The RAM Network in Pathogenic Fungi

ABSTRACT The r egulation of A ce2 and m orphogenesis (RAM) network is a protein kinase signaling pathway conserved among eukaryotes from yeasts to humans. Among fungi, the RAM network has been most extensively studied in the model yeast Saccharomyces cerevisiae and has been shown to regulate a range of cellular processes, including daughter cell-specific gene expression, cell cycle regulation, cell separation, mating, polarized growth, maintenance of cell wall integrity, and stress signaling. Increasing numbers of recent studies on the role of the RAM network in pathogenic fungal species have revealed that this network also plays an important role in the biology and pathogenesis of these organisms. In addition to providing a brief overview of the RAM network in S. cerevisiae , we summarize recent developments in the understanding of RAM network function in the human fungal pathogens Candida albicans , Candida glabrata , Cryptococcus neoformans , Aspergillus fumigatus , and Pneumocystis spp.

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Mitotic Recombination and Adaptive Genomic Changes in Human Pathogenic Fungi

Genes ◽

10.3390/genes10110901 ◽

2019 ◽

Vol 10 (11) ◽

pp. 901 ◽

Cited By ~ 10

Author(s):

Asiya Gusa ◽

Sue Jinks-Robertson

Keyword(s):

Fungal Pathogens ◽

Repetitive Sequences ◽

Pathogenic Fungi ◽

Genetic Alterations ◽

Fungal Species ◽

Chronic Infections ◽

Yeast Saccharomyces Cerevisiae ◽

Genomic Changes ◽

Break Site ◽

Repair Mechanisms

Genome rearrangements and ploidy alterations are important for adaptive change in the pathogenic fungal species Candida and Cryptococcus, which propagate primarily through clonal, asexual reproduction. These changes can occur during mitotic growth and lead to enhanced virulence, drug resistance, and persistence in chronic infections. Examples of microevolution during the course of infection were described in both human infections and mouse models. Recent discoveries defining the role of sexual, parasexual, and unisexual cycles in the evolution of these pathogenic fungi further expanded our understanding of the diversity found in and between species. During mitotic growth, damage to DNA in the form of double-strand breaks (DSBs) is repaired, and genome integrity is restored by the homologous recombination and non-homologous end-joining pathways. In addition to faithful repair, these pathways can introduce minor sequence alterations at the break site or lead to more extensive genetic alterations that include loss of heterozygosity, inversions, duplications, deletions, and translocations. In particular, the prevalence of repetitive sequences in fungal genomes provides opportunities for structural rearrangements to be generated by non-allelic (ectopic) recombination. In this review, we describe DSB repair mechanisms and the types of resulting genome alterations that were documented in the model yeast Saccharomyces cerevisiae. The relevance of similar recombination events to stress- and drug-related adaptations and in generating species diversity are discussed for the human fungal pathogens Candida albicans and Cryptococcus neoformans.

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Plasma Membrane MCC/Eisosome Domains Promote Stress Resistance in Fungi

Microbiology and Molecular Biology Reviews ◽

10.1128/mmbr.00063-19 ◽

2020 ◽

Vol 84 (4) ◽

Author(s):

Carla E. Lanze ◽

Rafael M. Gandra ◽

Jenna E. Foderaro ◽

Kara A. Swenson ◽

Lois M. Douglas ◽

...

Keyword(s):

Plasma Membrane ◽

Fungal Pathogens ◽

Composition Studies ◽

Copper Toxicity ◽

Fungal Species ◽

Content Type ◽

Functional Roles ◽

Wide Range ◽

Membrane Compartment ◽

Plasma Membrane Domain

SUMMARY There is growing appreciation that the plasma membrane orchestrates a diverse array of functions by segregating different activities into specialized domains that vary in size, stability, and composition. Studies with the budding yeast Saccharomyces cerevisiae have identified a novel type of plasma membrane domain known as the MCC (membrane compartment of Can1)/eisosomes that correspond to stable furrows in the plasma membrane. MCC/eisosomes maintain proteins at the cell surface, such as nutrient transporters like the Can1 arginine symporter, by protecting them from endocytosis and degradation. Recent studies from several fungal species are now revealing new functional roles for MCC/eisosomes that enable cells to respond to a wide range of stressors, including changes in membrane tension, nutrition, cell wall integrity, oxidation, and copper toxicity. The different MCC/eisosome functions are often intertwined through the roles of these domains in lipid homeostasis, which is important for proper plasma membrane architecture and cell signaling. Therefore, this review will emphasize the emerging models that explain how MCC/eisosomes act as hubs to coordinate cellular responses to stress. The importance of MCC/eisosomes is underscored by their roles in virulence for fungal pathogens of plants, animals, and humans, which also highlights the potential of these domains to act as novel therapeutic targets.

