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Medical Mycology Apr 2019The general ability and tendency of bacteria and fungi to assemble into bacterial communities, termed biofilms, poses unique challenges to the treatment of human... (Review)
Review
The general ability and tendency of bacteria and fungi to assemble into bacterial communities, termed biofilms, poses unique challenges to the treatment of human infections. Fungal biofilms, in particular, are associated with enhanced virulence in vivo and decreased sensitivity to antifungals. Much attention has been given to the complex cell wall structures in fungal organisms, yet beyond the cell surface, Aspergillus fumigatus and other fungi assemble a self-secreted extracellular matrix that is the hallmark of the biofilm lifestyle, protecting and changing the environment of resident members. Elucidation of the chemical and molecular detail of the extracellular matrix is crucial to understanding how its structure contributes to persistence and antifungal resistance in the host. We present a summary of integrated analyses of A. fumigatus biofilm architecture, including hyphae and the extracellular matrix, by scanning electron microscopy and A. fumigatus matrix composition by new top-down solid-state NMR approaches coupled with biochemical analysis. This combined methodology will be invaluable in formulating quantitative and chemical comparisons of A. fumigatus isolates that differ in virulence and are more or less resistant to antifungals. Ultimately, knowledge of the chemical and molecular requirements for matrix formation and function will drive the identification and development of new strategies to interfere with biofilm formation and virulence.
Topics: Aspergillus fumigatus; Biofilms; Extracellular Matrix; Hyphae; Magnetic Resonance Spectroscopy; Microscopy, Electron, Scanning
PubMed: 30816969
DOI: 10.1093/mmy/myy140 -
Natural Product Reports Oct 2014Siderophores are chelators synthesized by microbes to sequester iron. This article summarizes the knowledge on the fungal siderophore metabolism with a focus on... (Review)
Review
Siderophores are chelators synthesized by microbes to sequester iron. This article summarizes the knowledge on the fungal siderophore metabolism with a focus on Aspergillus fumigatus. In recent years, A. fumigatus became a role model for fungal biosynthesis, uptake and degradation of siderophores as well as regulation of siderophore-mediated iron handling and the elucidation of siderophore functions. Siderophore functions comprise uptake, intracellular transport and storage of iron. This proved to be crucial not only for adaptation to iron starvation conditions but also for germination, asexual and sexual propagation, antioxidative defense, mutual interaction, microbial competition as well as virulence in plant and animal hosts. Recent studies also indicate the high potential of siderophores and its biosynthetic pathway to improve diagnosis and therapy of fungal infections.
Topics: Aspergillus fumigatus; Molecular Structure; Polyketide Synthases; Siderophores
PubMed: 25140791
DOI: 10.1039/c4np00071d -
Applied and Environmental Microbiology Oct 2021An efficient reactive oxygen species (ROS) detoxification system is vital for the survival of the pathogenic fungus Aspergillus fumigatus within the host high-ROS...
An efficient reactive oxygen species (ROS) detoxification system is vital for the survival of the pathogenic fungus Aspergillus fumigatus within the host high-ROS environment of the host. Therefore, identifying and targeting factors essential for oxidative stress response is one approach to developing novel treatments for fungal infections. The oxidation resistance 1 (Oxr1) protein is essential for protection against oxidative stress in mammals, but its functions in pathogenic fungi remain unknown. The present study aimed to characterize the role of an Oxr1 homolog in A. fumigatus. The results indicated that the OxrA protein plays an important role in oxidative stress resistance by regulating the catalase function in A. fumigatus, and overexpression of catalase can rescue the phenotype associated with OxrA deficiency. Importantly, the deficiency of decreased the virulence of A. fumigatus and altered the host immune response. Using the Aspergillus-induced lung infection model, we demonstrated that the mutant strain induced less tissue damage along with decreased levels of lactate dehydrogenase (LDH) and albumin release. Additionally, the mutant caused inflammation at a lower degree, along with a markedly reduced influx of neutrophils to the lungs and a decreased secretion of cytokine usually associated with recruitment of neutrophils in mice. These results characterize the role of OxrA in A. fumigatus as a core regulator of oxidative stress resistance and fungal pathogenesis. Knowledge of ROS detoxification in fungal pathogens is useful in the design of new antifungal drugs and could aid in the study of oxidative stress resistance mechanisms. In this study, we demonstrate that OxrA protein localizes to the mitochondria and functions to protect against oxidative damage. We demonstrate that OxrA contributes to oxidative stress resistance by regulating catalase function, and overexpression of catalase (CatA or CatB) can rescue the phenotype that is associated with OxrA deficiency. Remarkably, a loss of OxrA attenuated the fungal virulence in a mouse model of invasive pulmonary aspergillosis and altered the host immune response. Therefore, our finding indicates that inhibition of OxrA might be an effective approach for alleviating A. fumigatus infection. The present study is, to the best of our knowledge, a pioneer in reporting the vital role of Oxr1 protein in pathogenic fungi.
