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PLoS Pathogens Jun 2024Invasive aspergillosis causes significant morbidity and mortality in immunocompromised patients. Natural killer (NK) cells are pivotal for antifungal defense. Thus far,...
Invasive aspergillosis causes significant morbidity and mortality in immunocompromised patients. Natural killer (NK) cells are pivotal for antifungal defense. Thus far, CD56 is the only known pathogen recognition receptor on NK cells triggering potent antifungal activity against Aspergillus fumigatus. However, the underlying cellular mechanisms and the fungal ligand of CD56 have remained unknown. Using purified cell wall components, biochemical treatments, and ger mutants with altered cell wall composition, we herein found that CD56 interacts with the A. fumigatus cell wall carbohydrate galactosaminogalactan (GAG). This interaction induced NK cell activation, degranulation, and secretion of immune-enhancing chemokines and cytotoxic effectors. Supernatants from GAG-stimulated NK cells elicited antifungal activity and enhanced antifungal effector responses of polymorphonuclear cells. In conclusion, we identified A. fumigatus GAG as a ligand of CD56 on human primary NK cells, stimulating potent antifungal effector responses and activating other immune cells.
PubMed: 38889192
DOI: 10.1371/journal.ppat.1012315 -
The Clinical Respiratory Journal Jun 2024
Allergic Bronchopulmonary Aspergillosis (ABPA) With Colonized Aspergillus fumigatus Detected by Metagenomic Next-Generation Sequencing on Tissue Samples: A Distinct Subset of ABPA With a Higher Risk of Exacerbation.
Topics: Humans; Aspergillosis, Allergic Bronchopulmonary; Aspergillus fumigatus; Male; High-Throughput Nucleotide Sequencing; Female; Middle Aged; Metagenomics; Adult; Disease Progression; Aged
PubMed: 38886877
DOI: 10.1111/crj.13794 -
FEMS Microbiology Ecology Jun 2024Fungi are increasingly recognized to play diverse roles within honey bee hives, acting as pathogens, mutualists, and commensals. Pollen products, essential for hive...
Fungi are increasingly recognized to play diverse roles within honey bee hives, acting as pathogens, mutualists, and commensals. Pollen products, essential for hive nutrition, host significant fungal communities with potential protective and nutritional benefits. In this study, we profile the fungal communities and antifungal properties of three pollen products from healthy and stressed hives: fresh pollen collected by forager bees from local plants; stored pollen packed into the comb inside the hive; and bee bread, which is stored pollen following anaerobic fermentation used for bee and larval nutrition. Using amplicon sequencing, we found significant differences in fungal community composition, with hive health and sample type accounting for 8.8% and 19.3% of variation in beta diversity, respectively. Pollen and bee bread extracts had species-specific antimicrobial activity and inhibited the fungal hive pathogens Ascosphaera apis, Aspergillus flavus, and Aspergillus fumigatus, and the bacterial hive pathogen Paenibacillus larvae. Activity was positively correlated with phenolic and antioxidant content and was diminished in stressed hives. The plant source of pollen determined by amplicon sequencing differed in stressed hives, suggesting altered foraging behaviour. These findings illustrate the complex interplay between honey bees, fungal communities, and hive products, which should be considered in hive management and conservation.
Topics: Bees; Animals; Pollen; Fungi; Stress, Physiological; Paenibacillus larvae; Mycobiome; Ascomycota; Anti-Infective Agents
PubMed: 38886123
DOI: 10.1093/femsec/fiae091 -
Mycopathologia Jun 2024A 67 year-old male was admitted in the ICU because of multi-organ failure due to sepsis secondary to Fournier's gangrene. He had sustained radical prostatectomy in the...
A 67 year-old male was admitted in the ICU because of multi-organ failure due to sepsis secondary to Fournier's gangrene. He had sustained radical prostatectomy in the last 48 hours. Peritoneal fluid and fatty tissue biopsies grew Aspergillus Fumigatus without concomitant pulmonary involvement. Postoperative acquisition via exogenous and endogenous routes is discussed, as this nosocomial entity is very rarely reported apart from peritoneal dialysis, especially in non-immunosuppressed patients.
Topics: Humans; Male; Aspergillus fumigatus; Aged; Peritonitis; Aspergillosis; Postoperative Complications; Prostatectomy
PubMed: 38878212
DOI: 10.1007/s11046-024-00858-x -
Archives of Microbiology Jun 2024Aspergillus fumigatus is a ubiquitous filamentous fungus commonly found in the environment. It is also an opportunistic human pathogen known to cause a range of... (Review)
Review
Aspergillus fumigatus is a ubiquitous filamentous fungus commonly found in the environment. It is also an opportunistic human pathogen known to cause a range of respiratory infections, such as invasive aspergillosis, particularly in immunocompromised individuals. Azole antifungal agents are widely used for the treatment and prophylaxis of Aspergillus infections due to their efficacy and tolerability. However, the emergence of azole resistance in A. fumigatus has become a major concern in recent years due to their association with increased treatment failures and mortality rates. The development of azole resistance in A. fumigatus can occur through both acquired and intrinsic mechanisms. Acquired resistance typically arises from mutations in the target enzyme, lanosterol 14-α-demethylase (Cyp51A), reduces the affinity of azole antifungal agents for the enzyme, rendering them less effective, while intrinsic resistance refers to a natural resistance of certain A. fumigatus isolates to azole antifungals due to inherent genetic characteristics. The current review aims to provide a comprehensive overview of azole antifungal resistance in A. fumigatus, discusses underlying resistance mechanisms, including alterations in the target enzyme, Cyp51A, and the involvement of efflux pumps in drug efflux. Impact of azole fungicide uses in the environment and the spread of resistant strains is also explored.
