Characterization of Aspergillus fumigatus Isolates from Air and Surfaces of the International Space Station

Knox, Benjamin P.; Blachowicz, Adriana; Palmer, Jonathan M.; Romsdahl, Jillian; Huttenlocher, Anna; Wang, Clay C. C.; Keller, Nancy P.; Venkateswaran, Kasthuri

doi:10.1128/msphere.00227-16

Cited by 97 publications

(111 citation statements)

References 61 publications

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“…Nucleotide variant analysis of our four isolates, identified a total number of variations ranging from 48,590 to 68,352 compared to reference strain Af293. This range fits in the genetic diversity for A. fumigatus reported previously and determined in 95 sequences ranging from 36 - 72,000 SNPs (16). The large number of identified variants and differences in the genome structure displays a broad genetic diversity in the studied isolates.…”

Section: Discussionsupporting

confidence: 87%

“…Some experimental infection studies have reported clinical isolates to be more virulent than environmental isolates (13–15). Moreover, two environmental isolates retrieved from an International Space Station were more virulent than the experimental strains Af293 and CEA10 (16). Additionally, an in-host study that analyzed the microevolution of 13 isogenic isolates of A. fumigatus obtained from the same patient over a period of 2 years, reported both increases and decreases in virulence among the isolates (17).…”

Section: Introductionmentioning

confidence: 99%

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Revealing virulence potential of clinical and environmental Aspergillus fumigatus isolates using Whole-genome sequencing

Puértolas-Balint

Rossen

Santos

et al. 2019

Preprint

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39Aspergillus fumigatus is an opportunistic airborne pathogen and the most common causative 40 agent of human fungal infections. A restricted number of virulence factors have been 41 described but none of them lead to a differentiation of the virulence level among different 42 strains. In this study, we analyzed the whole-genome sequence of a set of A. fumigatus isolates 43 from clinical and environmental origin to compare their genomes and to determine their 44 virulence profiles. For this purpose, a database containing 244 genes known to be associated 45 with virulence was built. The genes were classified according to their biological function into 46 factors involved in thermotolerance, resistance to immune responses, cell wall structure, 47 toxins and secondary metabolites, allergens, nutrient uptake and signaling and regulation. No 48 difference in virulence profiles was found between clinical isolates causing an infection and a 49 colonizing clinical isolate, nor between isolates from clinical and environmental origin. We 50 observed the presence of genetic repetitive elements located next to virulence related gene 51 groups, which could potentially influence their regulation. In conclusion, our genomic analysis 52 reveals that A. fumigatus, independently of their source of isolation, are potentially pathogenic 53 at the genomic level, which may lead to fatal infections in vulnerable patients. However, other 54 determinants such as genetic variations in virulence related genes and host-pathogen 55 interactions most likely influence A. fumigatus pathogenicity and further studies should be 56 performed. 57 58 Importance 59 Aspergillus spp. infections are among the most clinically relevant fungal infections also 60 presenting treatment difficulties due to increasing antifungal resistance. The lack of key 61 virulence factors and a broad genomic diversity complicates the development of targeted 62 diagnosis and novel treatment strategies. A widely spread variability in virulence has been 63 reported for experimental, clinical and environmental isolates. Here we provide supporting 64 evidence that members of this species are fully capable of establishing an infection in 65 immunosuppressed hosts according to their virulence content at the genomic level. Due to the 66 possible clinical complications, studies are urgently required linking strain's virulent 67 phenotype with the genotype to better understand the virulence activation of this important 68 fungal pathogen. 69 70 71 Results 131Virulence related genes screening showed that all A. fumigatus isolates included in this 132 study are potentially pathogenic. The genome sequences of nine A. fumigatus isolates 133 (Table 1) were screened for the presence of particular VRGs using our in-house database (see 134 Table S2). We identified the presence of all 244 VRGs (>90% coverage and >90% identity) in 135 the genome of seven isolates P1MR, P1MS, P2CS, Af293, 12-7505054, 08-19-02-30 and 08-19-136 02-46. In addition, 243 genes were present in the genomes of B5233 ...

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Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Revealing virulence potential of clinical and environmental Aspergillus fumigatus isolates using Whole-genome sequencing

Puértolas-Balint

Rossen

Santos

et al. 2019

Preprint

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“…We analyzed the genomes of 66 globally distributed strains of Aspergillus fumigatus for polymorphisms in SM gene clusters. We performed whole-genome sequencing on 8 strains, and collected the remaining 58 strains from publicly available databases including NCBI Genome and NCBI Short Read Archive (Figure 1, (Table S1) [28–32]. All publicly available strains of A. fumigatus with sequencing data passing quality thresholds (see Methods) or with assembled genomes were included in our analysis.…”

Section: Resultsmentioning

confidence: 99%

“…The strains used included both environmental and clinical strains and were isolated from multiple continents. Genome assemblies for 10 of these strains, including the Af293 and A1163 reference strains, were available for download from GenBank [28–32,70]. For 6 of these strains, short read sequences were also available from the NCBI Short Read Archive (SRA), which were used for variant discovery only (see Single nucleotide variant (SNV) and indel discovery) and not for genome assembly.…”

Section: Methodsmentioning

confidence: 99%

Drivers of genetic diversity in secondary metabolic gene clusters within a fungal species