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Remote homology clustering identifies lowly conserved families of effector proteins in plant-pathogenic fungi

Microbial Genomics ◽

10.1099/mgen.0.000637 ◽

2021 ◽

Vol 7 (9) ◽

Author(s):

Darcy A. B. Jones ◽

Paula M. Moolhuijzen ◽

James K. Hane

Keyword(s):

Fungal Pathogens ◽

Pathogenic Fungi ◽

Comparison Method ◽

Fungal Species ◽

Effector Proteins ◽

Plant Diseases ◽

Plant Host ◽

Homology Inference ◽

Developing Area ◽

Inference Methods

Plant diseases caused by fungal pathogens are typically initiated by molecular interactions between ‘effector’ molecules released by a pathogen and receptor molecules on or within the plant host cell. In many cases these effector-receptor interactions directly determine host resistance or susceptibility. The search for fungal effector proteins is a developing area in fungal-plant pathology, with more than 165 distinct confirmed fungal effector proteins in the public domain. For a small number of these, novel effectors can be rapidly discovered across multiple fungal species through the identification of known effector homologues. However, many have no detectable homology by standard sequence-based search methods. This study employs a novel comparison method (RemEff) that is capable of identifying protein families with greater sensitivity than traditional homology-inference methods, leveraging a growing pool of confirmed fungal effector data to enable the prediction of novel fungal effector candidates by protein family association. Resources relating to the RemEff method and data used in this study are available from https://figshare.com/projects/Effector_protein_remote_homology/87965.

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Extracellular Vesicle-Mediated RNA Release in Histoplasma capsulatum

mSphere ◽

10.1128/msphere.00176-19 ◽

2019 ◽

Vol 4 (2) ◽

Cited By ~ 9

Author(s):

Lysangela R. Alves ◽

Roberta Peres da Silva ◽

David A. Sanchez ◽

Daniel Zamith-Miranda ◽

Marcio L. Rodrigues ◽

...

Keyword(s):

Extracellular Vesicles ◽

Stress Responses ◽

Histoplasma Capsulatum ◽

Pathogenic Fungi ◽

Extracellular Vesicle ◽

Fungal Species ◽

Cellular Communication ◽

Content Type ◽

Rna Molecules ◽

Rna Content

ABSTRACT Eukaryotic cells, including fungi, release extracellular vesicles (EVs). These lipid bilayered compartments play essential roles in cellular communication and pathogenesis. EV composition is complex and includes proteins, glycans, pigments, and RNA. RNAs with putative roles in pathogenesis have been described in EVs produced by fungi. Here we describe the RNA content in EVs produced by the G186AR and G217B strains of Histoplasma capsulatum, an important human-pathogenic fungal pathogen. A total of 124 mRNAs were identified in both strains. In this set of RNA classes, 93 transcripts were enriched in EVs from the G217B strain, whereas 31 were enriched in EVs produced by the G186AR strain. This result suggests that there are important strain-specific properties in the mRNA composition of fungal EVs. We also identified short fragments (25 to 40 nucleotides in length) that were strain specific, with a greater number identified in EVs produced by the G217B strain. Remarkably, the most highly enriched processes were stress responses and translation. Half of these fragments aligned to the reverse strand of the transcript, suggesting the occurrence of microRNA (miRNA)-like molecules in fungal EVs. We also compared the transcriptome profiles of H. capsulatum with the RNA composition of EVs, and no correlation was observed. Taking the results together, our study provided information about the RNA molecules present in H. capsulatum EVs and about the differences in composition between the strains. In addition, we found no correlation between the most highly expressed transcripts in the cell and their presence in the EVs, reinforcing the idea that the RNAs were directed to the EVs by a regulated mechanism. IMPORTANCE Extracellular vesicles (EVs) play important roles in cellular communication and pathogenesis. The RNA molecules in EVs have been implicated in a variety of processes. EV-associated RNA classes have recently been described in pathogenic fungi; however, only a few reports of studies describing the RNAs in fungal EVs are available. Improved knowledge of EV-associated RNA will contribute to the understanding of their role during infection. In this study, we described the RNA content in EVs produced by two isolates of Histoplasma capsulatum. Our results add this important pathogen to the current short list of fungal species with the ability to use EVs for the extracellular release of RNA.

