Pan-azole- and multi-fungicide-resistant Aspergillus fumigatus is widespread in the United States

Applied and Environmental Microbiology, Journal Year: 2024, Volume and Issue: 90(4)

Published: April 1, 2024

ABSTRACT Aspergillus fumigatus is an important global fungal pathogen of humans. Azole drugs are among the most effective treatments for A. infection. Azoles also widely used in agriculture as fungicides against pathogens crops. Azole-resistant has been increasing Europe and Asia two decades where clinical resistance thought to be driven by agricultural use azole fungicides. The prevalent mechanisms tandem repeats (TR) cyp51A promoter coupled with mutations coding region which result multiple (pan-azole resistance). isolated from patients United States (U.S.), but little known about its environmental distribution. To better understand distribution azole-resistant U.S., we collected isolates sites eight states tested 202 sensitivity azoles. We found environments seven showing that it widespread U.S. sequenced representing range sample compared them publicly available worldwide phylogenetic, principal component, ADMIXTURE analyses. fell into three clades, TR-based pan-azole was largely a single clade strongly associated high levels gene flow indicating recombination between clades highlighting potential azole-resistance continue spreading IMPORTANCE humans causes over 250,000 invasive infections each year. It soils, plant debris, compost. first line defense antifungal . combat other fungi attack plants. problem 20 years recently reported (U.S.). Until this study, did not know much settings In around world. show resistant azoles strictly

Language: Английский

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Saturation transposon mutagenesis enables genome-wide identification of genes required for growth and fluconazole resistance in the human fungal pathogenCryptococcus neoformans

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 29, 2024

Abstract Fungi can cause devastating invasive infections, typically in immunocompromised patients. Treatment is complicated both by the evolutionary similarity between humans and fungi frequent emergence of drug resistance. Studies fungal pathogens have long been slowed a lack high-throughput tools community resources that are common model organisms. Here we demonstrate transposon mutagenesis sequencing (TN-seq) system Cryptococcus neoformans enables genome-wide determination gene essentiality. We employed random forest machine learning approach to classify genome as essential or nonessential, predicting 1,465 genes, including 302 human orthologs. These genes ideal targets for new antifungal development. TN-seq also measurement fitness contribution phenotypes interest. As proof principle, growth fluconazole, clinically used antifungal. show novel role well-studied RIM101 pathway fluconazole susceptibility. 5’ insertions transposons drive sensitization enabling screenlike assays nonessential components genome. Using this approach, mitochondrial function sensitivity, such tuning down many via resistance fluconazole. Our assay will be valuable future studies C. , particularly examining consequences genotypic diversity.

Language: Английский

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Aspergillus flavus pangenome (AflaPan) uncovers novel aflatoxin and secondary metabolite associated gene clusters

BMC Plant Biology, Journal Year: 2024, Volume and Issue: 24(1)

Published: May 1, 2024

Abstract Background Aspergillus flavus is an important agricultural and food safety threat due to its production of carcinogenic aflatoxins. It has high level genetic diversity that adapted various environments. Recently, we reported two reference genomes A. isolates, AF13 ( MAT1-2 highly aflatoxigenic isolate) NRRL3357 MAT1-1 moderate aflatoxin producer). Where, insertion 310 kb in included producing gene bZIP transcription factor, named atfC . Observations significant genomic variants between these isolates contrasting phenotypes prompted investigation into variation among other with the goal discovering novel genes potentially associated regulation. Present study was designed three main objectives: (1) collection large number from diverse sources including maize plants field soils; (2) whole genome sequencing collected development a pangenome; (3) pangenome-wide association (Pan-GWAS) identify secondary metabolite cluster genes. Results Pangenome analysis 346 identified total 17,855 unique orthologous clusters, mere 41% (7,315) core 59% (10,540) accessory indicating accumulation during domestication. 5,994 clusters not annotated either or genomes. Pan-genome wide variations 391 pan-genes production. Interestingly, most significantly (94%; 369 associations) belonged expansion resulted incorporation new metabolites. Conclusion In summary, this provides complete pangenome framework for species along pathogen survival The indicated , however AflaPan closed represents optimum Most importantly, newly will be source seeking mitigation strategies needs attention research.

