Biology subjects

Rhodes, J.

Publications and source records attributed to Rhodes, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Temozolomide Induces Aberrant RNA Alkylation and Widespread Translational Repression

Temozolomide (TMZ) is a frontline alkylating chemotherapy, yet its direct impact on RNA modification and global translation dynamics remains poorly understood. Here, we demonstrate that TMZ induces pervasive RNA alkylation causing severe translational impairment. TMZ directly deposits aberrant methyl groups onto single-stranded mRNA in vitro, creating physical lesions that lower translational efficiency. In glioblastoma cells, acute TMZ exposure triggers a rapid, widespread accumulation of m7G on cellular RNAs, leading to the significant attenuation of global protein synthesis. Nanopore direct RNA sequencing identified distinct guanine-specific error signatures and sequence context preferences associated with TMZ-induced damage. Using a quantitative yeast spike-in ribosome profiling strategy, we mapped this translational repression at transcript-level, revealing a global downregulation of translational efficiency. This widespread repression disproportionately targets highly interconnected networks essential for cellular proliferation, specifically chromosome organization. We show that the severity of this translational repression is driven by a transcript's coding guanine density, stability and translation initiation speed. Together, our findings suggest that TMZ-induced alkylation targets stable, highly translated, guanine-rich transcripts. This establishes aberrant RNA methylation and subsequent translational arrest as a potential mechanism of temozolomide cytotoxicity.

biochemistry↗

bioRxiv2026

The pangenome of Aspergillus fumigatus highlights the dynamics of gene gain-loss over evolutionary timescales in a human fungal pathogen

How fungal pathogens generate and maintain genetic diversity under sustained environmental drug pressure is central to understanding the emergence of antifungal resistance. In environmental moulds such as Aspergillus fumigatus, escalating exposure to agricultural fungicides that share targets with clinical azoles imposes chronic selection outside the host, yet the genomic mechanisms enabling long-term adaptation remains unclear. Here, we reconstruct the largest eukaryotic pangenome assembled to date, comprising over 1,000 A. fumigatus isolates collected across 34 countries spanning a century. Using network-based orthogroup clustering combined with ancestral state reconstruction, we show that the A. fumigatus pangenome is open and shaped by continual gene gain and loss. Pangenome-wide association analyses identify accessory genes associated with itraconazole resistance, indicating that resistance evolution occurs within broader genomic backgrounds and beyond canonical target-site mutations. We further reveal that the accessory genome is structured into distinct evolutionary cohorts, including lineage-restricted gene sets enriched for mobile genetic element- associated domains, notably Starship-linked genes. These patterns suggest that Starships contribute to clade-specific genome architecture while remaining largely constrained by phylogenetic boundaries. Time-calibrated phylogenetic modelling reveals a relatively slow rate of gene turnover--approximately two orthogroup events per century--demonstrating that large-scale genome evolution in A. fumigatus is decoupled from elevated point mutation rates and contrasts sharply with bacterial systems. Together, these findings establish a quantitative framework for fungal pangenome evolution and reveal how structured accessory genome dynamics underpin antifungal resistance and long-term adaptation in this major human pathogen. Significance StatementAntifungal resistance in Aspergillus fumigatus threatens global health, yet the genomic processes enabling long-term adaptation under environmental drug pressure remain poorly understood. Using a global, century-spanning pangenome, incorporating over 1,000 isolates, we quantify gene gain and loss dynamics in this major human pathogen. We show that the pangenome is open but evolves slowly, with only [~]2 gene turnover events per century. Accessory genes follow two distinct evolutionary modes: some are lineage-restricted, while others are broadly distributed and dynamically exchanged. Resistance is associated with lineage-specific accessory genes, highlighting a broader role of resistance formation than target-site mutations alone. These findings reveal how heterogeneous turnover dynamics shape adaptation to widespread antifungal exposure.