Topics: Aspergillus fumigatus; Azoles; Drug Resistance, Fungal; Antifungal Agents; Humans; Fungal Proteins; Aspergillosis; Microbial Sensitivity Tests; Cytochrome P-450 Enzyme System; Mutation
PubMed: 38878211
DOI: 10.1007/s00203-024-04026-z -
The Pediatric Infectious Disease Journal Jun 2024Central nervous system (CNS) aspergillosis is an opportunistic infection with an increasing incidence and a high mortality rate. It is seen in immunocompromised patients...
INTRODUCTION
Central nervous system (CNS) aspergillosis is an opportunistic infection with an increasing incidence and a high mortality rate. It is seen in immunocompromised patients as well as in immunocompetent patients. Here, we present disseminated aspergillosis in a child with nephrotic syndrome treated with long-term and aggressive systemic antifungal treatment and intraventricular (IVent) liposomal amphotericin B (L-AmB) as well as surgical excision and drainage due to difficulty in management.
CASE REPORT
A 10-year-old boy with nephrotic syndrome on steroid therapy was admitted with limping and weakness. The cranial magnetic resonance imaging showed multiple intraparenchymal scattered abscesses. The largest one was excised and drained. Abscess culture revealed Aspergillus fumigatus and histopathological examination revealed septate hyphae compatible with Aspergillosis. Intravenous (IV) voriconazole was started, and IV L-AmB was added. The size of lesions and perilesional edema continued to increase, and then IVent L-AmB was added. With IVent and systemic antifungal treatment, regression of the lesions was observed. He was followed up with oral voriconazole and weekly IVent L-AmB. After 2 and a half months, he was re-operated because of increased lesion size, number and perilesional edema, and IV voriconazole and other salvage antifungal therapies were started. Since the lesions had decreased and remained stable, IV voriconazole was switched to oral therapy, and he was followed up as an outpatient. Immunodeficiency diseases were excluded by immunological and genetic tests.
CONCLUSION
Management of central nervous system aspergillosis can be challenging despite long-term and aggressive systemic and IVent antifungal treatment as well as surgical excision and drainage.
PubMed: 38865571
DOI: 10.1097/INF.0000000000004422 -
Mycopathologia Jun 2024Aspergillosis encompasses a wide range of clinical conditions based on the interaction between Aspergillus and the host. It ranges from colonization to invasive... (Review)
Review
Aspergillosis encompasses a wide range of clinical conditions based on the interaction between Aspergillus and the host. It ranges from colonization to invasive aspergillosis. The human lung provides an entry door for Aspergillus. Aspergillus has virulence characteristics such as conidia, rapid growth at body temperature, and the production of specific proteins, carbohydrates, and secondary metabolites that allow A. fumigatus to infiltrate the lung's alveoli and cause invasive aspergillosis. Alveolar epithelial cells play an important role in both fungus clearance and immune cell recruitment via cytokine release. Although the innate immune system quickly clears conidia in immunocompetent hosts, A. fumigatus has evolved multiple virulence factors in order to escape immune response such as ROS detoxifying enzymes, the rodlet layer, DHN-melanin and toxins. Bacterial co-infections or interactions can alter the immune response, impact Aspergillus growth and virulence, enhance biofilm formation, confound diagnosis, and reduce treatment efficacy. The gut microbiome's makeup influences pulmonary immune responses generated by A. fumigatus infection and vice versa. The real-time PCR for Aspergillus DNA detection might be a particularly useful tool to diagnose pulmonary aspergillosis. Metagenomics analyses allow quick and easy detection and identification of a great variety of fungi in different clinical samples, although optimization is still required particularly for the use of NGS techniques. This review will analyze the current state of aspergillosis in light of recent discoveries in the microbiota and mycobiota.
Topics: Humans; Aspergillosis; Mycobiome; Aspergillus fumigatus; Aspergillus; Virulence Factors; Microbiota; Virulence; Metagenomics; Host-Pathogen Interactions
PubMed: 38864956
DOI: 10.1007/s11046-024-00853-2 -
Mycopathologia Jun 2024Aspergillus fumigatus is a saprophytic fungal pathogen that causes opportunistic infections in animals and humans. Azole resistance has been reported globally in human...
