Human Fungal Pathogens and Emerging Antifungal Resistance—A Global Public Health Problem?

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

Deadline for manuscript submissions: closed (1 April 2021) | Viewed by 24456

Special Issue Editor

Institute of Hygiene and Medical Microbiology, Medical University Innsbruck, Schöpfstrasse 41, 6020 Innsbruck, Austria
Interests: fungal infections; opportunistic pathogens; microbiology; fungal biology; molecular mycology; fungal biotechnology; alternative infection models
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Improvements in oncology and transplant medicine has led to increased patient populations with high susceptibility to severe fungal infections. These mostly opportunistic infections are a deadly threat to immunosuppressed patients. In addition, the worldwide growing number of diabetic patients display another patient cohort at risk. Progress in diagnosis has enabled faster species identification of fungal pathogens. Nevertheless, too late diagnosis, fast progression of disease, limited antifungal regimens, changes in epidemiology, and the increasing appearance of resistance result in unacceptably high mortality rates. To fight, or even prevent, severe fungal infections, it is necessary to further advance our understanding of virulence traits and their molecular mechanisms of action in order to identify targets for antifungal drug development.

This Special Issue is open to researchers in any related field willing to contribute significant discoveries, or relevant observations in fungal virulence, antifungal resistance mechanisms or identification of putative drug targets.

Dr. Ulrike Binder
Guest Editor

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Keywords

  • Fungal virulence
  • Opportunistic fungal pathogens
  • Emerging fungal pathogens
  • Fungal stress adaptation
  • Antifungal resistance mechanisms
  • Mechanism of action of (novel) antifungal drugs
  • Fungal cell wall
  • PAMPs, PRRs, and immune evasion
  • Secondary metabolites
  • Disease prevention
  • Diagnostic tools beyond culture
  • (Alternative) infection models
  • Fungal model systems
  • Aspergillus, Candida, Cryptococcus, Mucormycetes, Scedosporium

Published Papers (7 papers)