Topics: Animals; Aspergillosis; Aspergillus fumigatus; Catalase; Fungal Proteins; Mice; Oxidative Stress; Reactive Oxygen Species; Virulence
PubMed: 34524893
DOI: 10.1128/AEM.01120-21 -
Mycopathologia Dec 2014Zinc is an essential micronutrient required for the growth of all microorganisms. To grow in the lungs of a susceptible patient Aspergillus fumigatus must obtain zinc... (Review)
Review
Zinc is an essential micronutrient required for the growth of all microorganisms. To grow in the lungs of a susceptible patient Aspergillus fumigatus must obtain zinc from the surrounding tissues. The concentration of Zn(2+) ions in living tissues is much lower than that required for optimal fungal growth in vitro because most of them are tightly bound to proteins at the physiological pH. However, A. fumigatus has several zinc transporters (ZrfA, ZrfB and ZrfC) that enable it to uptake zinc efficiently under the extreme zinc-limiting conditions provided by a susceptible host. The ZafA transcriptional regulator induces the expression of these transporters and is essential for virulence. ZrfC is required for fungal growth within the host tissues, whereas ZrfA and ZrfB play an accessory role. The zinc-scavenging capacity of ZrfC relies on its unusually long N-terminus. In addition, ZrfC also enables A. fumigatus to overcome the inhibitory effect of calprotectin, which is an antimicrobial Zn/Mn-chelating protein synthesized in high amounts by neutrophils, even in immunosuppressed non-leucopenic animals. In summary, the regulation of zinc homeostasis and zinc acquisition could be promising targets for the discovery and development of a new generation of antifungals for the treatment of invasive pulmonary aspergillosis.
Topics: Aspergillus fumigatus; Gene Expression Regulation, Fungal; Membrane Transport Proteins; Virulence; Zinc
PubMed: 24947168
DOI: 10.1007/s11046-014-9764-2 -
Infection, Genetics and Evolution :... May 2003Aspergillus fumigatus, an important human pathogen, has been the subject of numerous epidemiological studies. This review gives a summary of the techniques used for... (Review)
Review
Aspergillus fumigatus, an important human pathogen, has been the subject of numerous epidemiological studies. This review gives a summary of the techniques used for revealing the genetic variability of A. fumigatus, including multilocus enzyme electrophoresis and methods based on DNA hybridization and amplification. Such studies have provided raw data for examining the structure of A. fumigatus populations. Several methods have been described for distinguishing recombination from clonality in fungal populations. In our studies, both the index of association test and the parsimony tree length permutation test were used for examining the reproductive mode of Aspergillus fumigatus populations. The tests were performed on isoenzyme and sequence specific DNA primer analysis data gathered from the literature. Both tests, together with other observations, supported the premise that recombination played an important role in A. fumigatus populations. A so-called epidemic population structure was observed in local populations isolated from patients. The prevalence of a single or some related electrophoretic types in such environments was attributed to some kind of selection pressure. Network methods were also used successfully to visualize the recombining structures of A. fumigatus populations. The applied techniques did not enable us to distinguish between the alternative hypotheses of whether past meiotic exchanges, parasexuality or a cryptic sexual stage were responsible for the recombining population structure of A. fumigatus.