evolutionary biology↗

bioRxiv2026

Genome variation of Sporothrix schenckii and Sporothrix brasiliensis

Sporotrichosis, a subcutaneous mycosis caused by dimorphic fungi of the Sporothrix genus, has become a major zoonotic epidemic in South America, primarily driven by Sporothrix brasiliensis. To elucidate the genomic basis of its emergence and antifungal adaptation, we analyzed whole-genome sequences from 94 Sporothrix isolates, integrating single-nucleotide polymorphism (SNP), copy number variation (CNV), and genome-wide association (GWAS) analyses. Comparative genomics revealed 610,242 SNPs within S. brasiliensis and 1,474,627 within S. schenckii, confirming a marked disparity in intraspecific diversity. Phylogenomic tree inference resolved six well-supported S. brasiliensis clades with limited internal divergence, reflecting recent population expansion, while S. schenckii displayed deep phylogeographic structure separating North and South American lineages. CNV profiling identified 158 affected genes in S. brasiliensis (60 gains, 98 losses) and 88 in S. schenckii (54 gains, 34 losses), concentrated near sub-telomeric regions. In S. brasiliensis, gains were enriched for kinases and intracellular trafficking functions, whereas losses involved genes related to translation and primary metabolism, suggesting regulatory reinforcement coupled with metabolic streamlining. A GWAS of itraconazole resistance identified 81 SNPs distributed across multiple scaffolds, with many located within genes related with transport, signaling, and redox balance, supporting a polygenic basis for azole response. Together, these results highlight distinct evolutionary strategies of closely related Sporothrix species and delineate the genomic changes associated with the emergence and drug tolerance of S. brasiliensis.

genomics↗

bioRxiv2026

Antarctic marine microplastics reveals environmental persistence and rapid evolution of Candida auris

Candida (Candidozyma) auris is a critical priority fungal pathogen that emerged two decades ago near simultaneously on multiple continents. Since emergence, C. auris resistance to all four classes of antifungal drugs has been described, including pan-drug resistant isolates, sometimes evolving within patients. Here, we confirm the first isolation of C. auris from Antarctica and show cold-adapted phenotypes and an affinity for binding to nylon. We also provide evidence to suggest mutator phenotypes contribute to the rapid evolution of C. auris and are responsible for the emergence of multiple, distinct genetic clades worldwide. Isolates in clades I, III and IV with a mutator phenotype displayed elevated mutation rates compared to non-auris Candida species. This phenotype had a complex genetic basis and was associated with drug resistance mutations. We postulate that the mutator phenotype has a significant effect on evolutionary potential and is responsible for the emergence and rapid spread of drug-resistance C. auris and novel genetic clades.

microbiology↗

bioRxiv2026

Global genomic epidemiology of Candida auris: analysis of 12,644 whole genome sequences from 1997-2024

Candida auris is a critical priority fungal pathogen (World Health Organization) that has emerged into human populations pre-1996 from an unknown environmental reservoir. Genomic sequencing data has been used extensively in the last decade, leading to a largely unharnessed dataset with potential to unlock understanding of emerging fungal pathogen evolution. Here, we compiled publicly available Illumina paired-end whole genome sequences (WGS) for variant calling, supplemented by isolates from the worlds first four-clade single-facility outbreak in Algeria (n = 7), totaling 12,644 WGS. We describe the geographic, clinical, and temporal epidemiology of the outbreak across the globe between 1997 and 2024, indicating a conserved six-clade structure. Despite the evidence of earlier species diversity in low- and lower-middle income countries (LLMIC), the majority of WGS derived from high-income (12,035, 93.2%) and upper-middle-income countries (719, 5.57%), where cases are believed to be imported from endemic regions, with few from lower-middle-income countries (165, 1.28%) and none from lower-income countries. Copy number variation was present, including azole drug target ERG11, with seven isolates displaying ten to fifteen copies. Alarmingly, the standing variation of C. auris reveals emerging variation in hot-spots of the echinocandin drug target FKS1, which encodes a {beta}-1,3-glucan synthase. Eighteen emerging FKS1 hot-spot variants have not been detected or described in databases, and mostly occured in Northern America (57/61, 93.4%), where echinocandin monotherapy is standard treatment. Well-studied FKS1 variants known to cause resistance are significantly more common in clade I isolates derived from urine compared to blood, consistent with a role for the urinary niche as a low echinocandin concentration safe-haven for the development of resistance. The insights from this global genomic epidemiology survey of C. auris highlight sequencing inequality and detect ongoing genomic innovation in clinical settings, raising predictable and urgent concerns around the ongoing use of echinocandin monotherapy and potential emerging antifungal drug resistance-related genotypes in high-income settings.

microbiology↗

bioRxiv2025

Distributed disruption and remodelling of synaptome architecture following traumatic brain injury

A single cortical impact in mice altered the number and molecular composition of excitatory synapses across 222 brain regions. Early effects targeted synapses with rapid protein turnover, followed by changes in slow-turnover synapses. This injury-induced remodelling of synaptome architecture mirrors responses to genetic mutation, ageing, sleep deprivation and experience, suggesting that reorganisation of excitatory synapse populations is a shared mechanism underlying brain plasticity across diverse conditions.