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Research

Jump to: Review

16 pages, 3468 KiB  
Article
The Peroxiredoxin Asp f3 Acts as Redox Sensor in Aspergillus fumigatus
by Jana Marie Boysen, Nauman Saeed, Thomas Wolf, Gianni Panagiotou and Falk Hillmann
Genes 2021, 12(5), 668; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12050668 - 29 Apr 2021
Cited by 7 | Viewed by 2327
Abstract
The human pathogenic fungus Aspergillus fumigatus is readily eradicated by the innate immunity of immunocompetent human hosts, but can cause severe infections, such as invasive aspergillosis (IA), in immunocompromised individuals. During infection, the fungal redox homeostasis can be challenged by reactive oxygen species [...] Read more.
The human pathogenic fungus Aspergillus fumigatus is readily eradicated by the innate immunity of immunocompetent human hosts, but can cause severe infections, such as invasive aspergillosis (IA), in immunocompromised individuals. During infection, the fungal redox homeostasis can be challenged by reactive oxygen species (ROS), either derived from the oxidative burst of innate immune cells or the action of antifungal drugs. The peroxiredoxin Asp f3 was found to be essential to cause IA in mice, but how Asp f3 integrates with fungal redox homeostasis remains unknown. Here, we show that in vivo, Asp f3 acts as a sensor for ROS. While global transcription in fungal hyphae under minimal growth conditions was fully independent of Asp f3, a robust induction of the oxidative stress response required the presence of the peroxiredoxin. Hyphae devoid of Asp f3 failed to activate several redox active genes, like members of the gliotoxin biosynthesis gene cluster and integral members of the Afyap1 regulon, the central activator of the ROS defense machinery in fungi. Upon deletion of the asp f3 gene Afyap1 displayed significantly reduced nuclear localization during ROS exposure, indicating that Asp f3 can act as an intracellular redox sensor for several target proteins. Full article
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18 pages, 639 KiB  
Article
Point Mutations in the 14-α Sterol Demethylase Cyp51A or Cyp51C Could Contribute to Azole Resistance in Aspergillus flavus
by Jose Lucio, Irene Gonzalez-Jimenez, Olga Rivero-Menendez, Ana Alastruey-Izquierdo, Teresa Pelaez, Laura Alcazar-Fuoli and Emilia Mellado
Genes 2020, 11(10), 1217; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11101217 - 17 Oct 2020
Cited by 13 | Viewed by 3004
Abstract
Infections caused by Aspergillus species are being increasingly reported. Aspergillus flavus is the second most common species within this genus causing invasive infections in humans, and isolates showing azole resistance have been recently described. A. flavus has three cyp51-related genes (cyp [...] Read more.
Infections caused by Aspergillus species are being increasingly reported. Aspergillus flavus is the second most common species within this genus causing invasive infections in humans, and isolates showing azole resistance have been recently described. A. flavus has three cyp51-related genes (cyp51A, cyp51B, and cyp51C) encoding 14-α sterol demethylase-like enzymes which are the target of azole drugs. In order to study triazole drug resistance in A. flavus, three strains showing reduced azole susceptibility and 17 azole susceptible isolates were compared. The three cyp51-related genes were amplified and sequenced. A comparison of the deduced Cyp51A, Cyp51B, and Cyp51C protein sequences with other protein sequences from orthologous genes in different filamentous fungi led to a protein identity that ranged from 50% to 80%. Cyp51A and Cyp51C presented several synonymous and non-synonymous point mutations among both susceptible and non-susceptible strains. However, two amino acid mutations were present only in two resistant isolates: one strain harbored a P214L substitution in Cyp51A, and another a H349R in Cyp51C that also showed an increase of cyp51A and cyp51C gene expression compared to the susceptible strain ATCC2004304. Isolates that showed reduced in vitro susceptibility to clinical azoles exhibited a different susceptibility profile to demethylation inhibitors (DMIs). Although P214L substitution might contribute to azole resistance, the role of H349R substitution together with changes in gene expression remains unclear. Full article
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14 pages, 1804 KiB  
Article
Arginine Auxotrophy Affects Siderophore Biosynthesis and Attenuates Virulence of Aspergillus fumigatus
by Anna-Maria Dietl, Ulrike Binder, Ingo Bauer, Yana Shadkchan, Nir Osherov and Hubertus Haas
Genes 2020, 11(4), 423; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11040423 - 15 Apr 2020
Cited by 12 | Viewed by 3442
Abstract
Aspergillus fumigatus is an opportunistic human pathogen mainly infecting immunocompromised patients. The aim of this study was to characterize the role of arginine biosynthesis in virulence of A. fumigatus via genetic inactivation of two key arginine biosynthetic enzymes, the bifunctional acetylglutamate synthase/ornithine acetyltransferase [...] Read more.
Aspergillus fumigatus is an opportunistic human pathogen mainly infecting immunocompromised patients. The aim of this study was to characterize the role of arginine biosynthesis in virulence of A. fumigatus via genetic inactivation of two key arginine biosynthetic enzymes, the bifunctional acetylglutamate synthase/ornithine acetyltransferase (argJ/AFUA_5G08120) and the ornithine carbamoyltransferase (argB/AFUA_4G07190). Arginine biosynthesis is intimately linked to the biosynthesis of ornithine, a precursor for siderophore production that has previously been shown to be essential for virulence in A. fumigatus. ArgJ is of particular interest as it is the only arginine biosynthetic enzyme lacking mammalian homologs. Inactivation of either ArgJ or ArgB resulted in arginine auxotrophy. Lack of ArgJ, which is essential for mitochondrial ornithine biosynthesis, significantly decreased siderophore production during limited arginine supply with glutamine as nitrogen source, but not with arginine as sole nitrogen source. In contrast, siderophore production reached wild-type levels under both growth conditions in ArgB null strains. These data indicate that siderophore biosynthesis is mainly fueled by mitochondrial ornithine production during limited arginine availability, but by cytosolic ornithine production during high arginine availability via cytosolic arginine hydrolysis. Lack of ArgJ or ArgB attenuated virulence of A. fumigatus in the insect model Galleria mellonella and in murine models for invasive aspergillosis, indicating limited arginine availability in the investigated host niches. Full article
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Review

