Special Issue "Fungal Pathogenesis in Humans: The Growing Threat"

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Microbial Genetics and Genomics".

Deadline for manuscript submissions: closed (30 June 2018)

Special Issue Editor

Guest Editor
Dr. Fernando Leal

Instituto de Biología Funcional y Genómica / Dpto. Microbiología y Genética Consejo Superior de Investigaciones Científicas (CSIC)/Universidad de Salamanca, Salamanca, Spain
E-Mail
Interests: fungal pathogenesis; Aspergillus molecular genetics; virology; miRNAs

Special Issue Information

Dear Colleagues,

Cancer survival rates and successful organ transplantation in patients continues to increase due to improvements in early diagnosis and treatments. Since immuno-suppressive therapies are frequently used, the mortality rate due to secondary infections has become an ever-increasing problem. Opportunistic fungal infections are probably the deadliest threat to these patients due to their difficult early diagnosis, the limited effect of antifungal drugs and the appearance of resistances. In recent years, a considerable effort has been devoted to investigating the role of many virulence traits in the pathogenic outcome of fungal infections. New virulence factors (hypoxia adaptation, CO2 sensing, pH regulation, micronutrient acquisition, secondary metabolites, immunity regulators, etc.) have been reported and their molecular mechanisms of action are being thoroughly investigated. The recent application of gene-editing technologies such as CRISPr-Cas9, has opened a whole new window to the discovery of new fungal virulence factors. Accurate fungal genotyping, Next Generation Sequencing and RNAseq approaches will undoubtedly provide new clues to interpret the plethora of molecular interactions controlling these complex systems. Unraveling their intimate regulatory details will provide insights for a more target-focused search or a rational design of more specific antifungal agents.

This Special Issue is open to researchers in any related field willing to contribute significant discoveries, proofs of concept of new theories or relevant observations in fungal pathogenesis and its regulation.

Dr. Fernando Leal
Guest Editor

Manuscript Submission Information

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Keywords

  • Fungal virulence

  • Fungal genotyping

  • Biofilm formation

  • Immune evasion

  • CO2 sensing

  • pH regulation

  • Micronutrient acquisition

  • Trehalose biosynthesis

  • Secondary metabolites and toxins

  • Regulation of antifungals resistance

  • Criptococcus, Candida, Aspergillus, Scedosporium, Fusarium, Pneumocysits

Published Papers (10 papers)

