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Medical Mycology 2009Aspergillus fumigatus is a saprophytic fungus commonly found in soil and compost piles. In immunocompromised patients it takes on a sinister form as a potentially lethal... (Review)
Review
Aspergillus fumigatus is a saprophytic fungus commonly found in soil and compost piles. In immunocompromised patients it takes on a sinister form as a potentially lethal opportunistic human pathogen. We currently have a limited understanding of the in vivo growth mechanisms used by A. fumigatus during invasive pulmonary aspergillosis (IPA). The ability of A. fumigatus to adapt to various microenvironments encountered during growth in the human host may explain why A. fumigatus is the most frequently occurring opportunistic pathogenic mold. The transcriptional and metabolic responses to changing microenvironments found in the mammalian lung require the activation of pathways implicated in resistance to unique stresses. Thus, the production of primary metabolites in vivo may give clues to the critical pathways used by A. fumigatus to cause disease in human hosts. We recently have identified primary metabolites in the mammalian lung typically associated with fungal growth under hypoxic environments suggesting that A. fumigatus may encounter low oxygen tensions during IPA. These and other studies on A. fumigatus metabolism are the focus of this review.
Topics: Aspergillus fumigatus; Gene Expression Profiling; Humans; Metabolomics; Pulmonary Aspergillosis; Virulence
PubMed: 19253141
DOI: 10.1080/13693780802455313 -
Computers in Biology and Medicine Jan 2019Aspergillus fumigatus causes serious infections in humans, and its virulence correlates with hyphal growth, branching and formation of the filamentous mycelium. The...
BACKGROUND
Aspergillus fumigatus causes serious infections in humans, and its virulence correlates with hyphal growth, branching and formation of the filamentous mycelium. The filamentous mycelium is a complex structure inconvenient for quantity analysis. In this study, we monitored the branching of A. fumigatus filamentous mycelium in vitro at different points in time in order to assess the complexity degree and develop a dynamic model for the branching complexity.
METHOD
We used fractal analysis of microscopic images (FAMI) to measure the fractal dimensions (D) of the branching complexity within 24 h of incubation.
RESULTS
By photographing the filamentous mycelium dynamically and processing the images, the D variation curve of A. fumigatus complexity degree was obtained. We acquired the D variation curve which contained initial exponential period and stationary period of A. fumigatus branching. Further, the obtained data of D was modeled via the logistic model (LM) to develop a dynamic model of A. fumigatus branching for the prediction of the specific growth rate of branching value (0.23 h).
CONCLUSIONS
Developed FAMI and LM models present a simple and non-destructive method of predicting the evolution of branching complexity of A. fumigatus. These models are useful as laboratory measurements for the prediction of hyphal and mycelium development, especially relevant to the pathogenesis study of aspergillosis, as well as pathogenesis of other diseases caused by moulds.
Topics: Aspergillosis; Aspergillus fumigatus; Humans; Models, Biological; Mycelium
PubMed: 30529573
DOI: 10.1016/j.compbiomed.2018.11.022 -
Current Opinion in Microbiology Dec 2017In contrast to obligate pathogens opportunistic pathogens such as Aspergillus fumigatus do not need a specific host to propagate or survive. However several... (Review)
Review
In contrast to obligate pathogens opportunistic pathogens such as Aspergillus fumigatus do not need a specific host to propagate or survive. However several characteristics of the saprophytic life-style and the selective pressure encountered in the primary ecological niche contribute to the virulence of A. fumigatus. All fungi depend on metals for growth and proliferation, like iron, copper, zinc, manganese or calcium. In the recent past several studies explored the manifold impact of metals modulating virulence of pathogens. Components which might be scarce in the natural environment but also in the host due to nutritional immunity. This review recapitulates molecular constituents of metal ion uptake systems in A. fumigatus, their regulation and their significance at the host-pathogen battlefield.
