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Genes Dec 2021is a saprophytic mold and an opportunistic pathogen with a broad geographic and ecological distribution. is the most common etiological agent of aspergillosis,...
is a saprophytic mold and an opportunistic pathogen with a broad geographic and ecological distribution. is the most common etiological agent of aspergillosis, affecting over 8,000,000 individuals worldwide. Due to the rising number of infections and increasing reports of resistance to antifungal therapy, there is an urgent need to understand populations from local to global levels. However, many geographic locations and ecological niches remain understudied, including soil environments from arctic regions. In this study, we isolated 32 and 52 strains from soils in Iceland and the Northwest Territories of Canada (NWT), respectively. These isolates were genotyped at nine microsatellite loci and the genotypes were compared with each other and with those in other parts of the world. Though significantly differentiated from each other, our analyses revealed that populations from Iceland and NWT contained evidence for both clonal and sexual reproductions, and shared many alleles with each other and with those collected from across Europe, Asia, and the Americas. Interestingly, we found one triazole-resistant strain containing the TR /L98H mutation in the gene from NWT. This strain is closely related to a triazole-resistant genotype broadly distributed in India. Together, our results suggest that the northern soil populations of are significantly influenced by those from other geographic regions.
Topics: Alleles; Antifungal Agents; Arctic Regions; Aspergillosis; Aspergillus fumigatus; Drug Resistance, Fungal; Fungal Proteins; Genetic Variation; Genotype; Humans; Mutation; Soil; Triazoles
PubMed: 35052359
DOI: 10.3390/genes13010019 -
Environmental Microbiology Dec 2020The ubiquitous fungal pathogen Aspergillus fumigatus is the primary cause of opportunistic mould infections in humans. Aspergilli disseminate via asexual conidia... (Review)
Review
The ubiquitous fungal pathogen Aspergillus fumigatus is the primary cause of opportunistic mould infections in humans. Aspergilli disseminate via asexual conidia passively travelling through air currents to germinate within a broad range of environs, wherever suitable nutrients are found. Though the average human inhales hundreds of conidia daily, A. fumigatus invasive infections primarily affect the immunocompromised. At-risk individuals can develop often fatal invasive disease for which therapeutic options are limited. Regrettably, the global insurgence of isolates resistant to the triazoles, the frontline antifungal class used in medicine and agriculture to control A. fumigatus, is complicating the treatment of patients. Triazole antifungal resistance in A. fumigatus has become recognized as a global, yet poorly comprehended, problem. Due to a multitude of factors, the magnitude of resistant infections and their contribution to treatment outcomes are likely underestimated. Current studies suggest that human drug-resistant infections can be either environmentally acquired or de novo host selected during patient therapy. While much concerning development of resistance is yet unknown, recent investigations have revealed assorted underlying mechanisms enabling triazole resistance within individual clinical and environmental isolates. This review will provide an overview of triazole resistance as it is currently understood, as well as highlight some of the prominent biological mechanisms associated with clinical and environmental resistance to triazoles in A. fumigatus.
Topics: Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Drug Resistance, Fungal; Humans; Microbial Sensitivity Tests; Triazoles
PubMed: 33047482
DOI: 10.1111/1462-2920.15274 -
Frontiers in Cellular and Infection... 2019The ability of fungal pathogens to survive hostile environments within the host depends on rapid and robust stress responses. Stress-activated protein kinase (SAPK)... (Review)
Review
The ability of fungal pathogens to survive hostile environments within the host depends on rapid and robust stress responses. Stress-activated protein kinase (SAPK) pathways are conserved MAPK signaling modules that promote stress adaptation in all eukaryotic cells, including pathogenic fungi. Activation of the SAPK occurs via the dual phosphorylation of conserved threonine and tyrosine residues within a TGY motif located in the catalytic domain. This induces the activation and nuclear accumulation of the kinase and the phosphorylation of diverse substrates, thus eliciting appropriate cellular responses. The Hog1 SAPK has been extensively characterized in the model yeast . Here, we use this a platform from which to compare SAPK signaling mechanisms in three major fungal pathogens of humans, , and . Despite the conservation of SAPK pathways within these pathogenic fungi, evidence is emerging that their role and regulation has significantly diverged. However, consistent with stress adaptation being a common virulence trait, SAPK pathways are important pathogenicity determinants in all these major human pathogens. Thus, the development of drugs which target fungal SAPKs has the exciting potential to generate broad-acting antifungal treatments.
