiasis in cancer patients. We also highlight some recent findings, which suggest that chemotherapy may have more extensive effects beyond the human host, in particular towards C. albicans itself and the bacterial microbiota. The extent to which these additional effects contribute towards the development of candidiasis in chemotherapy-treated patients remains to be investigated. Full article
(This article belongs to the Special Issue Candida Albicans Infections)
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Open AccessReview
Studies of Immune Responses in Candida vaginitis
Pathogens 2015, 4(4), 697-707; https://doi.org/10.3390/pathogens4040697 - 09 Oct 2015
Cited by 11
Abstract
The widespread occurrence of vaginal candidiasis and the development of resistance against anti-fungal agents has stimulated interest in understanding the pathogenesis of this disease. The aim of our work was to characterize, in an animal model of vaginal candidiasis, the mechanisms that play [...] Read more.
The widespread occurrence of vaginal candidiasis and the development of resistance against anti-fungal agents has stimulated interest in understanding the pathogenesis of this disease. The aim of our work was to characterize, in an animal model of vaginal candidiasis, the mechanisms that play a role in the induction of mucosal immunity against C. albicans and the interaction between innate and adaptive immunity. Our studies evidenced the elicitation of cell-mediated immunity (CMIs) and antibody (Abs)-mediated immunity with a Th1 protective immunity. An immune response of this magnitude in the vagina was very encouraging to identify the proper targets for new strategies for vaccination or immunotherapy of vaginal candidiasis. Overall, our data provide clear evidence that it is possible to prevent C. albicans vaginal infection by active intravaginal immunization with aspartyl proteinase expressed as recombinant protein. This opens the way to a modality for anti-Candida protection at the mucosa. The recombinant protein Sap2 was assembled with virosomes, and a vaccine PEVION7 (PEV7) was obtained. The results have given evidence that the vaccine, constituted of virosomes and Secretory aspartyl proteinase 2 (Sap2) (PEV7), has an encouraging therapeutic potential for the treatment of recurrent vulvovaginal candidiasis. Full article
(This article belongs to the Special Issue Candida Albicans Infections)
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Open AccessReview
Systems Level Dissection of Candida Recognition by Dectins: A Matter of Fungal Morphology and Site of Infection
Pathogens 2015, 4(3), 639-661; https://doi.org/10.3390/pathogens4030639 - 21 Aug 2015
Cited by 9
Abstract
Candida albicans is an ubiquitous fungal commensal of human skin and mucosal surfaces, and at the same time a major life-threatening human fungal pathogen in immunocompromised individuals. Host defense mechanisms rely on the capacity of professional phagocytes to recognize Candida cell wall antigens. [...] Read more.
Candida albicans is an ubiquitous fungal commensal of human skin and mucosal surfaces, and at the same time a major life-threatening human fungal pathogen in immunocompromised individuals. Host defense mechanisms rely on the capacity of professional phagocytes to recognize Candida cell wall antigens. During the past decade, the host immune response to Candida was dissected in depth, highlighting the essential role of C-type lectin receptors, especially regarding the power of the Dectins’ family in discriminating between the tolerated yeast-like form of Candida and its invading counterpart, the hyphae. This review focuses on the immuno-modulatory properties of the Candida morphologies and their specific interactions with the host innate immune system in different body surfaces. Full article
(This article belongs to the Special Issue Candida Albicans Infections)
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Open AccessReview
Interleukin 17-Mediated Host Defense against Candida albicans
Pathogens 2015, 4(3), 606-619; https://doi.org/10.3390/pathogens4030606 - 12 Aug 2015
Cited by 29
Abstract
Candida albicans is part of the normal microbiota in most healthy individuals. However, it can cause opportunistic infections if host defenses are breached, with symptoms ranging from superficial lesions to severe systemic disease. The study of rare congenital defects in patients with chronic [...] Read more.
Candida albicans is part of the normal microbiota in most healthy individuals. However, it can cause opportunistic infections if host defenses are breached, with symptoms ranging from superficial lesions to severe systemic disease. The study of rare congenital defects in patients with chronic mucocutaneous candidiasis led to the identification of interleukin-17 (IL-17) as a key factor in host defense against mucosal fungal infection. Experimental infections in mice confirmed the critical role of IL-17 in mucocutaneous immunity against C. albicans. Research on mouse models has also contributed importantly to our current understanding of the regulation of IL-17 production by different cellular sources and its effector functions in distinct tissues. In this review, we highlight recent findings on IL-17-mediated immunity against C. albicans in mouse and man. Full article
(This article belongs to the Special Issue Candida Albicans Infections)
Open AccessReview
Elimination of Bloodstream Infections Associated with Candida albicans Biofilm in Intravascular Catheters
Pathogens 2015, 4(3), 457-469; https://doi.org/10.3390/pathogens4030457 - 29 Jun 2015
Cited by 20
Abstract
Intravascular catheters are among the most commonly inserted medical devices and they are known to cause a large number of catheter related bloodstream infections (BSIs). Biofilms are associated with many chronic infections due to the aggregation of microorganisms. One of these organisms is [...] Read more.