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24 pages, 915 KiB  
Review
Fungal Lysine Deacetylases in Virulence, Resistance, and Production of Small Bioactive Compounds
by Ingo Bauer and Stefan Graessle
Genes 2021, 12(10), 1470; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12101470 - 23 Sep 2021
Cited by 6 | Viewed by 2657
Abstract
The growing number of immunocompromised patients begs for efficient therapy strategies against invasive fungal infections. As conventional antifungal treatment is increasingly hampered by resistance to commonly used antifungals, development of novel therapy regimens is required. On the other hand, numerous fungal species are [...] Read more.
The growing number of immunocompromised patients begs for efficient therapy strategies against invasive fungal infections. As conventional antifungal treatment is increasingly hampered by resistance to commonly used antifungals, development of novel therapy regimens is required. On the other hand, numerous fungal species are industrially exploited as cell factories of enzymes and chemicals or as producers of medically relevant pharmaceuticals. Consequently, there is immense interest in tapping the almost inexhaustible fungal portfolio of natural products for potential medical and industrial applications. Both the pathogenicity and production of those small metabolites are significantly dependent on the acetylation status of distinct regulatory proteins. Thus, classical lysine deacetylases (KDACs) are crucial virulence determinants and important regulators of natural products of fungi. In this review, we present an overview of the members of classical KDACs and their complexes in filamentous fungi. Further, we discuss the impact of the genetic manipulation of KDACs on the pathogenicity and production of bioactive molecules. Special consideration is given to inhibitors of these enzymes and their role as potential new antifungals and emerging tools for the discovery of novel pharmaceutical drugs and antibiotics in fungal producer strains. Full article
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12 pages, 665 KiB  
Review
Role of the Non-Canonical RNAi Pathway in the Antifungal Resistance and Virulence of Mucorales
by José Tomás Cánovas-Márquez, María Isabel Navarro-Mendoza, Carlos Pérez-Arques, Carlos Lax, Ghizlane Tahiri, José Antonio Pérez-Ruiz, Damaris Lorenzo-Gutiérrez, Silvia Calo, Sergio López-García, Eusebio Navarro, Francisco Esteban Nicolás, Victoriano Garre and Laura Murcia
Genes 2021, 12(4), 586; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12040586 - 17 Apr 2021
Cited by 3 | Viewed by 2647
Abstract
Mucorales are the causal agents for the lethal disease known as mucormycosis. Mortality rates of mucormycosis can reach up to 90%, due to the mucoralean antifungal drug resistance and the lack of effective therapies. A concerning urgency among the medical and scientific community [...] Read more.
Mucorales are the causal agents for the lethal disease known as mucormycosis. Mortality rates of mucormycosis can reach up to 90%, due to the mucoralean antifungal drug resistance and the lack of effective therapies. A concerning urgency among the medical and scientific community claims to find targets for the development of new treatments. Here, we reviewed different studies describing the role and machinery of a novel non-canonical RNAi pathway (NCRIP) only conserved in Mucorales. Its non-canonical features are the independence of Dicer and Argonaute proteins. Conversely, NCRIP relies on RNA-dependent RNA Polymerases (RdRP) and an atypical ribonuclease III (RNase III). NCRIP regulates the expression of mRNAs by degrading them in a specific manner. Its mechanism binds dsRNA but only cuts ssRNA. NCRIP exhibits a diversity of functional roles. It represses the epimutational pathway and the lack of NCRIP increases the generation of drug resistant strains. NCRIP also regulates the control of retrotransposons expression, playing an essential role in genome stability. Finally, NCRIP regulates the response during phagocytosis, affecting the multifactorial process of virulence. These critical NCRIP roles in virulence and antifungal drug resistance, along with its exclusive presence in Mucorales, mark this pathway as a promising target to fight against mucormycosis. Full article