neuroscience↗

bioRxiv2025

An embryo-derived peptide signal directs endosperm polarity in Arabidopsis

Angiosperm seed formation requires the coordinated development of the products of double fertilization, the embryo and the endosperm. The endosperm mediates efficient nutrient transfer from surrounding maternal tissues to the developing embryo. This function requires a polarized tissue organization, which manifests as early polar gene expression and polar cellularization dynamics. We show that the receptor kinase HAIKU2 acts in coordination with the transcription factor WRKY10/MINISEED3 to ensure robust endosperm polarity establishment through the activity of the homeodomain transcription factors WUSCHEL-RELATED HOMEOBOX 8 and 9. This process depends on egg cell fertilization and is mediated through the peptide PATHOGEN-INDUCED PEPTIDE-LIKE 7, which acts as a HAIKU2 ligand. Our results reveal how a molecular paracrine dialogue between the embryo and endosperm ensures optimal seed developmental coordination.

plant biology↗

bioRxiv2025

Disulfide bond sculpts a peptide fold that mediates phytocytokine recognition

Precise ligand recognition by closely related leucine-rich repeat receptor kinases (LRR-RKs) is essential for plants to coordinate immunity, development, and environmental adaptation. Here, we show how HAESA-LIKE 3 (HSL3) specifically recognizes the folded, disulfide-stabilized CTNIP/SCREW phytocytokines in Arabidopsis. Quantitative binding assays define a minimal CTNIP4 region required for high-affinity HSL3 interaction and signaling activation. A 2.12 [A] crystal structure of the HSL3-CTNIP4 complex reveals a unique C-terminal receptor pocket that accommodates the peptides cyclic architecture through a combination of hydrophobic and polar contacts, a feature absent in the closely related HAE/HSL LRR-RKs. The cyclic CTNIP4 fold further establishes a largely hydrophobic interface that bridges HSL3 to the SERK co-receptor, forming a distinct activation surface. Together, these structural, biochemical and physiological insights uncover a previously unrecognised mechanism of peptide perception and receptor activation, highlighting how subtle architectural variations enable precise ligand selectivity among highly conserved plant receptor kinases.

plant biology↗

bioRxiv2024

Putative neofunctionalization of a Poales-specific EXO70 clade

EXO70s are uniquely expanded in land plants compared to all other eukaryotic lineages. The functional implications of this expansion and diversification on the conserved role of EXO70 as a subunit of the octameric exocyst complex have remained unresolved. We previously demonstrated barley (Hordeum vulgare) EXO70FX12, a member of the monocot-specific EXO70FX clade, is required for resistance to wheat stripe rust in conjunction with the leucine-rich repeat receptor kinase (LRR-RK) HvPUR1. Through phylogenetic analysis, we identified unique features of the EXO70FX clade, leading us to hypothesize that this clade experienced neofunctionalization. Using structural predictions and protein-protein interaction assays, we demonstrate that HvEXO70FX12 lost the ability to serve as a subunit within the exocyst complex. We predict that the EXO70FX clade has largely lost exocyst association and represents a novel acquisition that emerged during Poales diversification for immunity.

plant biology↗

bioRxiv2024

Genomic characterization of a persistent, azole-resistant C. parapsilosis strain responsible for a hospital outbreak during the first COVID-19 wave

Yeasts belonging to the Candida genus typically reside on the mucosal surface and within the respiratory and gastrointestinal tract as commensals. Under conditions of host vulnerability, they can act as opportunistic pathogens, leading to various forms of candidiasis, including candidemia. Such infections can be particularly problematic when caused by isolates that exhibit resistance to antifungal drugs, which is becoming more prevalent in many regions. One hundred and seven samples of Candida spp. were isolated from patients with candidemia in the hospital San Matteo in Pavia (Italy) over a period of 6 years, from 2015 to the first COVID wave in spring 2020. In order to understand the epidemiology of Candida infections in this hospital setting, the isolates were whole-genome sequenced which identified most as C. parapsilosis and C. albicans. Comparative genomics revealed that isolates of C. albicans were genomically diverse, indicating repeated introductions in the hospital from the community. C. parapsilosis isolates comprised two groups of highly similar isolates representing strains capable of long-term persistence in the hospital. All isolates of the main persistent group were resistant to fluconazole and presented variable levels of resistance to voriconazole and itraconazole, resulting from the Y132F substitution in erg11 and the N455D substitution in upc2. Interestingly, with the exception of the single isolate susceptible to both voriconazole and itraconazole, all the 61 isolates presented one unreported missense mutation in mrr1 (S1907C).