Aspergillus fumigatus is a saprophytic fungal pathogen that causes opportunistic infections in animals and humans. Azole resistance has been reported globally in human A. fumigatus isolates, but the prevalence of resistance in isolates from animals is largely unknown. A retrospective resistance surveillance study was performed using a collection of clinical A. fumigatus isolates from various animal species collected between 2015 and 2020. Agar-based azole resistance screening of all isolates was followed by in vitro antifungal susceptibility testing and cyp51A gene sequencing of the azole-resistant isolates. Over the 5 year period 16 (11.3%) of 142 A. fumigatus culture-positive animals harbored an azole-resistant isolate. Resistant isolates were found in birds (15%; 2/13), cats (21%; 6/28), dogs (8%; 6/75) and free-ranging harbor porpoise (33%; 2/6). Azole-resistance was cyp51A mediated in all isolates: 81.3% (T-67G/)TR/L98H, 12.5% TR/Y121F/T289A. In one azole-resistant A. fumigatus isolate a combination of C(-70)T/F46Y/C(intron7)T/C(intron66)T/M172V/E427K single-nucleotide polymorphisms in the cyp51A gene was found. Of the animals with an azole-resistant isolate and known azole exposure status 71.4% (10/14) were azole naive. Azole resistance in A. fumigatus isolates from animals in the Netherlands is present and predominantly cyp51A TR-mediated, supporting an environmental route of resistance selection. Our data supports the need to include veterinary isolates in resistance surveillance programs. Veterinarians should consider azole resistance as a reason for therapy failure when treating aspergillosis and consider resistance testing of relevant isolates.
Topics: Aspergillus fumigatus; Animals; Azoles; Drug Resistance, Fungal; Aspergillosis; Antifungal Agents; Netherlands; Microbial Sensitivity Tests; Retrospective Studies; Fungal Proteins; Birds; Cats; Dogs; Cytochrome P-450 Enzyme System
PubMed: 38864903
DOI: 10.1007/s11046-024-00850-5 -
Nature Communications Jun 2024More than 10 million people suffer from lung diseases caused by the pathogenic fungus Aspergillus fumigatus. Azole antifungals represent first-line therapeutics for most...
More than 10 million people suffer from lung diseases caused by the pathogenic fungus Aspergillus fumigatus. Azole antifungals represent first-line therapeutics for most of these infections but resistance is rising, therefore the identification of antifungal targets whose inhibition synergises with the azoles could improve therapeutic outcomes. Here, we generate a library of 111 genetically barcoded null mutants of Aspergillus fumigatus in genes encoding protein kinases, and show that loss of function of kinase YakA results in hypersensitivity to the azoles and reduced pathogenicity. YakA is an orthologue of Candida albicans Yak1, a TOR signalling pathway kinase involved in modulation of stress responsive transcriptional regulators. We show that YakA has been repurposed in A. fumigatus to regulate blocking of the septal pore upon exposure to stress. Loss of YakA function reduces the ability of A. fumigatus to penetrate solid media and to grow in mouse lung tissue. We also show that 1-ethoxycarbonyl-beta-carboline (1-ECBC), a compound previously shown to inhibit C. albicans Yak1, prevents stress-mediated septal spore blocking and synergises with the azoles to inhibit A. fumigatus growth.
Topics: Aspergillus fumigatus; Animals; Antifungal Agents; Protein Serine-Threonine Kinases; Fungal Proteins; Mice; Protein-Tyrosine Kinases; Dyrk Kinases; Azoles; Aspergillosis; Lung; Spores, Fungal; Female
PubMed: 38862481
DOI: 10.1038/s41467-024-48592-8 -
Angewandte Chemie (International Ed. in... Jun 2024Invasive fungal disease accounts for ~3.8 million deaths annually, an unacceptable rate that urgently prompts the discovery of new knowledge-driven treatments. We report...
Invasive fungal disease accounts for ~3.8 million deaths annually, an unacceptable rate that urgently prompts the discovery of new knowledge-driven treatments. We report the use of camelid single-domain nanobodies (Nbs) against fungal β-1,3-glucanosyltransferases (Gel) involved in β-1,3-glucan transglycosylation. Crystal structures of two Nbs with Gel4 from Aspergillus fumigatus revealed binding to a dissimilar CBM43 domain and a highly conserved catalytic domain across fungal species, respectively. Anti-Gel4 active site Nb3 showed significant antifungal efficacy in vitro and in vivo prophylactically and therapeutically against different A. fumigatus and Cryptococcus neoformans isolates, reducing the fungal burden and disease severity, thus significantly improving immunocompromised animal survival. Notably, C. deneoformans (serotype D) strains were more susceptible to Nb3 and genetic Gel deletion than C. neoformans (serotype A) strains, indicating a key role for β-1,3-glucan remodelling in C. deneoformans survival. These findings add new insights about the role of b-1,3-glucan in fungal biology and demonstrate the potential of nanobodies in targeting fungal enzymes to combat invasive fungal diseases.
PubMed: 38856634
DOI: 10.1002/anie.202405823