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30 pages, 2658 KiB  
Review
Iron Assimilation during Emerging Infections Caused by Opportunistic Fungi with emphasis on Mucorales and the Development of Antifungal Resistance
by Felicia Adelina Stanford and Kerstin Voigt
Genes 2020, 11(11), 1296; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11111296 - 30 Oct 2020
Cited by 21 | Viewed by 4589
Abstract
Iron is a key transition metal required by most microorganisms and is prominently utilised in the transfer of electrons during metabolic reactions. The acquisition of iron is essential and becomes a crucial pathogenic event for opportunistic fungi. Iron is not readily available in [...] Read more.
Iron is a key transition metal required by most microorganisms and is prominently utilised in the transfer of electrons during metabolic reactions. The acquisition of iron is essential and becomes a crucial pathogenic event for opportunistic fungi. Iron is not readily available in the natural environment as it exists in its insoluble ferric form, i.e., in oxides and hydroxides. During infection, the host iron is bound to proteins such as transferrin, ferritin, and haemoglobin. As such, access to iron is one of the major hurdles that fungal pathogens must overcome in an immunocompromised host. Thus, these opportunistic fungi utilise three major iron acquisition systems to overcome this limiting factor for growth and proliferation. To date, numerous iron acquisition pathways have been fully characterised, with key components of these systems having major roles in virulence. Most recently, proteins involved in these pathways have been linked to the development of antifungal resistance. Here, we provide a detailed review of our current knowledge of iron acquisition in opportunistic fungi, and the role iron may have on the development of resistance to antifungals with emphasis on species of the fungal basal lineage order Mucorales, the causative agents of mucormycosis. Full article
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17 pages, 1378 KiB  
Review
Genes, Pathways, and Mechanisms Involved in the Virulence of Mucorales
by Carlos Lax, Carlos Pérez-Arques, María Isabel Navarro-Mendoza, José Tomás Cánovas-Márquez, Ghizlane Tahiri, José Antonio Pérez-Ruiz, Macario Osorio-Concepción, Laura Murcia-Flores, Eusebio Navarro, Victoriano Garre and Francisco Esteban Nicolás
Genes 2020, 11(3), 317; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11030317 - 16 Mar 2020
Cited by 42 | Viewed by 5157
Abstract
The order Mucorales is a group of ancient fungi with limited tools for gene manipulation. The main consequence of this manipulation unwillingness is the limited knowledge about its biology compared to other fungal groups. However, the emerging of mucormycosis, a fungal infection caused [...] Read more.
The order Mucorales is a group of ancient fungi with limited tools for gene manipulation. The main consequence of this manipulation unwillingness is the limited knowledge about its biology compared to other fungal groups. However, the emerging of mucormycosis, a fungal infection caused by Mucorales, is attracting the medical spotlight in recent years because the treatments available are not efficient in reducing the high mortality associated with this disease. The result of this renewed interest in Mucorales and mucormycosis is an extraordinarily productive effort to unveil their secrets during the last decade. In this review, we describe the most compelling advances related to the genetic study of virulence factors, pathways, and molecular mechanisms developed in these years. The use of a few genetic study models has allowed the characterization of virulence factors in Mucorales that were previously described in other pathogens, such as the uptake iron systems, the mechanisms of dimorphism, and azole resistances. More importantly, recent studies are identifying new genes and mechanisms controlling the pathogenic potential of Mucorales and their interactions with the host, offering new alternatives to develop specific strategies against mucormycosis. Full article
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