genomics↗

bioRxiv2024

Genomic epidemiology of emerging terbinafine-resistant Trichophyton indotineae

Dermatophyte skin infections affect around a quarter of the worlds population and are a growing public health concern due to increasing incidence of novel species causing severe infections that are resistant to antifungal treatments. Trichophyton species cause the greatest burden of dermatophytosis worldwide, with the T. mentagrophytes species complex being particularly associated with the emergence of new aggressive infections. One emerging species, T. indotineae (originally T. mentagrophytes genotype VIII) is notable for the extensive nature of the often inflammatory infection, its clinical resistance to terbinafine antifungal treatment, and its rapid global spread. To better understand the epidemiology of this disease, we sourced isolates from severe cases of dermatophytosis in the United Kingdom, Ireland, France, Canada and India for the period 2018-2023, including the type strain from Japan. We used whole-genome sequencing to confirm 90 isolates were T. indotineae, and antifungal susceptibility testing indicated that over half of these (62%) were resistant to terbinafine (MIC [≥]1 mg/L). Pairwise genetic distances showed very high identity with only 147 (1-414) SNPs separating isolates that were nested within a monophyletic phylogeny, supporting a single evolutionary origin of T. indotineae. That no clear geographic clustering of isolates was observed confirms the rapid transcontinental spread of T. indotineae from its likely centre of diversity in Asia. Genome-wide analyses identified multiple non-synonymous SNPs in SQLE (ERG1), the squalene epoxidase target of terbinafine, that were associated with terbinafine in vitro resistance [≥]1 mg/L. However, five isolates exhibited high MIC values without SQLE mutations, suggesting the presence of alternative resistance mechanisms. Our findings highlight the importance of better genomic surveillance to understand and manage this severe and rapidly emerging terbinafine-resistant dermatophyte.

genomics↗

bioRxiv2024

Xenosiderophore transporter gene expression and clade-specific filamentation in Candida auris killifish infection

Candida auris is a critical priority fungal pathogen (World Health Organization). Clinical management is challenging due to a high mortality rate, rapidly increasing antifungal resistance, and frequent nosocomial outbreaks. A critical bottleneck in understanding virulence is the lack of gene expression profiling models during infection. We developed a fish embryo yolk-sac microinjection model using Aphanius dispar (Arabian killifish; AK) at human body temperature. This enabled interrogation of infection dynamics via dual host-pathogen RNA-seq across five major clades of C. auris (I-V). Host responses included heat shock, complement activation, and nutritional immunity, notably haem oxygenase (HMOX) expression during clade IV infection. We identified a pathogen transcriptional signature across all five clades of C. auris strongly enriched for putative xenosiderophore transmembrane transporters. We describe this novel family and a sub-clade of five putative haem transport-related (HTR) genes. Only the basal clade V isolate formed filaments, associated with canonical and atypical regulators of morphogenesis. Clades I and IV demonstrated increased virulence, accompanied by up-regulation of three HTR genes in clade IV, and the non-mating mating-type locus (MTL) gene PIKA in both clades. Our study provides new insight into C. auris pathogenesis, highlighting species-wide in vivo up-regulation of XTC genes during host tissue infection. Significance statementCandida auris is an emerging human fungal pathogen and global public health threat, yet in vivo transcriptomic analysis of tissue infection has remained elusive. Using yolk-sac infection in Arabian killifish, we profiled gene expression across five major C. auris clades. We found that the basal clade V uniquely undergoes filamentation during infection, while all clades upregulate members of a large, expanded family of xenosiderophore transporter candidate genes. These findings highlight the important roles for iron acquisition and morphological switching in pathogenesis, revealing potential mechanisms of immune evasion and fungal persistence, and identifying candidate targets for antifungal therapy.

microbiology↗

bioRxiv2024

FungAMR: A comprehensive portrait of antimicrobial resistance mutations in fungi

Antimicrobial resistance (AMR) is a global threat. To optimize the use of our antifungal arsenal, we need rapid detection and monitoring tools that rely on high-quality AMR mutation data. Here, we performed a thorough manual curation of published AMR mutations in fungal pathogens to produce the FungAMR reference dataset. A total of 501 papers were curated, leading to 35,792 mutation entries all classified with the degree of evidence that supports their role in resistance. FungAMR covers 95 species, 246 genes and 208 drugs. We combined variant effect predictors with FungAMR resistance mutations and showed that these tools could be used to help predict the potential impact of mutations on AMR. Additionally, a comparative analysis among species revealed a high level of convergence in the molecular basis of resistance, highlighting some potentially universal resistance mutations. The analysis also showed that a significant number of resistance mutations lead to cross-resistance within antifungals of a class, as well as between classes for certain mutated genes. The acquisition of fungal resistance in the clinic and the field is an urging concern. Finally, we provide a computational tool, ChroQueTas, that leverages FungAMR to screen fungal genomes for AMR mutations. These resources are anticipated to have great utility for researchers in the fight against antifungal resistance.

