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Pathogens
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Candida albicans: A Major Fungal Pathogen of Humans
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Candida albicans: A Major Fungal Pathogen of Humans

A special issue of Pathogens (ISSN 2076-0817). This special issue belongs to the section "Fungal Pathogens".

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 41790

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Dr. Jonathan Richardson

E-Mail Website
Guest Editor
Centre for Host-Microbiome Interactions, King’s College London, London SE1 1UL, UK
Interests: host-fungal interactions; fungal virulence factors and pathogenicity mechanisms
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Fungal diseases are a significant and growing challenge to healthcare that cause millions of life-threatening infections every year. Candida albicans is typically regarded as a commensal component of the human microbiota but frequently causes superficial infections in otherwise healthy individuals, and invasive life-threatening infections in those with compromised immunity. In 2017, the national cost of Candida-associated hospitalizations was estimated to be $1.4 billion in the USA alone [1]. C. albicans accounts for ~75% of all Candida infections, representing a serious medical challenge for worldwide communities, particularly in the ever-increasing immunocompromised patient population (e.g. chemotherapy, transplants, ICU).

Understanding the biology of C. albicans, how it interacts with the human host, and how it causes disease is of critical importance if we are to engage with and overcome the numerous challenges associated with effective treatment. In this Special Edition of Pathogens, "Candida albicans: a major fungal pathogen of humans" will present recent advances in our understanding of C. albicans in the context of host interaction, infection, and therapeutics.

Potential topics may include (but are not limited to):

  • Cell wall biology
  • Genomic plasticity and epigenetic diversity
  • Regulation of hypha development and contact sensing
  • Biofilms
  • Mucosal and systemic infection (and associated immune responses)
  • Acquisition of micronutrients
  • Therapeutics and diagnostics
  • Tolerance and resistance to antifungal drugs
  • Medical case reports

I look forward to your contributions to this valuable and thought-provoking Special Issue.

Reference

1. Benedict, K., Jackson, B. R., Chiller, T. & Beer, K. D. Estimation of Direct Healthcare Costs of Fungal Diseases in the United States. Clin Infect Dis 68, 1791–1797, doi:10.1093/cid/ciy776 (2019).

Dr. Jonathan Richardson
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pathogens is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Candida albicans
  • fungal infection
  • candidiasis
  • thrush
  • hyphae
  • innate
  • adaptive
  • mucosal
  • systemic
  • biofilm
  • antifungal

Published Papers (11 papers)

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Editorial

Jump to: Research, Review

3 pages, 188 KiB  
Editorial
Candida albicans: A Major Fungal Pathogen of Humans
by Jonathan P. Richardson
Pathogens 2022, 11(4), 459; https://doi.org/10.3390/pathogens11040459 - 11 Apr 2022
Cited by 6 | Viewed by 2202
Abstract
Fungal infections kill ~1 [...] Full article
(This article belongs to the Special Issue Candida albicans: A Major Fungal Pathogen of Humans)

Research

Jump to: Editorial, Review

12 pages, 2852 KiB  
Article
Sphingolipid Inhibitors as an Alternative to Treat Candidiasis Caused by Fluconazole-Resistant Strains
by Rodrigo Rollin-Pinheiro, Brayan Bayona-Pacheco, Levy Tenorio Sousa Domingos, Jose Alexandre da Rocha Curvelo, Gabriellen Menezes Migliani de Castro, Eliana Barreto-Bergter and Antonio Ferreira-Pereira
Pathogens 2021, 10(7), 856; https://doi.org/10.3390/pathogens10070856 - 07 Jul 2021
Cited by 12 | Viewed by 2681
Abstract
Candida species are fungal pathogens known to cause a wide spectrum of diseases, and Candida albicans and Candida glabrata are the most common associated with invasive infections. A concerning aspect of invasive candidiasis is the emergence of resistant isolates, especially those highly resistant [...] Read more.
Candida species are fungal pathogens known to cause a wide spectrum of diseases, and Candida albicans and Candida glabrata are the most common associated with invasive infections. A concerning aspect of invasive candidiasis is the emergence of resistant isolates, especially those highly resistant to fluconazole, the first choice of treatment for these infections. Fungal sphingolipids have been considered a potential target for new therapeutic approaches and some inhibitors have already been tested against pathogenic fungi. The present study therefore aimed to evaluate the action of two sphingolipid synthesis inhibitors, aureobasidin A and myriocin, against different C. albicans and C. glabrata strains, including clinical isolates resistant to fluconazole. Susceptibility tests of aureobasidin A and myriocin were performed using CLSI protocols, and their interaction with fluconazole was evaluated by a checkerboard protocol. All Candida strains tested were sensitive to both inhibitors. Regarding the evaluation of drug interaction, both aureobasidin A and myriocin were synergic with fluconazole, demonstrating that sphingolipid synthesis inhibition could enhance the effect of fluconazole. Thus, these results suggest that sphingolipid inhibitors in conjunction with fluconazole could be useful for treating candidiasis cases, especially those caused by fluconazole resistant isolates. Full article
(This article belongs to the Special Issue Candida albicans: A Major Fungal Pathogen of Humans)
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Graphical abstract

