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Clinical Microbiology Reviews Apr 1999Aspergillus fumigatus is one of the most ubiquitous of the airborne saprophytic fungi. Humans and animals constantly inhale numerous conidia of this fungus. The conidia... (Review)
Review
Aspergillus fumigatus is one of the most ubiquitous of the airborne saprophytic fungi. Humans and animals constantly inhale numerous conidia of this fungus. The conidia are normally eliminated in the immunocompetent host by innate immune mechanisms, and aspergilloma and allergic bronchopulmonary aspergillosis, uncommon clinical syndromes, are the only infections observed in such hosts. Thus, A. fumigatus was considered for years to be a weak pathogen. With increases in the number of immunosuppressed patients, however, there has been a dramatic increase in severe and usually fatal invasive aspergillosis, now the most common mold infection worldwide. In this review, the focus is on the biology of A. fumigatus and the diseases it causes. Included are discussions of (i) genomic and molecular characterization of the organism, (ii) clinical and laboratory methods available for the diagnosis of aspergillosis in immunocompetent and immunocompromised hosts, (iii) identification of host and fungal factors that play a role in the establishment of the fungus in vivo, and (iv) problems associated with antifungal therapy.
Topics: Animals; Antigens, Fungal; Aspergillosis; Aspergillus fumigatus; Disease Models, Animal; Humans; Serologic Tests; Virulence
PubMed: 10194462
DOI: 10.1128/CMR.12.2.310 -
Cold Spring Harbor Perspectives in... Nov 2014The genus Aspergillus contains etiologic agents of aspergillosis. The clinical manifestations of the disease range from allergic reaction to invasive pulmonary... (Review)
Review
The genus Aspergillus contains etiologic agents of aspergillosis. The clinical manifestations of the disease range from allergic reaction to invasive pulmonary infection. Among the pathogenic aspergilli, Aspergillus fumigatus is most ubiquitous in the environment and is the major cause of the disease, followed by Aspergillus flavus, Aspergillus niger, Aspergillus terreus, Aspergillus nidulans, and several species in the section Fumigati that morphologically resemble A. fumigatus. Patients that are at risk for acquiring aspergillosis are those with an altered immune system. Early diagnosis, species identification, and adequate antifungal therapy are key elements for treatment of the disease, especially in cases of pulmonary invasive aspergillosis that often advance very rapidly. Incorporating knowledge of the basic biology of Aspergillus species to that of the diseases that they cause is fundamental for further progress in the field.
Topics: Aspergillus fumigatus; Humans; Invasive Pulmonary Aspergillosis
PubMed: 25377144
DOI: 10.1101/cshperspect.a019786 -
Current Protein & Peptide Science 2014Incidence of fungal infections has increased alarmingly in past few decades. Of the fungal pathogens, the Aspergillus fumigatus has been a major cause of allergic... (Review)
Review
Incidence of fungal infections has increased alarmingly in past few decades. Of the fungal pathogens, the Aspergillus fumigatus has been a major cause of allergic bronchopulmonary aspergillosis (ABPA) which has five main stages--the acute, remission, exacerbation, glucocorticoid dependent and fibrotic stage. The diagnosis of ABPA remains difficult due to its overlapping clinical and radiological features with tuberculosis and cystic fibrosis. From past few decades, the crude fractions of A. fumigatus have been used for immunodiagnosis of ABPA. Most of the detection kits based on crude fractions of A. fumigatus are quite sensitive but have low specificity. Till date 21 known and 25 predicted allergens of A. fumigatus have been identified. Of these allergens, only five recombinants (rAsp f1-f4 and f6) are commercially used for diagnosis of allergic aspergillosis. Remaining allergens of A. fumigatus have been restricted for use in specific diagnosis of ABPA, due to sharing of common antigenic epitopes with other allergens. Complete sequencing of A. fumigatus genome identified 9926 genes and the reports on the proteome of A. fumigatus have shown the presence of large number of their corresponding proteins in the pathogen. The analysis of immunoproteomes developed from crude fractions of A. fumigatus by IgG/IgE reactivity with ABPA patients and animal sera have identified the panel of new antigens. A brief description on the current status of A. fumigatus antigens is provided in this review. The implementation of advance recombinant expression and peptidomic approaches on the A. fumigatus antigens may help in the selection of appropriate molecules for the development of tools for more specific early diagnosis of ABPA, and desensitization therapies for patients of allergic disorders.