microbiology↗

bioRxiv2024

What makes Candida auris pan-drug resistant? Integrative insights from genomic, transcriptomic, and phenomic analysis of clinical strains resistant to all four major classes of antifungal drugs

The global epidemic of drug-resistant Candida auris continues unabated. We do not know what caused the unprecedented appearance of pan-drug resistant (PDR) Candida auris strains in a hospitalized patient in New York; the initial report highlighted both known and unique mutations in the prominent gene targets of azoles, amphotericin B, echinocandins, and flucytosine antifungal drugs. However, the factors that allow C. auris to acquire multi-drug resistance and pan-drug resistance are not known. Therefore, we conducted a comprehensive genomic, transcriptomic, and phenomic analysis to better understand PDR C. auris. Among 1,570 genetic variants in drug-resistant C. auris, 299 were unique to PDR strains. The whole genome sequencing results suggested perturbations in genes associated with nucleotide biosynthesis, mRNA processing, and nuclear export of mRNA. Whole transcriptome sequencing of PDR C. auris revealed two genes to be significantly differentially expressed - a DNA repair protein and DNA replication-dependent chromatin assembly factor 1. Of 59 novel transcripts, 12 candidate transcripts had no known homology among expressed transcripts found in other organisms. We observed no fitness defects among multi-drug resistant (MDR) and PDR C. auris strains grown in nutrient-deficient or - enriched media at different temperatures. Phenotypic profiling revealed wider adaptability to nitrogenous nutrients with an uptick in the utilization of substrates critical in upper glycolysis and tricarboxylic acid cycle. Structural modelling of 33-amino acid deletion in the gene for uracil phosphoribosyl transferase suggested an alternate route in C. auris to generate uracil monophosphate that does not accommodate 5-fluorouracil as a substrate. Overall, we find evidence of metabolic adaptations in MDR and PDR C. auris in response to antifungal drug lethality without deleterious fitness costs.

microbiology↗

bioRxiv2024

Genomic epidemiology of Candida auris introduction and outbreaks in the United Kingdom

BackgroundCandida auris is a globally emerging fungal pathogen that causes nosocomial invasive infections, particularly in intensive care units (ICU). Four prominent genetic clades originating from distinct geographic regions have been identified: South Asia (Clade I), East Asia (Clade II), Africa (Clade III) and South America (Clade IV) with each clade presenting differing antifungal resistance profiles. We aimed to elucidate the epidemiology of this infection in the United Kingdom (UK) 2014 - 2019 using genomic approaches. MethodsGenome sequences from 24 isolates from six patients in four London hospitals were combined with genome sequences from 183 additional outbreak isolates from nine UK hospitals. These data were used to assess the numbers and timings of C. auris lineage introductions into the UK and to infer subsequent patterns of inter- and intra-hospital transmission. FindingsWe found evidence for at least three introductions of C. auris into the UK, one from Clade I and one from Clade III. The evolutionary rate of C. auris Clade I and Clade III were estimated at 2.764 x 10-4 and 3.186 x 10-4 substitutions per polymorphic site per year, respectively, with entry into the UK as 2013 and 2016 for Clades I and III respectively. We observed temporal and geographical evidence for multiple transmission events between hospitals and identified local within-hospital patient-to-patient transmission events. InterpretationThese data confirm that C. auris is a newly emerged infection in the UK with at least three original introductions into this country. Our analysis shows that hospital outbreaks are linked and confirms that transmission amongst patients has occurred, explaining local hospital outbreaks. Our findings argue that enhanced surveillance of C. auris infection within the UK is necessary in order to protect healthcare and to curtail expansion of this emerging infection. FundingThis work was supported by a Wellcome Trust Institutional Strategic Support Fund Springboard Fellowship, and by the Medical Research Council (MR/R015600/1), the Natural Environment Research Council (NE/P001165/1) and the Wellcome Trust (219551/Z/19/Z). Research in contextSince its first description in 2009, Candida auris has spread across the globe. For this study, authors considered all publications describing whole genome sequences of isolates within the UK up until 2020 to assess the genomic epidemiology of this fungal pathogen. This study adds value to the current understanding of C. auris epidemiology by undertaking the first analysis to assess transmission between and within hospitals using genomic data. We also provide the first in-depth temporal analysis to estimate likely times of introduction into the UK. These results have clinical implications, encouraging hospitals to identify yeast upon admission and to assess multiple isolates from single patients, which may harbour much diversity in terms of genetics and drug resistance.