8 pages, 1683 KiB  
Article
Metamorphic Protein Folding Encodes Multiple Anti-Candida Mechanisms in XCL1
by Acacia F. Dishman, Jie He, Brian F. Volkman and Anna R. Huppler
Pathogens 2021, 10(6), 762; https://doi.org/10.3390/pathogens10060762 - 17 Jun 2021
Cited by 2 | Viewed by 2298
Abstract
Candida species cause serious infections requiring prolonged and sometimes toxic therapy. Antimicrobial proteins, such as chemokines, hold great interest as potential additions to the small number of available antifungal drugs. Metamorphic proteins reversibly switch between multiple different folded structures. XCL1 is a metamorphic, [...] Read more.
Candida species cause serious infections requiring prolonged and sometimes toxic therapy. Antimicrobial proteins, such as chemokines, hold great interest as potential additions to the small number of available antifungal drugs. Metamorphic proteins reversibly switch between multiple different folded structures. XCL1 is a metamorphic, antimicrobial chemokine that interconverts between the conserved chemokine fold (an α–β monomer) and an alternate fold (an all-β dimer). Previous work has shown that human XCL1 kills C. albicans but has not assessed whether one or both XCL1 folds perform this activity. Here, we use structurally locked engineered XCL1 variants and Candida killing assays, adenylate kinase release assays, and propidium iodide uptake assays to demonstrate that both XCL1 folds kill Candida, but they do so via different mechanisms. Our results suggest that the alternate fold kills via membrane disruption, consistent with previous work, and the chemokine fold does not. XCL1 fold-switching thus provides a mechanism to regulate the XCL1 mode of antifungal killing, which could protect surrounding tissue from damage associated with fungal membrane disruption and could allow XCL1 to overcome candidal resistance by switching folds. This work provides inspiration for the future design of switchable, multifunctional antifungal therapeutics. Full article
(This article belongs to the Special Issue Candida albicans: A Major Fungal Pathogen of Humans)
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14 pages, 1733 KiB  
Article
The Synthesis and Evaluation of Multivalent Glycopeptoids as Inhibitors of the Adhesion of Candida albicans
by Harlei Martin, Hannah Masterson, Kevin Kavanagh and Trinidad Velasco-Torrijos
Pathogens 2021, 10(5), 572; https://doi.org/10.3390/pathogens10050572 - 08 May 2021
Cited by 2 | Viewed by 2426
Abstract
Multivalency is a strategy commonly used by medicinal carbohydrate chemists to increase the affinity of carbohydrate-based small molecules for their protein targets. Although this approach has been very successful in enhancing binding to isolated carbohydrate-binding proteins, anticipating the multivalent presentations that will improve [...] Read more.
Multivalency is a strategy commonly used by medicinal carbohydrate chemists to increase the affinity of carbohydrate-based small molecules for their protein targets. Although this approach has been very successful in enhancing binding to isolated carbohydrate-binding proteins, anticipating the multivalent presentations that will improve biological activity in cellular assays remains challenging. In this work we investigate linear molecular scaffolds for the synthesis of a low valency presentation of a divalent galactoside 1, previously identified by us as an inhibitor of the adhesion of opportunistic fungal pathogen Candida albicans to buccal epithelial cells (BECs). Adhesion inhibition assays revealed that multivalent glycoconjugate 3 is more effective at blocking C. albicans adherence to BECs upon initial exposure to epithelial cells. Interestingly, 3 did not seem to have any effect when it was pre-incubated with yeast cells, in contrast to the original lead compound 1, which caused a 25% reduction of adhesion. In competition assays, where yeast cells and BECs were co-incubated, multivalent glycoconjugate 3 inhibited up to 49% C. albicans adherence in a dose-dependent manner. The combined effect of compound 1 towards both yeast cells and BECs allowed it to achieve over 60% inhibition of the adhesion of C. albicans to BECs in competition assays. Full article
(This article belongs to the Special Issue Candida albicans: A Major Fungal Pathogen of Humans)
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Graphical abstract