Intravascular catheters are among the most commonly inserted medical devices and they are known to cause a large number of catheter related bloodstream infections (BSIs). Biofilms are associated with many chronic infections due to the aggregation of microorganisms. One of these organisms is the fungus Candida albicans. It has shown to be one of the leading causes of catheter-related BSIs. The presence of biofilm on intravascular catheters provide increased tolerance against antimicrobial treatments, thus alternative treatment strategies are sought. Traditionally, many strategies, such as application of combined antimicrobials, addition of antifungals, and removal of catheters, have been practiced, but they were not successful in eradicating BSIs. Since these fungal infections can result in significant morbidity, mortality, and increased healthcare cost, other promising preventive strategies, including antimicrobial lock therapy, chelating agents, alcohol, and biofilm disruptors, have been applied. In this review, current success and failure of these new approaches, and a comparison with the previous strategies are discussed in order to understand which preventative treatment is the most effective in controlling the catheter-related BSIs. Full article
(This article belongs to the Special Issue Candida Albicans Infections)
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Open AccessReview
Oropharyngeal Candidiasis in HIV Infection: Analysis of Impaired Mucosal Immune Response to Candida albicans in Mice Expressing the HIV-1 Transgene
Pathogens 2015, 4(2), 406-421; https://doi.org/10.3390/pathogens4020406 - 23 Jun 2015
Cited by 10
Abstract
IL-17-producing Th17 cells are of critical importance in host defense against oropharyngeal candidiasis (OPC). Speculation about defective Th17 responses to oral C. albicans infection in the context of HIV infection prompted an investigation of innate and adaptive immune responses to Candida albicans in [...] Read more.
IL-17-producing Th17 cells are of critical importance in host defense against oropharyngeal candidiasis (OPC). Speculation about defective Th17 responses to oral C. albicans infection in the context of HIV infection prompted an investigation of innate and adaptive immune responses to Candida albicans in transgenic mice expressing the genome of HIV-1 in immune cells and displaying an AIDS-like disease. Defective IL-17 and IL-22-dependent mucosal responses to C. albicans were found to determine susceptibility to OPC in these transgenic mice. Innate phagocytes were quantitatively and functionally intact, and individually dispensable for control of OPC and to prevent systemic dissemination of Candida to deep organs. CD8+ T-cells recruited to the oral mucosa of the transgenic mice limited the proliferation of C. albicans in these conditions of CD4+ T-cell deficiency. Therefore, the immunopathogenesis of OPC in the context of HIV infection involves defective T-cell-mediated immunity, failure of crosstalk with innate mucosal immune effector mechanisms, and compensatory cell responses, which limit Candida infection to the oral mucosa and prevent systemic dissemination. Full article
(This article belongs to the Special Issue Candida Albicans Infections)
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Other

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Open AccessBrief Report
Neutrophils Do Not Express IL-17A in the Context of Acute Oropharyngeal Candidiasis
Pathogens 2015, 4(3), 559-572; https://doi.org/10.3390/pathogens4030559 - 24 Jul 2015
Cited by 17
Abstract
IL-17 protects against pathogens by acting on nonhematopoietic cells to induce neutrophil recruitment through upregulation of chemokines and G-CSF. IL-17- and Th17-deficient humans and mice are susceptible to mucosal Candida albicans infections, linked to impaired neutrophil responses. IL-17 production is traditionally associated [...] Read more.
IL-17 protects against pathogens by acting on nonhematopoietic cells to induce neutrophil recruitment through upregulation of chemokines and G-CSF. IL-17- and Th17-deficient humans and mice are susceptible to mucosal Candida albicans infections, linked to impaired neutrophil responses. IL-17 production is traditionally associated with CD4+ Th17 cells. However, IL-17 is also expressed during innate responses to facilitate rapid pathogen clearance. Innate IL-17-expressing cells include various lymphocyte-type subsets, including ILC3, NKT, γδ-T and “natural” Th17 (nTh17) cells. Some reports suggest that neutrophils can express IL-17 during fungal infections. Here, we asked whether neutrophils serve as a source of IL-17 during acute oropharyngeal candidiasis (OPC) using an IL-17A fate-tracking reporter mouse. Mice were subjected to OPC for two days, and oral tissue was analyzed by flow cytometry. IL-17A was expressed by γδ-T cells and TCRβ+ natural Th17 (nTh17) cells, as recently reported. Although infiltrating neutrophils were recruited to the tongue following infection, they did not express the IL-17A reporter. Moreover, neutrophil-depleted mice exhibited normal transcription of both Il17a and downstream IL-17-dependent gene targets after Candida challenge. Thus, in acute OPC, neutrophils are not a measurable source of IL-17 production, nor are they necessary to trigger IL-17-dependent gene expression, although they are essential for ultimate pathogen control. Full article
(This article belongs to the Special Issue Candida Albicans Infections)
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