Topics: Adaptation, Physiological; Aspergillosis; Aspergillus fumigatus; Candida albicans; Candidiasis; Cryptococcosis; Cryptococcus neoformans; Fungal Proteins; Gene Expression Regulation, Fungal; Humans; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; Phosphorylation; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Stress, Physiological; Virulence
PubMed: 31380304
DOI: 10.3389/fcimb.2019.00261 -
Toxins Dec 2019Fumagillin is a mycotoxin produced, above all, by the saprophytic filamentous fungus . This mold is an opportunistic pathogen that can cause invasive aspergillosis, a... (Review)
Review
Fumagillin is a mycotoxin produced, above all, by the saprophytic filamentous fungus . This mold is an opportunistic pathogen that can cause invasive aspergillosis, a disease that has high mortality rates linked to it. Its ability to adapt to environmental stresses through the production of secondary metabolites, including several mycotoxins (gliotoxin, fumagillin, pseurotin A, etc.) also seem to play an important role in causing these infections. Since the discovery of the fumagillin in 1949, many studies have focused on this toxin and in this review we gather all the information currently available. First of all, the structural characteristics of this mycotoxin and the different methods developed for its determination are given in detail. Then, the biosynthetic gene cluster and the metabolic pathway involved in its production and regulation are explained. The activity of fumagillin on its target, the methionine aminopeptidase type 2 (MetAP2) enzyme, and the effects of blocking this enzyme in the host are also described. Finally, the applications that this toxin and its derivatives have in different fields, such as the treatment of cancer and its microsporicidal activity in the treatment of honeybee hive infections with Nosema spp., are reviewed. Therefore, this work offers a complete review of all the information currently related to the fumagillin mycotoxin secreted by , important because of its role in the fungal infection process but also because it has many other applications, notably in beekeeping, the treatment of infectious diseases, and in oncology.
Topics: Animals; Aspergillus fumigatus; Bees; Cyclohexanes; Fatty Acids, Unsaturated; Humans; Mycotoxins; Sesquiterpenes
PubMed: 31861936
DOI: 10.3390/toxins12010007 -
Triazole resistance in Aspergillus fumigatus: recent insights and challenges for patient management.Clinical Microbiology and Infection :... Jul 2019Triazole resistance in Aspergillus fumigatus is widespread and threatens first-line triazole therapy in patients with Aspergillus diseases. (Review)
Review
BACKGROUND
Triazole resistance in Aspergillus fumigatus is widespread and threatens first-line triazole therapy in patients with Aspergillus diseases.
OBJECTIVES
To give an overview of the microbiology, epidemiology and clinical significance of triazole resistance in aspergillosis.
SOURCES
PubMed search for articles on resistance in Aspergillus species.
CONTENT
Triazoles are not mutagenic but select resistance when spontaneous mutations occur that are better able to proliferate in the triazole-containing environment. The major target for resistance mutations involves the Cyp51A gene, encoding an enzyme involved in cell wall synthesis. Triazole-resistance selection environments include patient treatment and organic matter containing triazole fungicide residues. Reported resistance frequencies vary widely between countries and hospitals, and resistance significantly complicates the diagnosis and treatment of Aspergillus diseases. Cultures may harbour various resistance phenotypes and multiple colonies must be analysed to detect resistance. PCR tests have become available for resistance detection in culture-negative patients, but show limited sensitivity. Individuals with triazole-resistant invasive aspergillosis have a 21% higher day-42 mortality compared with triazole-susceptible infection, and to prevent excess mortality resistant cases require first-line therapy that covers resistance. The recent ESCMID-ECMM-ERS Aspergillus guideline recommends resistance testing in A. fumigatus and local resistance surveillance. If resistance rates exceed 10% liposomal amphotericin B or triazole and echinocandin first-line therapy should be considered.
IMPLICATIONS
Triazole resistance significantly complicates the management of aspergillosis and multidisciplinary research from a 'One-health' perspective is required to retain the triazole class for medical use.