Topics: Aspergillus fumigatus; Clone Cells; DNA, Fungal; Forecasting; Genetic Variation; Genetics, Population; Humans; Isoenzymes; Phylogeny; Recombinant Proteins; Recombination, Genetic
PubMed: 12797968
DOI: 10.1016/s1567-1348(02)00156-9 -
International Journal of Medical... Jun 2011Aspergillus fumigatus as prime pathogen to cause aspergillosis has evolved as a saprophyte, but is also able to infect and colonise immunocompromised hosts. Based on the... (Review)
Review
Aspergillus fumigatus as prime pathogen to cause aspergillosis has evolved as a saprophyte, but is also able to infect and colonise immunocompromised hosts. Based on the 'dual use' hypothesis of fungal pathogenicity, general characteristics have to be considered as unspecific virulence determinants, among them stress adaptation capacities. The susceptible, warm-blooded mammalian host represents a specific ecological niche that poses several kinds of stress conditions to the fungus during the course of infection. Detailed knowledge about the cellular pathways and adaptive traits that have evolved in A. fumigatus to counteract situations of stress and varying environmental conditions is crucial for the identification of novel and specific antifungal targets. Comprehensive profiling data accompanied by mutant analyses have shed light on such stressors, and nutritional deprivation, oxidative stress, hypoxia, elevated temperature, alkaline pH, extensive secretion, and, in particular during treatment with antifungals, cell membrane perturbations appear to represent the major hazards A. fumigatus has to cope with during infection. Further efforts employing innovative approaches and advanced technologies will have to be made to expand our knowledge about the scope of the A. fumigatus adaptome that is relevant for disease.
Topics: Adaptation, Physiological; Aspergillus fumigatus; Host-Pathogen Interactions; Humans; Mutation; Signal Transduction; Stress, Physiological; Virulence
PubMed: 21565548
DOI: 10.1016/j.ijmm.2011.04.008 -
Medical Mycology May 2005Aspergillus fumigatus has long been considered to reproduce only by asexual means. However, accumulating evidence suggest that a sexual stage for A. fumigatus may yet be... (Review)
Review
Aspergillus fumigatus has long been considered to reproduce only by asexual means. However, accumulating evidence suggest that a sexual stage for A. fumigatus may yet be identified. We describe results from published and ongoing studies involving population genetic analyses, genome analysis, studies of mating-type gene presence and distribution, expression of sex-related genes, and taxonomic work which support the assertion that A. fumigatus has the potential to reproduce by sexual means. The consequences of sexual reproduction for the population biology and disease management of the species are discussed. The possible mechanisms of evolution of asexuality are then considered. It is proposed that asexual species may arise in one step by mutation or loss of a key gene(s), and/or there may be a 'slow decline' in sexual fertility within the species as a whole. Thus, it is argued that species should not be considered simply as sexual or asexual, but rather as individual isolates being present on a continuum of sexual fertility, with the implications for understanding sexuality/asexuality in A. fumigatus discussed.
Topics: Aspergillus fumigatus; Evolution, Molecular; Fungal Proteins; Genes, Fungal; Genes, Mating Type, Fungal; Recombination, Genetic; Reproduction, Asexual
PubMed: 16110786
DOI: 10.1080/13693780400029015 -
Frontiers in Cellular and Infection... 2019Dendritic cells (DCs) are antigen presenting cells which serve as a passage between the innate and the acquired immunity. Aspergillosis is a major lethal condition in...