Topics: Allergens; Animals; Antigens, Fungal; Aspergillosis, Allergic Bronchopulmonary; Aspergillus fumigatus; Humans; Peptide Library; Proteomics
PubMed: 24818760
DOI: 10.2174/1389203715666140512120605 -
Current Opinion in Infectious Diseases Dec 2018Aspergillus fumigatus is a ubiquitous saprophytic fungus that can cause life-threatening invasive aspergillosis in immunocompromised patients. Apart from the immune... (Review)
Review
PURPOSE OF REVIEW
Aspergillus fumigatus is a ubiquitous saprophytic fungus that can cause life-threatening invasive aspergillosis in immunocompromised patients. Apart from the immune status of the host only a few characterized virulence factors have been identified. In this review, we describe the role of iron in the manifestation of A. fumigatus virulence.
RECENT FINDINGS
We gathered recent clinical evidence suggesting that tissue iron overload increases the risk of invasive aspergillosis occurrence. Furthermore, we summarize the mechanisms that A. fumigatus employs to achieve iron homeostasis and their importance in A. fumigatus proliferation in vitro. We describe two recent in-vivo models that clearly demonstrate the importance of iron in A. fumigatus growth and invasion.
SUMMARY
Based on these recent findings, therapy aimed at managing A. fumigatus iron homeostasis locally could make conditions more favorable to the host.
Topics: Aspergillosis; Aspergillus fumigatus; Humans; Immunocompromised Host; Iron; Iron Overload; Models, Biological; Risk Factors
PubMed: 30379731
DOI: 10.1097/QCO.0000000000000487 -
Current Protocols in Microbiology Sep 2019Aspergillus fumigatus is an opportunistic human fungal pathogen, capable of causing invasive aspergillosis in patients with compromised immune systems. The fungus was...
Aspergillus fumigatus is an opportunistic human fungal pathogen, capable of causing invasive aspergillosis in patients with compromised immune systems. The fungus was long considered a purely asexual organism. However, a sexual cycle was reported in 2009, with methods described to induce mating under laboratory conditions. The presence of a sexual cycle now offers a valuable tool for classical genetic analysis of the fungus, such as allowing determination of whether traits of interest are mono- or poly-genic in nature. For example, the sexual cycle is currently being exploited to determine the genetic basis of traits of medical importance such as resistance to azole antifungals and virulence, and to characterize the genes involved. The sexual cycle can also be used to assess the possibility of gene flow between isolates. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. This unit describes protocols for culturing of A. fumigatus and for inducing sexual reproduction between compatible MAT1-1 and MAT1-2 isolates of the species. The unit also provides working methods for harvesting sexual structures, isolating single-spore progeny and confirming whether sexual recombination has occurred. © The Authors. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Topics: Aspergillosis; Aspergillus fumigatus; Culture Media; Genes, Mating Type, Fungal; Humans; Mycology; Polymerase Chain Reaction; Preservation, Biological; Spores, Fungal
PubMed: 31518066
DOI: 10.1002/cpmc.87 -
Canadian Journal of Microbiology Jul 2018The genus Aspergillus includes fungal species that cause major health issues of significant economic importance. These microorganisms are also the culprit for production... (Review)
Review
The genus Aspergillus includes fungal species that cause major health issues of significant economic importance. These microorganisms are also the culprit for production of carcinogenic aflatoxins in grain storages, contaminating crops, and economically straining the production process. Aspergillus fumigatus is a very important pathogenic species, being responsible for high human morbidity and mortality on a global basis. The prevalence of these infections in immunosuppressed individuals is on the rise, and physicians struggle with the diagnosis of these deadly pathogens. Several virulence determinants facilitate fungal invasion and evasion of the host immune response. Metabolic functions are also important for virulence and drug resistance, since they allow fungi to obtain nutrients for their own survival and growth. Following a positive diagnostic identification, mortality rates remain high due, in part, to emerging resistance to frequently used antifungal drugs. In this review, we discuss the role of the main virulence, drug target, and drug resistance determinants. We conclude with the review of new technologies being developed to treat aspergillosis. In particular, microsphere and nanoparticle delivery systems are discussed in the context of improving drug bioavailability. Aspergillus will likely continue to cause problematic infections in immunocompromised patients, so it is imperative to improve treatment options.