Topics: Animals; Aspergillosis; Aspergillus fumigatus; Homeostasis; Humans; Iron; Virulence
PubMed: 29179120
DOI: 10.1016/j.mib.2017.11.015 -
Philosophical Transactions of the Royal... Dec 2016Aspergillus fungi are the cause of an array of diseases affecting humans, animals and plants. The triazole antifungal agents itraconazole, voriconazole, isavuconazole... (Review)
Review
Aspergillus fungi are the cause of an array of diseases affecting humans, animals and plants. The triazole antifungal agents itraconazole, voriconazole, isavuconazole and posaconazole are treatment options against diseases caused by Aspergillus However, resistance to azoles has recently emerged as a new therapeutic challenge in six continents. Although de novo azole resistance occurs occasionally in patients during azole therapy, the main burden is the aquisition of resistance through the environment. In this setting, the evolution of resistance is attributed to the widespread use of azole-based fungicides. Although ubiquitously distributed, A. fumigatus is not a phytopathogen. However, agricultural fungicides deployed against plant pathogenic moulds such as Fusarium, Mycospaerella and A. flavus also show activity against A. fumigatus in the environment and exposure of non-target fungi is inevitable. Further, similarity in molecule structure between azole fungicides and antifungal drugs results in cross-resistance of A. fumigatus to medical azoles. Clinical studies have shown that two-thirds of patients with azole-resistant infections had no previous history of azole therapy and high mortality rates between 50% and 100% are reported in azole-resistant invasive aspergillosis. The resistance phenotype is associated with key mutations in the cyp51A gene, including TR/L98H, TR and TR/Y121F/T289A resistance mechanisms. Early detection of resistance is of paramount importance and if demonstrated, either with susceptibility testing or through molecular analysis, azole monotherapy should be avoided. Liposomal amphotericin B or a combination of voriconazole and an echinocandin are recomended for azole-resistant aspergillosis.This article is part of the themed issue 'Tackling emerging fungal threats to animal health, food security and ecosystem resilience'.
Topics: Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Azoles; Drug Resistance, Fungal; Fungicides, Industrial; Phenotype
PubMed: 28080986
DOI: 10.1098/rstb.2015.0460 -
MSphere May 2020is an opportunistic and allergenic pathogenic fungus, responsible for fungal infections in humans. infections are usually treated with polyenes, azoles, or...
is an opportunistic and allergenic pathogenic fungus, responsible for fungal infections in humans. infections are usually treated with polyenes, azoles, or echinocandins. Echinocandins, such as caspofungin, can inhibit the biosynthesis of the β-1,3-glucan polysaccharide, affecting the integrity of the cell wall and leading to fungal death. In some strains, caspofungin treatment at high concentrations induces an increase of fungal growth, a phenomenon called the aspofungin aradoxical ffect (CPE). Here, we analyze the proteome and phosphoproteome of the wild-type strain and of mitogen-activated protein kinase (MAPK) and null mutant strains during CPE (2 μg/ml caspofungin for 1 h). The wild-type proteome showed 75 proteins and 814 phosphopeptides (corresponding to 520 proteins) altered in abundance in response to caspofungin treatment. The Δ (Δ caspofungin/wild-type caspofungin) and Δ (Δ caspofungin/wild-type caspofungin) strains displayed 626 proteins and 1,236 phosphopeptides (corresponding to 703 proteins) and 101 proteins and 1,217 phosphopeptides (corresponding to 645 proteins), respectively, altered in abundance. Functional characterization of the phosphopeptides from the wild-type strain exposed to caspofungin showed enrichment for transcription factors, protein kinases, and cytoskeleton proteins. Proteomic analysis of the Δ and Δ mutants indicated that control of proteins involved in metabolism, such as in production of secondary metabolites, was highly represented in both mutants. Results of functional categorization of phosphopeptides from both mutants were very similar and showed a high number of proteins with decreased phosphorylation of proteins involved in transcriptional control, DNA/RNA binding, cell cycle control, and DNA processing. This report reveals novel transcription factors involved in caspofungin tolerance. is an opportunistic human-pathogenic fungus causing allergic reactions or systemic infections, such as invasive pulmonary aspergillosis in immunocompromised patients. Caspofungin is an echinocandin that impacts the construction of the fungal cell wall by inhibiting the biosynthesis of the β-1,3-glucan polysaccharide. Caspofungin is a fungistatic drug and is recommended as a second-line therapy for treatment of aspergillosis. Treatment at high concentrations induces an increase of fungal growth, a phenomenon called the aspofungin aradoxical ffect (CPE). Collaboration between the mitogen-activated protein kinases (MAPK) of the cell wall integrity (MapkA) and high-osmolarity glycerol (SakA) pathways is essential for CPE. Here, we investigate the global proteome and phosphoproteome of wild-type, Δ, and Δ strains upon CPE. This study showed intense cross talk between the two MAPKs for the CPE and identified novel protein kinases and transcription factors possibly important for CPE. Increased understanding of how the modulation of protein phosphorylation may affect the fungal growth in the presence of caspofungin represents an important step in the development of new strategies and methods to combat the fungus inside the host.