Dendritic cells (DCs) are antigen presenting cells which serve as a passage between the innate and the acquired immunity. Aspergillosis is a major lethal condition in immunocompromised patients caused by the adaptable saprophytic fungus . The healthy human immune system is capable to ward off infections however immune-deficient patients are highly vulnerable to invasive aspergillosis. can persist during infection due to its ability to survive the immune response of human DCs. Therefore, the study of the metabolism specific to the context of infection may allow us to gain insight into the adaptation strategies of both the pathogen and the immune cells. We established a metabolic model of central metabolism during infection of DCs and calculated the metabolic pathway (elementary modes; EMs). Transcriptome data were used to identify pathways activated when is challenged with DCs. In particular, amino acid metabolic pathways, alternative carbon metabolic pathways and stress regulating enzymes were found to be active. Metabolic flux modeling identified further active enzymes such as alcohol dehydrogenase, inositol oxygenase and GTP cyclohydrolase participating in different stress responses in . These were further validated by qRT-PCR from RNA extracted under these different conditions. For DCs, we outlined the activation of metabolic pathways in response to the confrontation with . We found the fatty acid metabolism plays a crucial role, along with other metabolic changes. The gene expression data and their analysis illuminate additional regulatory pathways activated in the DCs apart from interleukin regulation. In particular, Toll-like receptor signaling, NOD-like receptor signaling and RIG-I-like receptor signaling were active pathways. Moreover, we identified subnetworks and several novel key regulators such as UBC, EGFR, and CUL3 of DCs to be activated in response to . In conclusion, we analyze the metabolic and regulatory responses of and DCs when confronted with each other.
Topics: Aspergillus fumigatus; Cytokines; Dendritic Cells; Gene Expression; Host-Pathogen Interactions; Humans; Interleukins; Metabolic Networks and Pathways; NLR Proteins; Signal Transduction; Toll-Like Receptors; Transcriptome
PubMed: 31192161
DOI: 10.3389/fcimb.2019.00168 -
Antimicrobial Agents and Chemotherapy Mar 2019infections are associated with high mortality rates and high treatment costs. Limited available antifungals and increasing antifungal resistance highlight an urgent...
infections are associated with high mortality rates and high treatment costs. Limited available antifungals and increasing antifungal resistance highlight an urgent need for new antifungals. Thioredoxin reductase (TrxR) is essential for maintaining redox homeostasis and presents as a promising target for novel antifungals. We show that ebselen [2-phenyl-1,2-benzoselenazol-3(2H)-one] is an inhibitor of TrxR ( = 0.22 μM) and inhibits growth of spp., with MIC values of 16 to 64 µg/ml. Mass spectrometry analysis demonstrates that ebselen interacts covalently with a catalytic cysteine of TrxR, Cys148. We also present the X-ray crystal structure of TrxR and use modeling of the enzyme-inhibitor complex to outline key molecular interactions. This provides a scaffold for future design of potent and selective antifungal drugs that target TrxR, improving the potency of ebselen toward inhbition of growth.
Topics: Antifungal Agents; Aspergillus fumigatus; Azoles; Crystallography, X-Ray; Drug Resistance, Fungal; Humans; Isoindoles; Microbial Sensitivity Tests; Molecular Conformation; Molecular Docking Simulation; Organoselenium Compounds; Thioredoxin-Disulfide Reductase
PubMed: 30642940
DOI: 10.1128/AAC.02281-18 -
Current Opinion in Microbiology Dec 2013Aspergillus fumigatus is an opportunistic fungal pathogen that causes life-threatening infections in immunocompromised individuals. Siderophore-mediated iron acquisition... (Review)
Review
Aspergillus fumigatus is an opportunistic fungal pathogen that causes life-threatening infections in immunocompromised individuals. Siderophore-mediated iron acquisition has been shown to be essential for virulence. New studies have revealed that enzymes involved in siderophore biosynthesis and uptake are compartmentalized in peroxisomes and endosome-like vesicles, respectively. Gene and protein expression studies have revealed coordinated regulation of siderophore and sterol metabolism linked to the common precursor mevalonate. Several A. fumigatus transcription factors have been identified that are unexpectedly involved in the regulation of iron homeostasis. New diagnostic and drug treatments are being developed that exploit the requirement of A. fumigatus for extracellular siderophores.
Topics: Aspergillus fumigatus; Gene Expression Regulation, Fungal; Homeostasis; Iron; Mevalonic Acid; Organelles; Transcription, Genetic; Virulence
PubMed: 23962820
DOI: 10.1016/j.mib.2013.07.012