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Research

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Open AccessArticle Role of Homologous Recombination Genes in Repair of Alkylation Base Damage by Candida albicans
Received: 14 August 2018 / Accepted: 27 August 2018 / Published: 7 September 2018
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Abstract
Candida albicans mutants deficient in homologous recombination (HR) are extremely sensitive to the alkylating agent methyl-methane-sulfonate (MMS). Here, we have investigated the role of HR genes in the protection and repair of C. albicans chromosomes by taking advantage of the heat-labile property (55
[...] Read more.
Candida albicans mutants deficient in homologous recombination (HR) are extremely sensitive to the alkylating agent methyl-methane-sulfonate (MMS). Here, we have investigated the role of HR genes in the protection and repair of C. albicans chromosomes by taking advantage of the heat-labile property (55 °C) of MMS-induced base damage. Acute MMS treatments of cycling cells caused chromosome fragmentation in vitro (55 °C) due to the generation of heat-dependent breaks (HDBs), but not in vivo (30 °C). Following removal of MMS wild type, cells regained the chromosome ladder regardless of whether they were transferred to yeast extract/peptone/dextrose (YPD) or to phosphate buffer saline (PBS); however, repair of HDB/chromosome restitution was faster in YPD, suggesting that it was accelerated by metabolic energy and further fueled by the subsequent overgrowth of survivors. Compared to wild type CAI4, chromosome restitution in YPD was not altered in a Carad59 isogenic derivative, whereas it was significantly delayed in Carad51 and Carad52 counterparts. However, when post-MMS incubation took place in PBS, chromosome restitution in wild type and HR mutants occurred with similar kinetics, suggesting that the exquisite sensitivity of Carad51 and Carad52 mutants to MMS is due to defective fork restart. Overall, our results demonstrate that repair of HDBs by resting cells of C. albicans is rather independent of CaRad51, CaRad52, and CaRad59, suggesting that it occurs mainly by base excision repair (BER). Full article
(This article belongs to the Special Issue Fungal Pathogenesis in Humans: The Growing Threat)
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Open AccessFeature PaperArticle Pathogenesis of the Candida parapsilosis Complex in the Model Host Caenorhabditis elegans
Received: 18 June 2018 / Revised: 25 July 2018 / Accepted: 25 July 2018 / Published: 8 August 2018
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Abstract
Caenorhabditis elegans is a valuable tool as an infection model toward the study of Candida species. In this work, we endeavored to develop a C. elegans-Candida parapsilosis infection model by using the fungi as a food source. Three species of
[...] Read more.
Caenorhabditis elegans is a valuable tool as an infection model toward the study of Candida species. In this work, we endeavored to develop a C. elegans-Candida parapsilosis infection model by using the fungi as a food source. Three species of the C. parapsilosis complex (C. parapsilosis (sensu stricto), Candida orthopsilosis and Candida metapsilosis) caused infection resulting in C. elegans killing. All three strains that comprised the complex significantly diminished the nematode lifespan, indicating the virulence of the pathogens against the host. The infection process included invasion of the intestine and vulva which resulted in organ protrusion and hyphae formation. Importantly, hyphae formation at the vulva opening was not previously reported in C. elegans-Candida infections. Fungal infected worms in the liquid assay were susceptible to fluconazole and caspofungin and could be found to mount an immune response mediated through increased expression of cnc-4, cnc-7, and fipr-22/23. Overall, the C. elegans-C. parapsilosis infection model can be used to model C. parapsilosis host-pathogen interactions. Full article
(This article belongs to the Special Issue Fungal Pathogenesis in Humans: The Growing Threat)
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Open AccessArticle Golgi Reassembly and Stacking Protein (GRASP) Participates in Vesicle-Mediated RNA Export in Cryptococcus neoformans
Received: 1 July 2018 / Revised: 25 July 2018 / Accepted: 31 July 2018 / Published: 8 August 2018
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Abstract
Golgi reassembly and stacking protein (GRASP) is required for polysaccharide secretion and virulence in Cryptococcus neoformans. In fungal species, extracellular vesicles (EVs) participate in the export of polysaccharides, proteins and RNA. In the present work, we investigated if EV-mediated RNA export is
[...] Read more.
Golgi reassembly and stacking protein (GRASP) is required for polysaccharide secretion and virulence in Cryptococcus neoformans. In fungal species, extracellular vesicles (EVs) participate in the export of polysaccharides, proteins and RNA. In the present work, we investigated if EV-mediated RNA export is functionally connected with GRASP in C. neoformans using a graspΔ mutant. Since GRASP-mediated unconventional secretion involves autophagosome formation in yeast, we included the atg7Δ mutant with defective autophagic mechanisms in our analysis. All fungal strains exported EVs but deletion of GRASP or ATG7 profoundly affected vesicular dimensions. The mRNA content of the graspΔ EVs differed substantially from that of the other two strains. The transcripts associated to the endoplasmic reticulum were highly abundant transcripts in graspΔ EVs. Among non-coding RNAs (ncRNAs), tRNA fragments were the most abundant in both mutant EVs but graspΔ EVs alone concentrated 22 exclusive sequences. In general, our results showed that the EV RNA content from atg7Δ and WT were more related than the RNA content of graspΔ, suggesting that GRASP, but not the autophagy regulator Atg7, is involved in the EV export of RNA. This is a previously unknown function for a key regulator of unconventional secretion in eukaryotic cells. Full article
(This article belongs to the Special Issue Fungal Pathogenesis in Humans: The Growing Threat)
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Open AccessArticle Genome-Wide Comparative Analysis of Aspergillus fumigatus Strains: The Reference Genome as a Matter of Concern
Received: 28 June 2018 / Revised: 13 July 2018 / Accepted: 16 July 2018 / Published: 19 July 2018
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Abstract
Aspergillus fumigatus is a ubiquitous saprophytic mold and a major pathogen in immunocompromised patients. The effectiveness of triazole compounds, the A. fumigatus first line treatment, is being threatened by a rapid and global emergence of azole resistance. Whole genome sequencing (WGS) has emerged
[...] Read more.
Aspergillus fumigatus is a ubiquitous saprophytic mold and a major pathogen in immunocompromised patients. The effectiveness of triazole compounds, the A. fumigatus first line treatment, is being threatened by a rapid and global emergence of azole resistance. Whole genome sequencing (WGS) has emerged as an invaluable tool for the analysis of genetic differences between A. fumigatus strains, their genetic background, and antifungal resistance development. Although WGS analyses can provide a valuable amount of novel information, there are some limitations that should be considered. These analyses, based on genome-wide comparative data and single nucleotide variant (SNV) calling, are dependent on the quality of sequencing, assembling, the variant calling criteria, as well as on the suitable selection of the reference genome, which must be genetically close to the genomes included in the analysis. In this study, 28 A. fumigatus genomes sequenced in-house and 73 available in public data bases have been analyzed. All genomes were distributed in four clusters and showed a variable number of SNVs depending on the genome used as reference (Af293 or A1163). Each reference genome belonged to a different cluster. The results highlighted the importance of choosing the most suitable A. fumigatus reference genome to avoid misleading conclusions. Full article
(This article belongs to the Special Issue Fungal Pathogenesis in Humans: The Growing Threat)
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Open AccessArticle Dual RNA-Seq Analysis of Trichophyton rubrum and HaCat Keratinocyte Co-Culture Highlights Important Genes for Fungal-Host Interaction
Received: 30 May 2018 / Revised: 11 July 2018 / Accepted: 16 July 2018 / Published: 19 July 2018
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Abstract
The dermatophyte Trichophyton rubrum is the major fungal pathogen of skin, hair, and nails that uses keratinized substrates as the primary nutrients during infection. Few strategies are available that permit a better understanding of the molecular mechanisms involved in the interaction of T.