genomics↗

bioRxiv2023

Optimal investments in private land conservation depend more on landholder preferences than climate change

Effective private land conservation strategies that consider both landholder preferences and future climatic conditions are critical for preserving biodiversity and ecosystem services. Yet, the interaction and relative importance of these factors for conservation planning performance is unknown. Here, we assess the importance of considering landholder preferences and climate change for prioritising locations for conservation tenders to recruit landholders for conservation covenants. To achieve this we develop a planning framework that accounts for the tender process to optimise investment across regions and apply it to koala-focused tenders in New South Wales (NSW), Australia, exploring four planning approaches that consider or are ignorant to landholder preferences and the tender process and/or climate change. We find that optimal investments depend more on landholder preferences than climate change, and when landholder preferences are ignored, there is little benefit in accounting for climate change. Our analysis reveals new insights into this important interaction.

ecology↗

bioRxiv2023

Determining the microbial species content in tissue from Alzheimer's and Parkinson's Disease patients

The aetiology of Alzheimers disease (AD) and Parkinsons Disease (PD) are unknown and tend to manifest at a later stage in life; even though these diseases have different pathogenic mechanisms, they are both characterized by neuroinflammation in the brain. Links between bacterial and viral infection and AD/PD has been suggested in several studies, however, few have attempted to establish a link between fungal infection and AD/PD. In this study we develop and describe a nanopore-based sequencing approach to characterise the presence or absence of fungi in both human brain tissue and cerebrospinal fluid (CSF). This approach detects fungal DNA in human brain and CSF samples even at low levels, whereas our quantitative polymerase chain reaction (qPCR) assay (FungiQuant) was unable to detect fungal DNA in the same samples. Comparison against kit-controls showed ubiquitous low-level fungal contamination that we observed in healthy human brains and CSF as well AD/PD brains and CSF. We use this technique to demonstrate the presence of fungal DNA in healthy human brains as well as AD/PD brains, with Alternaria spp., Colletotrichum graminicola, and Filobasidium floriforme as the most prominent species. In addition, antibiotic resistant Pseudomonas spp. was identified within the brain of an AD patient. Our method will be broadly applicable to investigating potential links between microbial infection and AD/PD.

microbiology↗

bioRxiv2023

Genomic epidemiology of European Aspergillus fumigatus causing COVID-19-associated pulmonary aspergillosis in Europe

The opportunistic fungus Aspergillus fumigatus has been found to cause coinfections in patients with severe SARS-CoV-2 virus infection, leading to COVID-19-associated pulmonary aspergillosis (CAPA). The CAPA all-cause mortality rate is approximately 50% and may be complicated by azole-resistance. Genomic epidemiology can help shed light on the genetics of A. fumigatus causing CAPA including the prevalence of alleles that are associated with azole-resistance. Here, a population genomic analysis of 21 CAPA isolates from four European countries is presented. The CAPA isolates were compared with A. fumigatus from a wider population of 167 non-CAPA clinical isolates and 73 environmental isolates. Bioinformatic analysis and antifungal susceptibility testing were performed to quantify resistance and identify possible genetically-encoded azole-resistant mechanisms. Phylogenetic analysis of the 21 CAPA isolates showed a lack of genetic distinction from the wider A. fumigatus population, with isolates distributed within two distinct clades (A and B), with the majority of the CAPA isolates in clade B (71.4%). The prevalence of phenotypic azole-resistance in CAPA was 14.3% (n=3/21); all three CAPA isolates contained a known resistance-associated cyp51A polymorphism. CAPA isolates are drawn from the wider A. fumigatus population rather than forming a unique genetic background showing that COVID-19 patients are susceptible to the entire A. fumigatus population. However, the relatively high prevalence of azole-resistance alleles that we document poses a threat to treatment success rates, warranting enhanced detection and surveillance of A. fumigatus genotypes in these patients. Furthermore, potential changes to antifungal first-line treatment guidelines may be needed to improve patient outcomes.

microbiology↗