20 pages, 3120 KiB  
Article
Fungicidal Activity of a Safe 1,3,4-Oxadiazole Derivative Against Candida albicans
by Daniella Renata Faria, Raquel Cabral Melo, Glaucia Sayuri Arita, Karina Mayumi Sakita, Franciele Abigail Vilugron Rodrigues-Vendramini, Isis Regina Grenier Capoci, Tania Cristina Alexandrino Becker, Patrícia de Souza Bonfim-Mendonça, Maria Sueli Soares Felipe, Terezinha Inez Estivalet Svidzinski and Erika Seki Kioshima
Pathogens 2021, 10(3), 314; https://doi.org/10.3390/pathogens10030314 - 07 Mar 2021
Cited by 10 | Viewed by 2281
Abstract
Candida albicans is the most common species isolated from nosocomial bloodstream infections. Due to limited therapeutic arsenal and increase of drug resistance, there is an urgent need for new antifungals. Therefore, the antifungal activity against C. albicans and in vivo toxicity of a [...] Read more.
Candida albicans is the most common species isolated from nosocomial bloodstream infections. Due to limited therapeutic arsenal and increase of drug resistance, there is an urgent need for new antifungals. Therefore, the antifungal activity against C. albicans and in vivo toxicity of a 1,3,4-oxadiazole compound (LMM6) was evaluated. This compound was selected by in silico approach based on chemical similarity. LMM6 was highly effective against several clinical C. albicans isolates, with minimum inhibitory concentration values ranging from 8 to 32 µg/mL. This compound also showed synergic effect with amphotericin B and caspofungin. In addition, quantitative assay showed that LMM6 exhibited a fungicidal profile and a promising anti-biofilm activity, pointing to its therapeutic potential. The evaluation of acute toxicity indicated that LMM6 is safe for preclinical trials. No mortality and no alterations in the investigated parameters were observed. In addition, no substantial alteration was found in Hippocratic screening, biochemical or hematological analyzes. LMM6 (5 mg/kg twice a day) was able to reduce both spleen and kidneys fungal burden and further, promoted the suppresses of inflammatory cytokines, resulting in infection control. These preclinical findings support future application of LMM6 as potential antifungal in the treatment of invasive candidiasis. Full article
(This article belongs to the Special Issue Candida albicans: A Major Fungal Pathogen of Humans)
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13 pages, 2804 KiB  
Article
Antifungal Activity of Capridine β as a Consequence of Its Biotransformation into Metabolite Affecting Yeast Topoisomerase II Activity
by Iwona Gabriel, Kamila Rząd, Ewa Paluszkiewicz and Katarzyna Kozłowska-Tylingo
Pathogens 2021, 10(2), 189; https://doi.org/10.3390/pathogens10020189 - 09 Feb 2021
Cited by 5 | Viewed by 1992
Abstract
In the last few years, increasing importance is attached to problems caused by fungal pathogens. Current methods of preventing fungal infections remain unsatisfactory. There are several antifungal compounds which are highly effective in some cases, however, they have limitations in usage: Nephrotoxicity and [...] Read more.
In the last few years, increasing importance is attached to problems caused by fungal pathogens. Current methods of preventing fungal infections remain unsatisfactory. There are several antifungal compounds which are highly effective in some cases, however, they have limitations in usage: Nephrotoxicity and other adverse effects. In addition, the frequent use of available fungistatic drugs promotes drug resistance. Therefore, there is an urgent need for the development of a novel antifungal drug with a different mechanism of action, blocking of the fungal DNA topoisomerases activity appear to be a promising idea. According to previous studies on the m-AMSA moderate inhibitory effect on fungal topoisomerase II, we have decided to study Capridine β (also acridine derivative) antifungal activity, as well as its inhibitory potential on yeast topoisomerase II (yTOPOII). Results indicated that Capridine β antifungal activity depends on the kind of strains analyzed (MICs range 0.5–64 μg mL−1) and is related to its biotransformation in the cells. An investigation of metabolite formation, identified as Capridine β reduction product (IE1) by the fungus Candida albicans was performed. IE1 exhibited no activity against fungal cells due to an inability to enter the cells. Although no antifungal activity was observed, in contrast to Capridine β, biotransformation metabolite totally inhibited the yTOPOII-mediated relaxation at concentrations lower than detected for m-AMSA. The closely related Capridine β only slightly diminished the catalytic activity of yTOPOII. Full article
(This article belongs to the Special Issue Candida albicans: A Major Fungal Pathogen of Humans)
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Review

