Population genomics confirms acquisition of drug-resistant Aspergillus fumigatus infection by humans from the environment

Nature Microbiology, Journal Year: 2022, Volume and Issue: 7(5), P. 663 - 674

Published: April 25, 2022

Abstract Infections caused by the fungal pathogen Aspergillus fumigatus are increasingly resistant to first-line azole antifungal drugs. However, despite its clinical importance, little is known about how susceptible patients acquire infection from drug-resistant genotypes in environment. Here, we present a population genomic analysis of 218 A. isolates across UK and Ireland (comprising 153 143 65 environmental isolates). First, phylogenomic shows strong genetic structuring into two clades (A B) with interclade recombination majority resistance found within clade Second, show occurrences where azole-resistant near-identical were obtained both sources, indicating high confidence transmitted Third, genome-wide scans identified selective sweeps multiple regions polygenic basis trait some backgrounds. These signatures positive selection seen for loci containing canonical genes encoding fungicide ergosterol biosynthetic pathway, while other under have no defined function. Lastly, pan-genome linked previously unknown mechanisms. Understanding drivers evolving drug needs urgent attention, especially light increasing numbers severe viral respiratory tract infections who opportunistic superinfections.

Language: Английский

---

Evolution of the human pathogenic lifestyle in fungi

Nature Microbiology, Journal Year: 2022, Volume and Issue: 7(5), P. 607 - 619

Published: May 4, 2022

Fungal pathogens cause more than a billion human infections every year, resulting in 1.6 million deaths annually. Understanding the natural history and evolutionary ecology of fungi is helping us understand how disease-relevant traits have repeatedly evolved. Different types mechanisms genetic variation contributed to evolution fungal pathogenicity specific differences distinguish from non-pathogens. Insights into traits, elements, ecological that contribute are crucial for developing strategies both predict emergence develop drugs combat them.

Language: Английский

---

An Overlooked and Underrated Endemic Mycosis—Talaromycosis and the Pathogenic Fungus Talaromyces marneffei

Clinical Microbiology Reviews, Journal Year: 2023, Volume and Issue: 36(1)

Published: Jan. 17, 2023

Talaromycosis is an invasive mycosis endemic in tropical and subtropical Asia caused by the pathogenic fungus Talaromyces marneffei. Approximately 17,300 cases of T. marneffei infection are diagnosed annually, reported mortality rate extremely high (~1/3). Despite devastating impact talaromycosis on immunocompromised individuals, particularly HIV-positive persons, increase occurrences HIV-uninfected diagnostic therapeutic approaches for have received far too little attention worldwide. In 2021, scientists living countries where raised a global demand it to be recognized as neglected disease. Therefore,

Language: Английский

---

The pan-genome of Aspergillus fumigatus provides a high-resolution view of its population structure revealing high levels of lineage-specific diversity driven by recombination

PLoS Biology, Journal Year: 2022, Volume and Issue: 20(11), P. e3001890 - e3001890

Published: Nov. 17, 2022

Aspergillus fumigatus is a deadly agent of human fungal disease where virulence heterogeneity thought to be at least partially structured by genetic variation between strains. While population genomic analyses based on reference genome alignments offer valuable insights into how gene variants are distributed across populations, these approaches fail capture intraspecific in genes absent from the genome. Pan-genomic de novo assemblies promising alternative reference-based genomics with potential address full repertoire species. Here, we evaluate 260 sequences A . including 62 newly sequenced strains, using combination genomics, phylogenomics, and pan-genomics. Our results high-resolution assessment structure recombination frequency, phylogenetically presence–absence variation, evidence for metabolic specificity, distribution putative antifungal resistance genes. Although disperses primarily via asexual conidia, identified extraordinarily high levels lowest linkage disequilibrium decay value reported any species date. We provide 3 primary populations , occurring only rarely often within them. These both distinct patterns unique suites accessory present exclusively each clade. Accessory displayed functional enrichment nitrogen carbohydrate metabolism suggesting that may stratified environmental niche specialization. Similarly, alleles were phylogeny. Altogether, pan-genome represents one largest pan-genomes date many unrepresented Af293 highlight inadequacy relying single-reference genome-based approach evaluating power combined elucidate structure, diversity, ecological drivers clinically relevant fungi.

Language: Английский

---

Combined pangenomics and transcriptomics reveals core and redundant virulence processes in a rapidly evolving fungal plant pathogen

BMC Biology, Journal Year: 2023, Volume and Issue: 21(1)

Published: Feb. 6, 2023

Studying genomic variation in rapidly evolving pathogens potentially enables identification of genes supporting their "core biology", being present, functional and expressed by all strains or "flexible varying between strains. Genes flexible biology may be considered to "accessory", whilst the "core" gene set is likely important for common features a pathogen species biology, including virulence on host genotypes. The wheat-pathogenic fungus Zymoseptoria tritici represents one most threats global food security was focus this study.