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Comparative Genomics and the Evolution of Pathogenicity in Human Pathogenic Fungi

Eukaryotic Cell ◽

10.1128/ec.00242-10 ◽

2010 ◽

Vol 10 (1) ◽

pp. 34-42 ◽

Cited By ~ 72

Author(s):

Gary P. Moran ◽

David C. Coleman ◽

Derek J. Sullivan

Keyword(s):

Fungal Pathogens ◽

Direct Interaction ◽

Pathogenic Fungi ◽

Gene Families ◽

Fungal Pathogenesis ◽

Individual Species ◽

Fungal Virulence ◽

Content Type ◽

Sequencing Technologies ◽

Genes Encoding

ABSTRACTBecause most fungi have evolved to be free-living in the environment and because the infections they cause are usually opportunistic in nature, it is often difficult to identify specific traits that contribute to fungal pathogenesis. In recent years, there has been a surge in the number of sequenced genomes of human fungal pathogens, and comparison of these sequences has proved to be an excellent resource for exploring commonalities and differences in how these species interact with their hosts. In order to survive in the human body, fungi must be able to adapt to new nutrient sources and environmental stresses. Therefore, genes involved in carbohydrate and amino acid metabolism and transport and genes encoding secondary metabolites tend to be overrepresented in pathogenic species (e.g.,Aspergillus fumigatus). However, it is clear that human commensal yeast species such asCandida albicanshave also evolved a range of specific factors that facilitate direct interaction with host tissues. The evolution of virulence across the human pathogenic fungi has occurred largely through very similar mechanisms. One of the most important mechanisms is gene duplication and the expansion of gene families, particularly in subtelomeric regions. Unlike the case for prokaryotic pathogens, horizontal transfer of genes between species and other genera does not seem to have played a significant role in the evolution of fungal virulence. New sequencing technologies promise the prospect of even greater numbers of genome sequences, facilitating the sequencing of multiple genomes and transcriptomes within individual species, and will undoubtedly contribute to a deeper insight into fungal pathogenesis.

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Robust Transcriptional Response to Heat Shock Impacting Diverse Cellular Processes despite Lack of Heat Shock Factor in Microsporidia

mSphere ◽

10.1128/msphere.00219-19 ◽

2019 ◽

Vol 4 (3) ◽

Cited By ~ 1

Author(s):

Nora K. McNamara-Bordewick ◽

Mia McKinstry ◽

Jonathan W. Snow

Keyword(s):

Heat Shock ◽

Stress Responses ◽

Target Genes ◽

Treatment Strategies ◽

Pathogenic Fungi ◽

Fungal Species ◽

Content Type ◽

Novel Treatment ◽

Novel Treatment Strategies ◽

Insight Into

ABSTRACT The majority of fungal species prefer the 12° to 30°C range, and relatively few species tolerate temperatures higher than 35°C. Our understanding of the mechanisms underpinning the ability of some species to grow at higher temperatures is incomplete. Nosema ceranae is an obligate intracellular fungal parasite that infects honey bees and can cause individual mortality and contribute to colony collapse. Despite a reduced genome, this species is strikingly thermotolerant, growing optimally at the colony temperature of 35°C. In characterizing the heat shock response (HSR) in N. ceranae, we found that this and other microsporidian species have lost the transcriptional regulator HSF and possess a reduced set of putative core HSF1-dependent HSR target genes. Despite these losses, N. ceranae demonstrates robust upregulation of the remaining HSR target genes after heat shock. In addition, thermal stress leads to alterations in genes involved in various metabolic pathways, ribosome biogenesis and translation, and DNA repair. These results provide important insight into the stress responses of microsporidia. Such a new understanding will allow new comparisons with other pathogenic fungi and potentially enable the discovery of novel treatment strategies for microsporidian infections affecting food production and human health. IMPORTANCE We do not fully understand why some fungal species are able to grow at temperatures approaching mammalian body temperature. Nosema ceranae, a microsporidium, is a type of fungal parasite that infects honey bees and grows optimally at the colony temperature of 35°C despite possessing cellular machinery for responding to heat stress that is notably simpler than that of other fungi. We find that N. ceranae demonstrates a robust and broad response to heat shock. These results provide important insight into the stress responses of this type of fungus, allow new comparisons with other pathogenic fungi, and potentially enable the discovery of novel treatment strategies for this type of fungus.

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Posttranslational Modifications of Proteins in the Pathobiology of Medically Relevant Fungi

Eukaryotic Cell ◽

10.1128/ec.05238-11 ◽

2011 ◽

Vol 11 (2) ◽

pp. 98-108 ◽

Cited By ~ 45

Author(s):

Michelle D. Leach ◽

Alistair J. P. Brown

Keyword(s):

Saccharomyces Cerevisiae ◽

Candida Albicans ◽

Cell Growth ◽

Aspergillus Fumigatus ◽

Posttranslational Modifications ◽

Fungal Pathogens ◽

Content Type ◽

Cellular Processes ◽

Peptide Modifications ◽

Fungal Kingdom

ABSTRACTPosttranslational modifications of proteins drive a wide variety of cellular processes in eukaryotes, regulating cell growth and division as well as adaptive and developmental processes. With regard to the fungal kingdom, most information about posttranslational modifications has been generated through studies of the model yeastsSaccharomyces cerevisiaeandSchizosaccharomyces pombe, where, for example, the roles of protein phosphorylation, glycosylation, acetylation, ubiquitination, sumoylation, and neddylation have been dissected. More recently, information has begun to emerge for the medically important fungal pathogensCandida albicans,Aspergillus fumigatus, andCryptococcus neoformans, highlighting the relevance of posttranslational modifications for virulence. We review the available literature on protein modifications in fungal pathogens, focusing in particular upon the reversible peptide modifications sumoylation, ubiquitination, and neddylation.