Topics: Antifungal Agents; Aspergillus fumigatus; Caspofungin; Fungal Proteins; Mass Spectrometry; Phosphopeptides; Phosphorylation; Proteome; Proteomics; Signal Transduction; Transcription Factors
PubMed: 32461274
DOI: 10.1128/mSphere.00365-20 -
Medical Mycology Journal 2016Aspergillosis is an important deep mycosis. The causative agents are Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, and Aspergillus terreus, of which A.... (Review)
Review
Aspergillosis is an important deep mycosis. The causative agents are Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, and Aspergillus terreus, of which A. fumigatus is the most prevalent. Cryptic Aspergillus spp., which morphologically resemble representative species of each Aspergillus section, also cause aspergillosis. Most of the cryptic species reveal different susceptibility patterns and/or different secondary metabolite profiles, also called exometabolome in this manuscript, from those representative species. On the other hand, azole-resistant A. fumigatus strains in clinical specimens and in the environment have been reported. Therefore, it is imperative to precisely identify the species, including cryptic Aspergillus spp., and evaluate the susceptibility of isolates.In this manuscript, some of the causative cryptic Aspergillus spp. are briefly reviewed. In addition, the exometabolome of Aspergillus section Fumigati is described. Finally, azole resistance of A. fumigatus is also discussed, in reference to several studies from Japan.
Topics: Antifungal Agents; Aspergillosis; Aspergillus; Aspergillus fumigatus; Azoles; Drug Resistance, Fungal; Humans; Metabolome
PubMed: 27904060
DOI: 10.3314/mmj.16.005 -
Clinical and Experimental Allergy :... Apr 2000Various putative virulence factors of Aspergillus fumigatus have been studied over the past decades. A. fumigatus gliotoxin is a potent inhibitor of the mucociliary... (Review)
Review
Various putative virulence factors of Aspergillus fumigatus have been studied over the past decades. A. fumigatus gliotoxin is a potent inhibitor of the mucociliary system. Several fungal metabolites interfere with phagocytosis and opsonization including toxins, 'conidial inhibitory factor', 'A. fumigatus diffusible product' and 'complement inhibitory factor'. A. fumigatus can bind specifically to different host tissues components, whereas toxins give a general and significant immunosuppressive effect on host defences. Circumstantial evidence links the production of elastinolytic proteases with the ability to cause disease. However, none of the reports demonstrates conclusively a decisive role for any of the virulence factors described thus far. It is conceivable that proteolytic enzyme activities such as those expressed by AFAlp are one of a number of factors, each with a minor effect, that combine to facilitate disease progression.