Language: Английский

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The human fungal pathogen Aspergillus fumigatus can produce the highest known number of meiotic crossovers

PLoS Biology, Journal Year: 2023, Volume and Issue: 21(9), P. e3002278 - e3002278

Published: Sept. 14, 2023

Sexual reproduction involving meiosis is essential in most eukaryotes. This produces offspring with novel genotypes, both by segregation of parental chromosomes as well crossovers between homologous chromosomes. A sexual cycle for the opportunistic human pathogenic fungus Aspergillus fumigatus known, but genetic consequences have remained unknown. Among other Aspergilli, it known that A. flavus has a moderately high recombination rate an average 4.2 per chromosome pair, whereas nidulans contrast higher 9.3 pair. Here, we show cross strains they produce 29.9 pair and large variation total map length across additional strain crosses. more than twice seen any organism, which discuss relation to model systems. We validate this through mapping resistance laboratory antifungal acriflavine using standing undescribed ABC efflux transporter. then demonstrate sufficient one common multidrug resistant haplotypes found cyp51A gene (TR34/L98H) crosses among parents harboring either 2 nearby variants, possibly explaining early spread such haplotypes. Our results suggest genomic studies species should reassess assumptions about linkage regions. The finding unparalleled crossover provides opportunities understand why these rates are not generally

Language: Английский

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Genomic diversity of the pathogenic fungus Aspergillus fumigatus in Japan reveals the complex genomic basis of azole resistance

Communications Biology, Journal Year: 2024, Volume and Issue: 7(1)

Published: March 14, 2024

Abstract Aspergillus fumigatus is a pathogenic fungus with global distribution. The emergence of azole-resistant A. (AR Af ) other than the TR-mutants problem in Japan. Additionally, genetic diversity strains Japan remains relatively unknown. Here we show isolated as well complexity distribution strains. First, analyzed genome sequences 171 from antifungal susceptibility these Next, conducted population analysis 876 by combining available genomic data for worldwide, which were grouped six clusters. Finally, genome-wide association study identified loci associated AR strains, but not TR-mutants. These results highlight mechanism underlying

Language: Английский

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Giant transposons promote strain heterogeneity in a major fungal pathogen

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 28, 2024

Fungal infections are difficult to prevent and treat in large part due strain heterogeneity. However, the genetic mechanisms driving pathogen variation remain poorly understood. Here, we determined extent which

Language: Английский

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Evolutionary origin and population diversity of a cryptic hybrid pathogen

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Sept. 28, 2024

Language: Английский

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Using genomics to understand the mechanisms of virulence and drug resistance in fungal pathogens

Biochemical Society Transactions, Journal Year: 2022, Volume and Issue: 50(3), P. 1259 - 1268

Published: June 17, 2022

Fungal pathogens pose an increasingly worrying threat to human health, food security and ecosystem diversity. To tackle fungal infections improve current diagnostic therapeutic tools it is necessary understand virulence antifungal drug resistance mechanisms in diverse species. Recent advances genomics approaches have provided a suitable framework these phenotypes, which ultimately depend on genetically encoded determinants. In this work, we review how the study of genome sequences has been key ascertain bases traits. We focus contribution comparative genomics, population directed evolution studies. addition, discuss different types genomic mutations (small or structural variants) contribute intraspecific differences resistance. Finally, challenges field anticipate future directions solve them. summary, work provides short overview can be used pathogens.

Language: Английский

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Examination of Genome-Wide Ortholog Variation in Clinical and Environmental Isolates of the Fungal Pathogen Aspergillus fumigatus

mBio, Journal Year: 2022, Volume and Issue: 13(4)

Published: June 29, 2022

Aspergillus fumigatus is both an environmental saprobe and opportunistic human fungal pathogen. Knowledge of genomic variation across A. isolates essential for understanding the evolution pathogenicity, virulence, resistance to antifungal drugs. Here, we investigated 206 (133 clinical 73 isolates), aiming identify genes with variable presence test whether this was related or origin isolates. The PanOrtho genome consists 13,085 ortholog groups, which 7,773 (59.4%) are shared by all (core groups) 5,312 (40.6%) vary in their gene (accessory groups plus singletons). Despite differences distribution orthologs isolates, no significant were observed among versus when phylogeny accounted for. Orthologs that differ tend occur at low frequency and/or be restricted specific isolates; thus, degree conservation between high. These results suggest within cannot associated

Language: Английский

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A heterologous expression platform in Aspergillus nidulans for the elucidation of cryptic secondary metabolism biosynthetic gene clusters: discovery of the Aspergillus fumigatus sartorypyrone biosynthetic pathway

Chemical Science, Journal Year: 2023, Volume and Issue: 14(40), P. 11022 - 11032

Published: Jan. 1, 2023

Secondary metabolites are important for the pathogenesis of fungus Aspergillus fumigatus which causes lethal Aspergillosis. Expressing groups A. genes in nidulans reveals new secondary metabolites.

Language: Английский

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