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16 pages, 1187 KiB  
Review
Role of Cellular Metabolism during Candida-Host Interactions
by Aize Pellon, Neelu Begum, Shervin Dokht Sadeghi Nasab, Azadeh Harzandi, Saeed Shoaie and David L. Moyes
Pathogens 2022, 11(2), 184; https://doi.org/10.3390/pathogens11020184 - 28 Jan 2022
Cited by 13 | Viewed by 4091
Abstract
Microscopic fungi are widely present in the environment and, more importantly, are also an essential part of the human healthy mycobiota. However, many species can become pathogenic under certain circumstances, with Candida spp. being the most clinically relevant fungi. In recent years, the [...] Read more.
Microscopic fungi are widely present in the environment and, more importantly, are also an essential part of the human healthy mycobiota. However, many species can become pathogenic under certain circumstances, with Candida spp. being the most clinically relevant fungi. In recent years, the importance of metabolism and nutrient availability for fungi-host interactions have been highlighted. Upon activation, immune and other host cells reshape their metabolism to fulfil the energy-demanding process of generating an immune response. This includes macrophage upregulation of glucose uptake and processing via aerobic glycolysis. On the other side, Candida modulates its metabolic pathways to adapt to the usually hostile environment in the host, such as the lumen of phagolysosomes. Further understanding on metabolic interactions between host and fungal cells would potentially lead to novel/enhanced antifungal therapies to fight these infections. Therefore, this review paper focuses on how cellular metabolism, of both host cells and Candida, and the nutritional environment impact on the interplay between host and fungal cells. Full article
(This article belongs to the Special Issue Candida albicans: A Major Fungal Pathogen of Humans)
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21 pages, 2486 KiB  
Review
Amino Acid Sensing and Assimilation by the Fungal Pathogen Candida albicans in the Human Host
by Fitz Gerald S. Silao and Per O. Ljungdahl
Pathogens 2022, 11(1), 5; https://doi.org/10.3390/pathogens11010005 - 22 Dec 2021
Cited by 10 | Viewed by 6439
Abstract
Nutrient uptake is essential for cellular life and the capacity to perceive extracellular nutrients is critical for coordinating their uptake and metabolism. Commensal fungal pathogens, e.g., Candida albicans, have evolved in close association with human hosts and are well-adapted to using diverse [...] Read more.
Nutrient uptake is essential for cellular life and the capacity to perceive extracellular nutrients is critical for coordinating their uptake and metabolism. Commensal fungal pathogens, e.g., Candida albicans, have evolved in close association with human hosts and are well-adapted to using diverse nutrients found in discrete host niches. Human cells that cannot synthesize all amino acids require the uptake of the “essential amino acids” to remain viable. Consistently, high levels of amino acids circulate in the blood. Host proteins are rich sources of amino acids but their use depends on proteases to cleave them into smaller peptides and free amino acids. C. albicans responds to extracellular amino acids by pleiotropically enhancing their uptake and derive energy from their catabolism to power opportunistic virulent growth. Studies using Saccharomyces cerevisiae have established paradigms to understand metabolic processes in C. albicans; however, fundamental differences exist. The advent of CRISPR/Cas9-based methods facilitate genetic analysis in C. albicans, and state-of-the-art molecular biological techniques are being applied to directly examine growth requirements in vivo and in situ in infected hosts. The combination of divergent approaches can illuminate the biological roles of individual cellular components. Here we discuss recent findings regarding nutrient sensing with a focus on amino acid uptake and metabolism, processes that underlie the virulence of C. albicans. Full article
(This article belongs to the Special Issue Candida albicans: A Major Fungal Pathogen of Humans)
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16 pages, 2562 KiB  
Review
On and Off: Epigenetic Regulation of C. albicans Morphological Switches
by Elise Iracane, Samuel Vega-Estévez and Alessia Buscaino
Pathogens 2021, 10(11), 1463; https://doi.org/10.3390/pathogens10111463 - 11 Nov 2021
Cited by 8 | Viewed by 2568
Abstract
The human fungal pathogen Candida albicans is a dimorphic opportunistic pathogen that colonises most of the human population without creating any harm. However, this fungus can also cause life-threatening infections in immunocompromised individuals. The ability to successfully colonise different host niches is critical [...] Read more.