Language: Английский

---

Genome-scale metabolic modeling of Aspergillus fumigatus strains reveals growth dependencies on the lung microbiome

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: July 20, 2023

Aspergillus fumigatus, an opportunistic human pathogen, frequently infects the lungs of people with cystic fibrosis and is one most common causes infectious-disease death in immunocompromised patients. Here, we construct 252 strain-specific, genome-scale metabolic models this important fungal pathogen to study better understand component its pathogenic versatility. The show that 23.1% A. fumigatus reactions are not conserved across strains mainly associated amino acid, nucleotide, nitrogen metabolism. Profiles non-conserved growth-supporting reaction fluxes sufficient differentiate strains, for example by environmental or clinical origin. In addition, shotgun metagenomics analysis sputum from 40 patients (15 females, 25 males) before after diagnosis colonization suggests fungus shapes lung microbiome towards a more beneficial growth environment aromatic acid availability shikimate pathway. Our findings starting points development drugs intervention strategies targeting needs survival non-native lung.

Language: Английский

---

A secondary mechanism of action for triazole antifungals in Aspergillus fumigatus mediated by hmg1

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

Published: April 29, 2024

Abstract Triazole antifungals function as ergosterol biosynthesis inhibitors and are frontline therapy for invasive fungal infections, such aspergillosis. The primary mechanism of action triazoles is through the specific inhibition a cytochrome P450 14-α-sterol demethylase enzyme, Cyp51A/B, resulting in depletion cellular ergosterol. Here, we uncover clinically relevant secondary within pathway. We provide evidence that triazole-mediated Cyp51A/B activity generates sterol intermediate perturbations likely decoded by sensing functions HMG-CoA reductase Insulin-Induced Gene orthologs increased pathway activity. This, turn, results negative feedback regulation reductase, rate-limiting step biosynthesis. also domain mutations previously identified generating resistance clinical isolates Aspergillus fumigatus partially disrupt this triazole-induced feedback. Therefore, our data point to triazoles: induction downregulation Abrogation acquired diminishes triazole antifungal against pathogens underpins reductase-mediated resistance.

Language: Английский

---

Recent developments in Aspergillus fumigatus research: diversity, drugs, and disease

Microbiology and Molecular Biology Reviews, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 10, 2025

SUMMARY Advances in modern medical therapies for many previously intractable human diseases have improved patient outcomes. However, successful disease treatment outcomes are often prevented due to invasive fungal infections caused by the environmental mold Aspergillus fumigatus . As contemporary antifungal not experienced same robust advances as other therapies, defining mechanisms of A. initiation and progression remains a critical research priority. To this end, World Health Organization recently identified priority pathogen Centers Disease Control has highlighted emergence triazole-resistant isolates. The expansion diversity host populations susceptible aspergillosis complex dynamic genotypic phenotypic call reinvigorated assessment pathobiological drug-susceptibility mechanisms. Here, we summarize recent advancements field discuss challenges our understanding heterogeneity its pathogenesis diverse populations.

Language: Английский

---

Microbiota manipulation through the secretion of effector proteins is fundamental to the wealth of lifestyles in the fungal kingdom

FEMS Microbiology Reviews, Journal Year: 2022, Volume and Issue: 46(5)

Published: May 23, 2022

Abstract Fungi are well-known decomposers of organic matter that thrive in virtually any environment on Earth where they encounter wealths other microbes. Some fungi evolved symbiotic lifestyles, including pathogens and mutualists, have mostly been studied binary interactions with their hosts. However, we now appreciate such greatly influenced by the ecological context which take place. While establishing symbioses, not only interact hosts but also host-associated microbiota. Thus, target host its associated microbiota as a single holobiont. Recent studies shown fungal manipulate means secreted effector proteins selective antimicrobial activity to stimulate disease development. In this review, discuss contexts effector-mediated manipulation is relevant for lifestyle argue plants animals beneficial niche occur. Moreover, reason likely already ancestors encountered microbial competition long before symbiosis land mammalian evolved. claim fundamental biology.

Language: Английский

---

Comparative genomic study of the Penicillium genus elucidates a diverse pangenome and 15 lateral gene transfer events

IMA Fungus, Journal Year: 2023, Volume and Issue: 14(1)

Published: Feb. 1, 2023

Abstract The Penicillia are known to produce a wide range natural products—some with devastating outcome for the agricultural industry and others unexploited potential in different applications. However, large-scale overview of biosynthetic species has been lacking. In this study, we sequenced 93 Penicillium isolates and, together eleven published genomes that hold similar assembly characteristics, established phylogeny as well defining pangenome. A total 5612 genes were shared between ≥ 98 corresponding approximately half average number genome holds. We further identified 15 lateral gene transfer events have occurred collection isolates, which might played an important role, such niche adaption, evolution these fungi. comprehensive characterization genomic diversity genus supersedes single-reference genomes, do not necessarily capture entire genetic variation.

Language: Английский

---