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The dermatophyte Trichophyton rubrum is the major fungal pathogen of skin, hair, and nails that uses keratinized substrates as the primary nutrients during infection. Few strategies are available that permit a better understanding of the molecular mechanisms involved in the interaction of T. rubrum with the host because of the limitations of models mimicking this interaction. Dual RNA-seq is a powerful tool to unravel this complex interaction since it enables simultaneous evaluation of the transcriptome of two organisms. Using this technology in an in vitro model of co-culture, this study evaluated the transcriptional profile of genes involved in fungus-host interactions in 24 h. Our data demonstrated the induction of glyoxylate cycle genes, ERG6 and TERG_00916, which encodes a carboxylic acid transporter that may improve the assimilation of nutrients and fungal survival in the host. Furthermore, genes encoding keratinolytic proteases were also induced. In human keratinocytes (HaCat) cells, the SLC11A1, RNASE7, and CSF2 genes were induced and the products of these genes are known to have antimicrobial activity. In addition, the FLG and KRT1 genes involved in the epithelial barrier integrity were inhibited. This analysis showed the modulation of important genes involved in T. rubrum–host interaction, which could represent potential antifungal targets for the treatment of dermatophytoses. Full article
(This article belongs to the Special Issue Fungal Pathogenesis in Humans: The Growing Threat)
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Open AccessFeature PaperArticle The Transcription Factor ZafA Regulates the Homeostatic and Adaptive Response to Zinc Starvation in Aspergillus fumigatus
Received: 24 May 2018 / Revised: 20 June 2018 / Accepted: 20 June 2018 / Published: 26 June 2018
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Abstract
One of the most important features that enables Aspergillus fumigatus to grow within a susceptible individual and to cause disease is its ability to obtain Zn2+ ions from the extremely zinc-limited environment provided by host tissues. Zinc uptake from this source in
[...] Read more.
One of the most important features that enables Aspergillus fumigatus to grow within a susceptible individual and to cause disease is its ability to obtain Zn2+ ions from the extremely zinc-limited environment provided by host tissues. Zinc uptake from this source in A. fumigatus relies on ZIP transporters encoded by the zrfA, zrfB and zrfC genes. The expression of these genes is tightly regulated by the ZafA transcription factor that regulates zinc homeostasis and is essential for A. fumigatus virulence. We combined the use of microarrays, Electrophoretic Mobility Shift Assays (EMSA) analyses, DNase I footprinting assays and in silico tools to better understand the regulation of the homeostatic and adaptive response of A. fumigatus to zinc starvation. We found that under zinc-limiting conditions, ZafA functions mainly as a transcriptional activator through binding to a zinc response sequence located in the regulatory regions of its target genes, although it could also function as a repressor of a limited number of genes. In addition to genes involved in the homeostatic response to zinc deficiency, ZafA also influenced, either directly or indirectly, the expression of many other genes. It is remarkable that the expression of many genes involved in iron uptake and ergosterol biosynthesis is strongly reduced under zinc starvation, even though only the expression of some of these genes appeared to be influenced directly or indirectly by ZafA. In addition, it appears to exist in A. fumigatus a zinc/iron cross-homeostatic network to allow the adaptation of the fungus to grow in media containing unbalanced Zn:Fe ratios. The adaptive response to oxidative stress typically linked to zinc starvation was also mediated by ZafA, as was the strong induction of genes involved in gliotoxin biosynthesis and self-protection against endogenous gliotoxin. This study has expanded our knowledge about the regulatory and metabolic changes displayed by A. fumigatus in response to zinc starvation and has helped us to pinpoint new ZafA target genes that could be important for fungal pathogens to survive and grow within host tissues and, hence, for virulence. Full article
(This article belongs to the Special Issue Fungal Pathogenesis in Humans: The Growing Threat)
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Open AccessFeature PaperArticle Portrait of Matrix Gene Expression in Candida glabrata Biofilms with Stress Induced by Different Drugs
Received: 6 March 2018 / Revised: 29 March 2018 / Accepted: 5 April 2018 / Published: 10 April 2018
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Abstract
(1) Background: Candida glabrata is one of the most significant Candida species associated with severe cases of candidiasis. Biofilm formation is an important feature, closely associated with antifungal resistance, involving alterations of gene expression or mutations, which can result in the failure of
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(1) Background: Candida glabrata is one of the most significant Candida species associated with severe cases of candidiasis. Biofilm formation is an important feature, closely associated with antifungal resistance, involving alterations of gene expression or mutations, which can result in the failure of antifungal treatments. Hence, the main goal of this work was to evaluate the role of a set of genes, associated with matrix production, in the resistance of C. glabrata biofilms to antifungal drugs. (2) Methods: the determination of the expression of BGL2, XOG1, FKS1, FKS2, GAS2, KNH1, UGP1, and MNN2 genes in 48-h biofilm’s cells of three C. glabrata strains was performed through quantitative real-time PCR (RT-qPCR), after contact with Fluconazole (Flu), Amphotericin B (AmB), Caspofungin (Csf), or Micafungin (Mcf). (3) Results: Mcf induced a general overexpression of the selected genes. It was verified that the genes related to the production of β-1,3-glucans (BGL2, XOG1, GAS2) had the highest expressions. (4) Conclusion: though β-1,6-glucans and mannans are an essential part of the cell and biofilm matrix, C. glabrata biofilm cells seem to contribute more to the replacement of β-1,3-glucans. Thus, these biopolymers seem to have a greater impact on the biofilm matrix composition and, consequently, a role in the biofilm resistance to antifungal drugs. Full article
(This article belongs to the Special Issue Fungal Pathogenesis in Humans: The Growing Threat)
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Open AccessArticle Genome-Wide Identification of circRNAs in Pathogenic Basidiomycetous Yeast Cryptococcus neoformans Suggests Conserved circRNA Host Genes over Kingdoms
Received: 9 January 2018 / Revised: 9 February 2018 / Accepted: 19 February 2018 / Published: 26 February 2018
Cited by 1 | PDF Full-text (2169 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Circular RNAs (circRNAs), a novel class of ubiquitous and intriguing noncoding RNA, have been found in a number of eukaryotes but not yet basidiomycetes. In this study, we identified 73 circRNAs from 39.28 million filtered RNA reads from the basidiomycete Cryptococcus neoformans JEC21
[...] Read more.
Circular RNAs (circRNAs), a novel class of ubiquitous and intriguing noncoding RNA, have been found in a number of eukaryotes but not yet basidiomycetes. In this study, we identified 73 circRNAs from 39.28 million filtered RNA reads from the basidiomycete Cryptococcus neoformans JEC21 using next-generation sequencing (NGS) and the bioinformatics tool circular RNA identification (CIRI). Furthermore, mapping of newly found circRNAs to the genome showed that 73.97% of the circRNAs originated from exonic regions, whereas 20.55% were from intergenic regions and 5.48% were from intronic regions. Enrichment analysis of circRNA host genes was conducted based on the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway databases. The results reveal that host genes are mainly responsible for primary metabolism and, interestingly, ribosomal protein production. Furthermore, we uncovered a high-level circRNA that was a transcript from the guanosine triphosphate (GTP)ase gene CNM01190 (gene ID: 3255052) in our yeast. Coincidentally, YPT5, CNM01190′s ortholog of the GTPase in Schizosaccharomyces pombe, protists, and humans, has already been proven to generate circRNAs. Additionally, overexpression of RNA debranching enzyme DBR1 had varied influence on the expression of circRNAs, indicating that multiple circRNA biosynthesis pathways exist in C. neoformans. Our study provides evidence for the existence of stable circRNAs in the opportunistic human pathogen C. neoformans and raises a question regarding their role related to pathogenesis in this yeast. Full article
(This article belongs to the Special Issue Fungal Pathogenesis in Humans: The Growing Threat)
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Review