Lind

Wisecaver

Lameiras

et al. 2017

Preprint

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SummaryFilamentous fungi produce a diverse array of secondary metabolites (SMs) critical for defense, virulence, and communication. The metabolic pathways that produce SMs are found in contiguous gene clusters in fungal genomes, an atypical arrangement for metabolic pathways in other eukaryotes. Comparative studies of filamentous fungal species have shown that SM gene clusters are often either highly divergent or uniquely present in one or a handful of species, hampering efforts to determine the genetic basis and evolutionary drivers of SM gene cluster divergence. Here we examined SM variation in 66 cosmopolitan strains of a single species, the opportunistic human pathogen Aspergillus fumigatus. Investigation of genome-wide within-species variation revealed five general types of variation in SM gene clusters: non-functional gene polymorphisms, gene gain and loss polymorphisms, whole cluster gain and loss polymorphisms, allelic polymorphisms where different alleles corresponded to distinct, non-homologous clusters, and location polymorphisms in which a cluster was found to differ in its genomic location across strains. These polymorphisms affect the function of representative A. fumigatus SM gene clusters, such as those involved in the production of gliotoxin, fumigaclavine, and helvolic acid, as well as the function of clusters with undefined products. In addition to enabling the identification of polymorphisms whose detection requires extensive genome-wide synteny conservation (e.g., mobile gene clusters and non-homologous cluster alleles), our approach also implicated multiple underlying genetic drivers, including point mutations, recombination, genomic deletion and insertion events, as well as horizontal gene transfer from distant fungi. Finally, most of the variants that we uncover within A. fumigatus have been previously hypothesized to contribute to SM gene cluster diversity across entire fungal classes and phyla. We suggest that the drivers of genetic diversity operating within a fungal species shown here are sufficient to explain SM cluster macroevolutionary patterns.

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“…These results are in agreement with studies in A. fumigatus that have described great strain heterogeneity in traits such as growth, fitness and enzyme secretion between different environmental and clinical isolates (24, 37). Indeed, the number of SNPs, obtained during strain pairwise comparison, in the genomes of different A. fumigatus strains, range between ~13,500 (24) and ~50,000 (38, 39). Strain heterogeneity has therefore mainly been investigated in environmental and clinical isolates of A. fumigatus, whereas similar studies have not been carried out for A. nidulans isolates.…”

Section: Resultsmentioning

confidence: 99%

Functional characterization of clinical isolates of the opportunistic fungal pathogenAspergillus nidulans

Bastos

Valero²,

Silva³

et al. 2020

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AbstractAspergillus nidulans is an opportunistic fungal pathogen in patients with immunodeficiency and virulence of A. nidulans isolates has mainly been studied in the context of the chronic granulomatous disease (CGD), with characterization of clinical isolates obtained from non-CGD patients remaining elusive. This study therefore carried out a detailed biological characterization of two A. nidulans clinical isolates (CIs), obtained from a patient with breast carcinoma and pneumonia and from a patient with cystic fibrosis that underwent lung transplantation, and compared them to the reference, non-clinical A4 strain. Both CIs presented increased growth in comparison to the reference strain in the presence of physiologically-relevant carbon sources. Metabolomic analyses showed that the three strains are metabolically very different from each other in these carbon sources. Furthermore, the CIs were highly susceptible to cell wall perturbing agents but not to other physiologically-relevant stresses. Genome analyses identified several frame-shift variants in genes encoding cell wall integrity (CWI) signalling components. Significant differences in CWI signalling were confirmed by western blotting among the three strains. In vivo virulence studies using several different models revealed that strain MO80069 had significantly higher virulence in hosts with impaired neutrophil function when compared to the other strains. In summary, this study presents detailed biological characterization of two A. nidulans sensu stricto clinical isolates. Just like in A. fumigatus, strain heterogeneity exists in A. nidulans clinical strains that can define virulence traits. Further studies are required to fully characterize A. nidulans strain-specific virulence traits and pathogenicity.ImportanceImmunocompromised patients are susceptible to infections with opportunistic filamentous fungi from the genus Aspergillus. Although A. fumigatus is the main etiological agent of Aspergillus spp.-related infections, other species, such as A. nidulans are prevalent in a condition-specific manner. A. nidulans is a predominant infective agent in patients suffering from chronic granulomatous disease (CGD). A. nidulans isolates have mainly been studied in the context of CGD, although infection with A. nidulans also occurs in non-CGD patients. This study carried out a detailed biological characterization of two non-CGD A. nidulans clinical isolates and compared it to a reference strain. Phenotypic, metabolomic and genomic analyses highlight fundamental differences in carbon source utilization, stress responses and maintenance of cell wall integrity among the strains. One clinical strain had increased virulence in models with impaired neutrophil function. Just as in A. fumigatus, strain heterogeneity exists in A. nidulans clinical strains that can define virulence traits.

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Characterization of Aspergillus fumigatus Isolates from Air and Surfaces of the International Space Station

Cited by 97 publications

References 61 publications

Revealing virulence potential of clinical and environmental Aspergillus fumigatus isolates using Whole-genome sequencing

Revealing virulence potential of clinical and environmental Aspergillus fumigatus isolates using Whole-genome sequencing

Drivers of genetic diversity in secondary metabolic gene clusters within a fungal species

Functional characterization of clinical isolates of the opportunistic fungal pathogenAspergillus nidulans

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