Topics: Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Drug Resistance, Fungal; Humans; Immunocompromised Host; Nanoparticles; Virulence; Virulence Factors
PubMed: 29586541
DOI: 10.1139/cjm-2017-0749 -
Virulence Dec 2021is the leading cause of life-threatening invasive mold infections in immunocompromised individuals. This ubiquitous saprophyte possesses several natural attributes...
is the leading cause of life-threatening invasive mold infections in immunocompromised individuals. This ubiquitous saprophyte possesses several natural attributes allowing it to evade the immune system, including the ability to withstand high toxic Cu concentrations within the phagosomes of macrophages and neutrophils. We previously established that at high levels, Cu binds and activates the transcription factor AceA, which upregulates the expression of the Cu exporter CrpA to expel excess Cu. Deletion of or result in extreme Cu sensitivity and attenuated virulence.To identify other elements participating in resistance to Cu, we performed a genome-wide analysis of the transcriptome by RNAseq to analyze the AceA-dependent response of to excess Cu. We deleted key genes whose transcription was strongly upregulated by high Cu, including those encoding homologs of the three Cu chaperones and . Detailed analysis of these genes indicates that in is an essential gene with a possible role in respiration, the gene product participates in reductive iron uptake and encodes the Cu chaperone activating Sod1. Interestingly, although the -null strain was extremely sensitive to high Cu and oxidative stress, it was not attenuated in virulence in a mouse model of invasive pulmonary aspergillosis.Our work provides (i) a detailed view of the genome-wide transcriptional response of to excess Cu, (ii) identification of the AceA-dependent transcriptome and (iii) analysis of the roles of the three Cu chaperones and
Topics: Animals; Aspergillus fumigatus; Copper; Fungal Proteins; Mice; Molecular Chaperones; Transcription Factors; Virulence
PubMed: 34468270
DOI: 10.1080/21505594.2021.1958057 -
Current Opinion in Microbiology Dec 2019The human lung is continually exposed to airborne conidia of the fungus Aspergillus fumigatus (AF) and related species. The innate immune system efficiently eliminates... (Review)
Review
The human lung is continually exposed to airborne conidia of the fungus Aspergillus fumigatus (AF) and related species. The innate immune system efficiently eliminates inhaled AF conidia from the lung in normal individuals, but immunocompromised patients are at risk for highly lethal invasive aspergillosis (IA). Some individuals not at risk for IA may still suffer from failed clearance of AF in the form of noninvasive colonization associated with conditions such as allergic bronchopulmonary aspergillosis. Understanding of normal innate immune function against AF as well as failures of these functions will enable better treatment of these patient groups. In this review, we will focus on recent research that elucidates mechanisms of host defense and their failures resulting in colonization as well as tissue invasion.
Topics: Aspergillosis; Aspergillus fumigatus; Host-Pathogen Interactions; Humans; Immunity, Innate; Lung
PubMed: 31103956
DOI: 10.1016/j.mib.2019.04.003 -
PLoS Pathogens Aug 2021Aspergillus fumigatus is a saprophytic, filamentous fungus found in soils and compost and the causative agent of several pulmonary diseases in humans, birds, and other... (Review)
Review
Aspergillus fumigatus is a saprophytic, filamentous fungus found in soils and compost and the causative agent of several pulmonary diseases in humans, birds, and other mammals. A. fumigatus and other filamentous fungi grow as networks of filamentous hyphae that have characteristics of a classic microbial biofilm. These characteristics include production of an extracellular matrix (ECM), surface adhesion, multicellularity, and increased antimicrobial drug resistance. A. fumigatus biofilm growth occurs in vivo at sites of infection, highlighting the importance of defining mechanisms underlying biofilm development and associated emergent properties. We propose that there are 3 distinct phases in the development of A. fumigatus biofilms: biofilm initiation, immature biofilm, and mature biofilm. These stages are defined both temporally and by unique genetic and structural changes over the course of development. Here, we review known mechanisms within each of these stages that contribute to biofilm structure, ECM production, and increased resistance to contemporary antifungal drugs. We highlight gaps in our understanding of biofilm development and function that when addressed are expected to aid in the development of novel antifungal therapies capable of killing filamentous fungal biofilms.
Topics: Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Biofilms; Disease Progression; Drug Resistance, Fungal; Humans; Microbial Viability
PubMed: 34437655
DOI: 10.1371/journal.ppat.1009794 -
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