Topics: Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Disease Management; Drug Resistance, Fungal; Humans; Invasive Fungal Infections; Microbial Sensitivity Tests; Mutation; Polymerase Chain Reaction; Triazoles
PubMed: 30580035
DOI: 10.1016/j.cmi.2018.11.027 -
Microbiology and Immunology Mar 2022Aspergillus fumigatus, a ubiquitous pathogen, causes aspergillosis in humans, especially in immunodeficient patients. Azoles are frontline antifungal drugs for treating... (Review)
Review
Aspergillus fumigatus, a ubiquitous pathogen, causes aspergillosis in humans, especially in immunodeficient patients. Azoles are frontline antifungal drugs for treating aspergillosis. The recent global emergence of azole resistance in A. fumigatus has become a serious problem worldwide. It has arisen through two routes: long-term azole medical therapy, called the patient route, and the use of azole fungicides in its habitats especially for agricultural activities, called the environmental route. Resistant strains developed through the latter route show cross-resistance to medical azoles because of the identical molecular target Cyp51A between azole compounds used for medical treatment and agricultural disease control. In azole-resistant strains arising through the environmental route, A. fumigatus is observed frequently to possess mutations in the cyp51A gene linked to tandem repeats in the promoter region such as TR /L98H and TR /Y121F/T289A. The results of microsatellite genotyping analyses of resistant A. fumigatus strains have suggested a transboundary spread of this microorganism in many countries. Diverse actors are involved in the global highway of transmission. Therefore, the matter must be addressed as a "One Health" issue. This review presents a background of azole resistance in A. fumigatus and introduces newly discovered difficulties generated as this pathogen spreads worldwide.
Topics: Antifungal Agents; Aspergillus fumigatus; Azoles; Drug Resistance, Fungal; Fungal Proteins; Humans; Microbial Sensitivity Tests; Mutation
PubMed: 34870333
DOI: 10.1111/1348-0421.12957 -
Medical Mycology Journal 2023Aspergillus species have been identified morphologically in most clinical laboratories without conducting antifungal susceptibility tests (ASTs). This review aimed to... (Review)
Review
Aspergillus species have been identified morphologically in most clinical laboratories without conducting antifungal susceptibility tests (ASTs). This review aimed to evaluate the importance of accurate identification and ASTs of Aspergillus spp. strains for adequate clinical management of Aspergillus infections. The Aspergillus spp. were identified by gene sequencing, and ASTs for itraconazole and voriconazole were conducted. In Aspergillus section Nigri, the rate of detection of cryptic species was high, and Aspergillus tubingensis with lower susceptibility to azoles was frequently identified. Azole-resistant Aspergillus fumigatus was detected at a high rate in patients with chronic pulmonary aspergillosis managed with long-term azole treatment. In conclusion, accurate identification of Aspergillus spp. and ASTs are needed to carry out appropriate treatment. Moreover, we hope that these microbiological tests will be widely used in clinical laboratories to improve clinical practice.
Topics: Humans; Antifungal Agents; Drug Resistance, Fungal; Microbial Sensitivity Tests; Aspergillus; Aspergillus fumigatus; Azoles; Fungal Proteins
PubMed: 38030277
DOI: 10.3314/mmj.23-004 -
The European Respiratory Journal Jan 2023Variable clinical outcomes are reported with fungal sensitisation in chronic obstructive pulmonary disease (COPD), and it remains unclear which fungi and what allergens...
BACKGROUND
Variable clinical outcomes are reported with fungal sensitisation in chronic obstructive pulmonary disease (COPD), and it remains unclear which fungi and what allergens associate with the poorest outcomes. The use of recombinant as opposed to crude allergens for such assessment is unknown.
METHODS
A prospective multicentre assessment of stable COPD (n=614) was undertaken in five hospitals across three countries: Singapore, Malaysia and Hong Kong. Clinical and serological assessment was performed against a panel of 35 fungal allergens including crude and recombinant and non- allergens. Unsupervised clustering and topological data analysis (TDA) approaches were employed using the measured sensitisation responses to elucidate if sensitisation subgroups exist and their related clinical outcomes.
RESULTS
sensitisation was associated with increased exacerbations in COPD. Unsupervised cluster analyses revealed two "fungal sensitisation" groups. The first was characterised by sensitisation and increased exacerbations, poorer lung function and worse prognosis. Polysensitisation in this group conferred even poorer outcome. The second group, characterised by sensitisation, was more symptomatic. Significant numbers of individuals demonstrated sensitisation responses to only recombinant (as opposed to crude) allergens f 1, 3, 5 and 6, and exhibited increased exacerbations, poorer lung function and an overall worse prognosis. TDA validated these findings and additionally identified a subgroup within -sensitised COPD of patients with frequent exacerbations.
CONCLUSION
sensitisation is a treatable trait in COPD. Measuring sensitisation responses to recombinant allergens identifies an important patient subgroup with poor COPD outcomes that remains overlooked by assessment of only crude allergens.