The human fungal pathogen Candida albicans is a dimorphic opportunistic pathogen that colonises most of the human population without creating any harm. However, this fungus can also cause life-threatening infections in immunocompromised individuals. The ability to successfully colonise different host niches is critical for establishing infections and pathogenesis. C. albicans can live and divide in various morphological forms critical for its survival in the host. Indeed, C. albicans can grow as both yeast and hyphae and can form biofilms containing hyphae. The transcriptional regulatory network governing the switching between these different forms is complex but well understood. In contrast, non-DNA based epigenetic modulation is emerging as a crucial but still poorly studied regulatory mechanism of morphological transition. This review explores our current understanding of chromatin-mediated epigenetic regulation of the yeast to hyphae switch and biofilm formation. We highlight how modification of chromatin structure and non-coding RNAs contribute to these morphological transitions. Full article
(This article belongs to the Special Issue Candida albicans: A Major Fungal Pathogen of Humans)
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29 pages, 4131 KiB  
Review
From Jekyll to Hyde: The Yeast–Hyphal Transition of Candida albicans
by Eve Wai Ling Chow, Li Mei Pang and Yue Wang
Pathogens 2021, 10(7), 859; https://doi.org/10.3390/pathogens10070859 - 07 Jul 2021
Cited by 33 | Viewed by 9745
Abstract
Candida albicans is a major fungal pathogen of humans, accounting for 15% of nosocomial infections with an estimated attributable mortality of 47%. C. albicans is usually a benign member of the human microbiome in healthy people. Under constant exposure to highly dynamic environmental [...] Read more.
Candida albicans is a major fungal pathogen of humans, accounting for 15% of nosocomial infections with an estimated attributable mortality of 47%. C. albicans is usually a benign member of the human microbiome in healthy people. Under constant exposure to highly dynamic environmental cues in diverse host niches, C. albicans has successfully evolved to adapt to both commensal and pathogenic lifestyles. The ability of C. albicans to undergo a reversible morphological transition from yeast to filamentous forms is a well-established virulent trait. Over the past few decades, a significant amount of research has been carried out to understand the underlying regulatory mechanisms, signaling pathways, and transcription factors that govern the C. albicans yeast-to-hyphal transition. This review will summarize our current understanding of well-elucidated signal transduction pathways that activate C. albicans hyphal morphogenesis in response to various environmental cues and the cell cycle machinery involved in the subsequent regulation and maintenance of hyphal morphogenesis. Full article
(This article belongs to the Special Issue Candida albicans: A Major Fungal Pathogen of Humans)
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18 pages, 1008 KiB  
Review
Invasive Candida Infections in Neonates after Major Surgery: Current Evidence and New Directions
by Domenico Umberto De Rose, Alessandra Santisi, Maria Paola Ronchetti, Ludovica Martini, Lisa Serafini, Pasqua Betta, Marzia Maino, Francesco Cavigioli, Ilaria Cocchi, Lorenza Pugni, Elvira Bonanno, Chryssoula Tzialla, Mario Giuffrè, Jenny Bua, Benedetta Della Torre, Giovanna Nardella, Danila Mazzeo, Paolo Manzoni, Andrea Dotta, Pietro Bagolan, Cinzia Auriti and on behalf of Study Group of Neonatal Infectious Diseasesadd Show full author list remove Hide full author list
Pathogens 2021, 10(3), 319; https://doi.org/10.3390/pathogens10030319 - 09 Mar 2021
Cited by 11 | Viewed by 3389
Abstract
Infections represent a serious health problem in neonates. Invasive Candida infections (ICIs) are still a leading cause of mortality and morbidity in neonatal intensive care units (NICUs). Infants hospitalized in NICUs are at high risk of ICIs, because of several risk factors: broad [...] Read more.
Infections represent a serious health problem in neonates. Invasive Candida infections (ICIs) are still a leading cause of mortality and morbidity in neonatal intensive care units (NICUs). Infants hospitalized in NICUs are at high risk of ICIs, because of several risk factors: broad spectrum antibiotic treatments, central catheters and other invasive devices, fungal colonization, and impaired immune responses. In this review we summarize 19 published studies which provide the prevalence of previous surgery in neonates with invasive Candida infections. We also provide an overview of risk factors for ICIs after major surgery, fungal colonization, and innate defense mechanisms against fungi, as well as the roles of different Candida spp., the epidemiology and costs of ICIs, diagnosis of ICIs, and antifungal prophylaxis and treatment. Full article
(This article belongs to the Special Issue Candida albicans: A Major Fungal Pathogen of Humans)
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