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Open AccessReview Host-Pathogen Interactions Mediated by MDR Transporters in Fungi: As Pleiotropic as it Gets!
Received: 18 May 2018 / Revised: 21 June 2018 / Accepted: 27 June 2018 / Published: 2 July 2018
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Abstract
Fungal infections caused by Candida, Aspergillus, and Cryptococcus species are an increasing problem worldwide, associated with very high mortality rates. The successful prevalence of these human pathogens is due to their ability to thrive in stressful host niche colonization sites, to
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Fungal infections caused by Candida, Aspergillus, and Cryptococcus species are an increasing problem worldwide, associated with very high mortality rates. The successful prevalence of these human pathogens is due to their ability to thrive in stressful host niche colonization sites, to tolerate host immune system-induced stress, and to resist antifungal drugs. This review focuses on the key role played by multidrug resistance (MDR) transporters, belonging to the ATP-binding cassette (ABC), and the major facilitator superfamilies (MFS), in mediating fungal resistance to pathogenesis-related stresses. These clearly include the extrusion of antifungal drugs, with C. albicans CDR1 and MDR1 genes, and corresponding homologs in other fungal pathogens, playing a key role in this phenomenon. More recently, however, clues on the transcriptional regulation and physiological roles of MDR transporters, including the transport of lipids, ions, and small metabolites, have emerged, linking these transporters to important pathogenesis features, such as resistance to host niche environments, biofilm formation, immune system evasion, and virulence. The wider view of the activity of MDR transporters provided in this review highlights their relevance beyond drug resistance and the need to develop therapeutic strategies that successfully face the challenges posed by the pleiotropic nature of these transporters. Full article
(This article belongs to the Special Issue Fungal Pathogenesis in Humans: The Growing Threat)
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Other