Topics: Humans; Aspergillus fumigatus; Allergens; Prospective Studies; Immunoglobulin E; Pulmonary Disease, Chronic Obstructive; Aspergillus
PubMed: 35926878
DOI: 10.1183/13993003.00507-2022 -
Biochemistry Nov 2023Nicotinamide adenine dinucleotide (NAD) is an essential molecule in all kingdoms of life, mediating energy metabolism and cellular signaling. Recently, a new class of...
Nicotinamide adenine dinucleotide (NAD) is an essential molecule in all kingdoms of life, mediating energy metabolism and cellular signaling. Recently, a new class of highly active fungal surface NADases was discovered. The enzyme from the opportunistic human pathogen was thoroughly characterized. It harbors a catalytic domain that resembles that of the tuberculosis necrotizing toxin from , which efficiently cleaves NAD to nicotinamide and ADP-ribose, thereby depleting the dinucleotide pool. Of note, the NADase has an additional Ca-binding motif at the C-terminus of the protein. Despite the presence of NADases in several fungal divisions, the Ca-binding motif is uniquely found in the Eurotiales order, which contains species that have immense health and economic impacts on humans. To identify the potential roles of the metal ion-binding site in catalysis or protein stability, we generated and characterized NADase variants lacking the ability to bind calcium. X-ray crystallographic analyses revealed that the mutation causes a drastic and dynamic structural rearrangement of the homodimer, resulting in decreased thermal stability. Even though the calcium-binding site is at a long distance from the catalytic center, the structural reorganization upon the loss of calcium binding allosterically alters the active site, thereby negatively affecting NAD-glycohydrolase activity. Together, these findings reveal that this unique calcium-binding site affects the protein fold, stabilizing the dimeric structure, but also mediates long-range effects resulting in an increased catalytic rate.
Topics: Humans; NAD+ Nucleosidase; NAD; Aspergillus fumigatus; Calcium; Niacinamide
PubMed: 37934975
DOI: 10.1021/acs.biochem.3c00360 -
The FEBS Journal Apr 2021Aspergillus fumigatus infections are rising at a disconcerting rate in tandem with antifungal resistance rates. Efforts to develop novel antifungals have been hindered...
Aspergillus fumigatus infections are rising at a disconcerting rate in tandem with antifungal resistance rates. Efforts to develop novel antifungals have been hindered by the limited knowledge of fundamental biological and structural mechanisms of A. fumigatus propagation. Biosynthesis of NTPs, the building blocks of DNA and RNA, is catalysed by NDK. An essential enzyme in A. fumigatus, NDK poses as an attractive target for novel antifungals. NDK exhibits broad substrate specificity across species, using both purines and pyrimidines, but the selectivity of such nucleosides in A. fumigatus NDK is unknown, impeding structure-guided inhibitor design. Structures of NDK in unbound- and NDP-bound states were solved, and NDK activity was assessed in the presence of various NTP substrates. We present the first instance of a unique substrate binding mode adopted by CDP and TDP specific to A. fumigatus NDK that illuminates the structural determinants of selectivity. Analysis of the oligomeric state reveals that A. fumigatus NDK adopts a hexameric assembly in both unbound- and NDP-bound states, contrary to previous reports suggesting it is tetrameric. Kinetic analysis revealed that ATP exhibited the greatest turnover rate (321 ± 33.0 s ), specificity constant (626 ± 110.0 mm ·s ) and binding free energy change (-37.0 ± 3.5 kcal·mol ). Comparatively, cytidine nucleosides displayed the slowest turnover rate (53.1 ± 3.7 s ) and lowest specificity constant (40.2 ± 4.4 mm ·s ). We conclude that NDK exhibits nucleoside selectivity whereby adenine nucleosides are used preferentially compared to cytidine nucleosides, and these insights can be exploited to guide drug design. ENZYMES: Nucleoside-diphosphate kinase (EC 2.7.4.6). DATABASE: Structural data are available in the PDB database under the accession numbers: Unbound-NDK (6XP4), ADP-NDK (6XP7), GDP-NDK (6XPS), IDP-NDK (6XPU), UDP-NDK (6XPT), CDP-NDK (6XPW), TDP-NDK (6XPV).
Topics: Aspergillosis; Aspergillus fumigatus; Escherichia coli; Humans; Kinetics; Nucleoside-Diphosphate Kinase; Nucleosides; Phosphorylation; Protein Conformation; Substrate Specificity
PubMed: 33089641
DOI: 10.1111/febs.15607