Topics: Aspergillosis; Aspergillus fumigatus; Fungal Proteins; Humans; Mycotoxins; Virulence
PubMed: 10718844
DOI: 10.1046/j.1365-2222.2000.00796.x -
Medical Mycology 2009Aspergillus fumigatus is an increasingly prevalent opportunistic fungal pathogen of various immuno-compromised individuals. It has the ability to filament within the... (Review)
Review
Aspergillus fumigatus is an increasingly prevalent opportunistic fungal pathogen of various immuno-compromised individuals. It has the ability to filament within the lungs forming dense intertwined mycelial balls. These morphological characteristics resemble those of microbial biofilms, which are matrix enclosed microbial populations, adherent to each other and/or to surfaces or interfaces. The purpose of this paper is to review some recent experiments that indicate the potential biofilm forming capacity of A. fumigatus in vitro. Initially it was established that conidial seeding density is important for stable biofilm development. In the optimized model conidial germination and filamentous growth characteristics were not observed until 8 h, after which a multi-cellular population expanded exponentially forming a thick structure (approx. 250 microm). Calcofluor white staining of this revealed the presence of extracellular polymeric matrix material, which increased as the biofilm matured. Subsequent antifungal sensitivity testing of this structure showed that azoles, polyenes and echinocandins were ineffective in reducing the cellular viability at therapeutically attainable concentrations. Microarray and real-time PCR analysis demonstrated the up-regulation of AfuMDR4 during multicellular growth and development, which may account the recalcitrance observed. Overall, A. fumigatus appears to possess the classical elements of biofilm growth, namely multicellularity, matrix production and sessile resistance. This controversial approach to understanding the biology of A. fumigatus infection may provide crucial information on how to treat this pathogenic fungus more effectively.
Topics: Animals; Antifungal Agents; Aspergillus fumigatus; Biofilms; Extracellular Matrix; Humans; Microbial Viability; Mycetoma
PubMed: 18654926
DOI: 10.1080/13693780802238834 -
Applied Microbiology and Biotechnology Jan 2012Gliotoxin (GT) is the prototype of the epidithiodioxopiperazine (ETP)-type fungal toxins. GT plays a critical role in the pathobiology of Aspergillus fumigatus. It... (Review)
Review
Gliotoxin (GT) is the prototype of the epidithiodioxopiperazine (ETP)-type fungal toxins. GT plays a critical role in the pathobiology of Aspergillus fumigatus. It modulates the immune response and induces apoptosis in different cell types. The toxicity has been attributed to the unusual intramolecular disulfide bridge, which is the functional motif of all ETPs. Because of the extraordinary structure and activity of GT, this fungal metabolite has been the subject of many investigations. The biosynthesis of GT involves unprecedented reactions catalysed by recently discovered enzymes. Here, we summarize the recent progress in elucidating the GT biosynthetic pathway and its role in virulence.
Topics: Aspergillus fumigatus; Biosynthetic Pathways; Gliotoxin; Immunosuppressive Agents; Virulence Factors
PubMed: 22094977
DOI: 10.1007/s00253-011-3689-1 -
Clinical Infectious Diseases : An... Feb 2016Azole resistance in Aspergillus fumigatus has emerged as a global health problem. Although the number of cases of azole-resistant aspergillosis is still limited,... (Review)
Review
Azole resistance in Aspergillus fumigatus has emerged as a global health problem. Although the number of cases of azole-resistant aspergillosis is still limited, resistance mechanisms continue to emerge, thereby threatening the role of the azole class in the management of diseases caused by Aspergillus. The majority of cases of azole-resistant disease are due to resistant A. fumigatus originating from the environment. Patient management is difficult due to the absence of patient risk factors, delayed diagnosis, and limited treatment options, resulting in poor treatment outcome. International and collaborative efforts are required to understand how resistance develops in the environment to allow effective measures to be implemented aimed at retaining the use of azoles both for food production and human medicine.
Topics: Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Azoles; Drug Resistance, Fungal; Environmental Microbiology; Humans
PubMed: 26486705
DOI: 10.1093/cid/civ885