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Open AccessConcept Paper Strengthening the One Health Agenda: The Role of Molecular Epidemiology in Aspergillus Threat Management
Received: 28 June 2018 / Revised: 14 July 2018 / Accepted: 16 July 2018 / Published: 19 July 2018
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Abstract
The United Nations’ One Health initiative advocates the collaboration of multiple sectors within the global and local health authorities toward the goal of better public health management outcomes. The emerging global health threat posed by Aspergillus species is an example of a management
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The United Nations’ One Health initiative advocates the collaboration of multiple sectors within the global and local health authorities toward the goal of better public health management outcomes. The emerging global health threat posed by Aspergillus species is an example of a management challenge that would benefit from the One Health approach. In this paper, we explore the potential role of molecular epidemiology in Aspergillus threat management and strengthening of the One Health initiative. Effective management of Aspergillus at a public health level requires the development of rapid and accurate diagnostic tools to not only identify the infecting pathogen to species level, but also to the level of individual genotype, including drug susceptibility patterns. While a variety of molecular methods have been developed for Aspergillus diagnosis, their use at below-species level in clinical settings has been very limited, especially in resource-poor countries and regions. Here we provide a framework for Aspergillus threat management and describe how molecular epidemiology and experimental evolution methods could be used for predicting resistance through drug exposure. Our analyses highlight the need for standardization of loci and methods used for molecular diagnostics, and surveillance across Aspergillus species and geographic regions. Such standardization will enable comparisons at national and global levels and through the One Health approach, strengthen Aspergillus threat management efforts. Full article
(This article belongs to the Special Issue Fungal Pathogenesis in Humans: The Growing Threat)
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