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Interplay between Candida albicans and the Antimicrobial Peptide Armory

Eukaryotic Cell ◽

10.1128/ec.00093-14 ◽

2014 ◽

Vol 13 (8) ◽

pp. 950-957 ◽

Cited By ~ 72

Author(s):

Marc Swidergall ◽

Joachim F. Ernst

Keyword(s):

Candida Albicans ◽

Defense Mechanisms ◽

Fungal Pathogens ◽

Pathogenic Fungi ◽

Resistance Mechanisms ◽

Immune Defense ◽

Basal Resistance ◽

Content Type ◽

Normal Human ◽

Molecular Patterns

ABSTRACTAntimicrobial peptides (AMPs) are key elements of innate immunity, which can directly kill multiple bacterial, viral, and fungal pathogens. The medically important fungusCandida albicanscolonizes different host niches as part of the normal human microbiota. Proliferation ofC. albicansis regulated through a complex balance of host immune defense mechanisms and fungal responses. Expression of AMPs against pathogenic fungi is differentially regulated and initiated by interactions of a variety of fungal pathogen-associated molecular patterns (PAMPs) with pattern recognition receptors (PRRs) on human cells. Inflammatory signaling and other environmental stimuli are also essential to control fungal proliferation and to prevent parasitism. To persist in the host,C. albicanshas developed a three-phase AMP evasion strategy, including secretion of peptide effectors, AMP efflux pumps, and regulation of signaling pathways. These mechanisms preventC. albicansfrom the antifungal activity of the major AMP classes, including cathelicidins, histatins, and defensins leading to a basal resistance. This minireview summarizes human AMP attack andC. albicansresistance mechanisms and current developments in the use of AMPs as antifungal agents.

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Dissecting Disease-Suppressive Rhizosphere Microbiomes by Functional Amplicon Sequencing and 10× Metagenomics

mSystems ◽

10.1128/msystems.01116-20 ◽

2021 ◽

Cited By ~ 1

Author(s):

Vittorio Tracanna ◽

Adam Ossowicki ◽

Marloes L. C. Petrus ◽

Sam Overduin ◽

Barbara R. Terlouw ◽

...

Keyword(s):

Fungal Pathogens ◽

Pathogenic Fungi ◽

Amplicon Sequencing ◽

Plant Pathogenic Fungi ◽

Content Type ◽

Major Threat ◽

Wide Range

Soil-borne plant-pathogenic fungi continue to be a major threat to agriculture and horticulture. The genus Fusarium in particular is one of the most devastating groups of soilborne fungal pathogens for a wide range of crops.

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Fungal pathogens of the genus Fusarium in winter wheat Triticum aestivum L. protected with fungicides in north-eastern Poland

Acta Agrobotanica ◽

10.5586/aa.2013.027 ◽

2013 ◽

Vol 66 (2) ◽

pp. 95-106 ◽

Cited By ~ 2

Author(s):

Agnieszka Pszczółkowska ◽

Adam Okorski ◽

Jacek Olszewski ◽

Joanna Jarmołkowicz

Keyword(s):

Winter Wheat ◽

Fungal Pathogens ◽

Crop Protection ◽

Pathogenic Fungi ◽

Triticum Aestivum L ◽

Fungal Species ◽

Diagnostic Methods ◽

Growth Stages ◽

Monthly Precipitation ◽

Wheat Grain

Various diagnostic methods were used to evaluate the effect of fungicide protection on the prevalence of pathogenic fungi in wheat grain. Winter wheat cv. Nutka and Zyta was grown during a field experiment established in the Production and Experimental Station in Bałcyny in 2006–2007. The experimental factor was chemical crop protection: epoxiconazole, kresoxim-methyl and fenpropimorph applied at growth stages BBCH 33–35 as well as dimoxystrobin and epoxiconazole applied at BBCH 51–53. In this experiment, microscopic observations and conventional PCR assays were used as complementary methods. The quantification of Fusarium poae DNA by qPCR demonstrated the effectiveness of chemical protection against the analyzed fungal species. Lower monthly precipitation levels and higher daily temperatures intensified grain infections, in particular those caused by F. poae. A significant correlation was determined between the number of F. poae cultures isolated from winter wheat grain and the quantity of pathogenic DNA in grain identified by qPCR. Grain infections caused by F. poae lowered yield and thousand seed weight.

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