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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 -
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 -
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 -
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 -
PLoS Pathogens Jul 2021Aspergillus fumigatus is an opportunistic human pathogen that causes aspergillosis, a spectrum of environmentally acquired respiratory illnesses. It has a cosmopolitan... (Review)
Review
Aspergillus fumigatus is an opportunistic human pathogen that causes aspergillosis, a spectrum of environmentally acquired respiratory illnesses. It has a cosmopolitan distribution and exists in the environment as a saprotroph on decaying plant matter. Azoles, which target Cyp51A in the ergosterol synthesis pathway, are the primary class of drugs used to treat aspergillosis. Azoles are also used to combat plant pathogenic fungi. Recently, an increasing number of azole-naive patients have presented with pan-azole-resistant strains of A. fumigatus. The TR34/L98H and TR46/Y121F/T289A alleles in the cyp51A gene are the most common ones conferring pan-azole resistance. There is evidence that these mutations arose in agricultural settings; therefore, numerous studies have been conducted to identify azole resistance in environmental A. fumigatus and to determine where resistance is developing in the environment. Here, we summarize the global occurrence of azole-resistant A. fumigatus in the environment based on available literature. Additionally, we have created an interactive world map showing where resistant isolates have been detected and include information on the specific alleles identified, environmental settings, and azole fungicide use. Azole-resistant A. fumigatus has been found on every continent, except for Antarctica, with the highest number of reports from Europe. Developed environments, specifically hospitals and gardens, were the most common settings where azole-resistant A. fumigatus was detected, followed by soils sampled from agricultural settings. The TR34/L98H resistance allele was the most common in all regions except South America where the TR46/Y121F/T289A allele was the most common. A major consideration in interpreting this survey of the literature is sampling bias; regions and environments that have been extensively sampled are more likely to show greater azole resistance even though resistance could be more prevalent in areas that are under-sampled or not sampled at all. Increased surveillance to pinpoint reservoirs, as well as antifungal stewardship, is needed to preserve this class of antifungals for crop protection and human health.
Topics: Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Azoles; Disease Reservoirs; Drug Resistance, Fungal; Humans
PubMed: 34324607
DOI: 10.1371/journal.ppat.1009711 -
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 -
Applied Microbiology and Biotechnology Dec 2024Aspergillus fumigatus is a ubiquitous pathogenic mold and causes several diseases, including mycotoxicosis, allergic reactions, and systemic diseases (invasive... (Review)
Review
Aspergillus fumigatus is a ubiquitous pathogenic mold and causes several diseases, including mycotoxicosis, allergic reactions, and systemic diseases (invasive aspergillosis), with high mortality rates. In its ecological niche, the fungus has evolved and mastered many reply strategies to resist and survive against negative threats, including harsh environmental stress and deficiency of essential nutrients from natural environments, immunity responses and drug treatments in host, and competition from symbiotic microorganisms. Hence, treating A. fumigatus infection is a growing challenge. In this review, we summarized A. fumigatus reply strategies and escape mechanisms and clarified the main competitive or symbiotic relationships between A. fumigatus, viruses, bacteria, or fungi in host microecology. Additionally, we discussed the contemporary drug repertoire used to treat A. fumigatus and the latest evidence of potential resistance mechanisms. This review provides valuable knowledge which will stimulate further investigations and clinical applications for treating and preventing A. fumigatus infections. KEY POINTS: • Harsh living environment was a great challenge for A. fumigatus survival. • A. fumigatus has evolved multiple strategies to escape host immune responses. • A. fumigatus withstands antifungal drugs via intrinsic escape mechanisms.
Topics: Aspergillus fumigatus; Aspergillosis; Hypersensitivity; Antifungal Agents; Ecosystem
PubMed: 38175242
DOI: 10.1007/s00253-023-12952-z -
Virulence Dec 2019spp and particularly the species are the causative agents of invasive aspergillosis, a progressive necrotizing pneumonia that occurs in immunocompromised patients. The... (Review)
Review
spp and particularly the species are the causative agents of invasive aspergillosis, a progressive necrotizing pneumonia that occurs in immunocompromised patients. The limited efficacy of currently available antifungals has led to interest in a better understanding of the molecular mechanisms underlying the pathogenesis of invasive aspergillosis in order to identify new therapeutic targets for this devastating disease. The exopolysaccharide galactosaminogalactan (GAG) plays an important role in the pathogenesis of experimental invasive aspergillosis. The present review article summarizes our current understanding of GAG composition and synthesis and the molecular mechanisms whereby GAG promotes virulence. Promising directions for future research and the prospect of GAG as both a therapy and therapeutic target are reviewed.
Topics: Animals; Aspergillosis; Aspergillus fumigatus; Biofilms; Biosynthetic Pathways; Fungal Proteins; Host-Pathogen Interactions; Humans; Mice; Polysaccharides; Virulence; Virulence Factors
PubMed: 30667338
DOI: 10.1080/21505594.2019.1568174