Revealing the Virulence Potential of Clinical and Environmental Aspergillus fumigatus Isolates Using Whole-Genome Sequencing

Puértolas-Balint, Fabiola; Rossen, John W. A.; Santos, Claudy Oliveira dos; Chlebowicz, Monika A.; Raangs, Erwin; Putten, M.L. van; Sola‐Campoy, Pedro J.; Han, Li; Schmidt, Martina; García-Cobos, Silvia

doi:10.3389/fmicb.2019.01970

Cited by 21 publications

(21 citation statements)

References 49 publications

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“…Our results showed an even higher frequency of cryptic species in environmental isolates, as corroborated by Simpson index value. As already shown in several studies [ 48 , 49 , 50 , 51 ], the environment represents the major source of Aspergillus isolates causing infections. Exposure to Aspergillus may occur at home, in agricultural/animal production, at the workplace, and during periods of hospitalization, among others.…”

Section: Discussionmentioning

confidence: 89%

Trends on Aspergillus Epidemiology—Perspectives from a National Reference Laboratory Surveillance Program

Sabino

Gonçalves

Melo

et al. 2021

JoF

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Identification of Aspergillus to species level is important since sibling species may display variable susceptibilities to multiple antifungal drugs and also because correct identification contributes to improve the knowledge of epidemiological studies. Two retrospective laboratory studies were conducted on Aspergillus surveillance at the Portuguese National Mycology Reference Laboratory. The first, covering the period 2017–2018, aimed to study the molecular epidemiology of 256 Aspergillus isolates obtained from patients with respiratory, subcutaneous, or systemic infections and from environmental samples. The second, using our entire collection of clinical and environmental A. fumigatus isolates (N = 337), collected between 2012 and 2019, aimed to determine the frequency of azole-resistant A. fumigatus isolates. Aspergillus fumigatus sensu stricto was the most frequent species in both clinical and environmental samples. Overall, and considering all Aspergillus sections identified, a high frequency of cryptic species was detected, based on beta-tubulin or calmodulin sequencing (37% in clinical and 51% in environmental isolates). Regarding all Fumigati isolates recovered from 2012–2019, the frequency of cryptic species was 5.3% (18/337), with the identification of A. felis (complex), A. lentulus, A. udagawae, A. hiratsukae, and A. oerlinghauensis. To determine the frequency of azole resistance of A. fumigatus, isolates were screened for azole resistance using azole-agars, and 53 possible resistant isolates were tested by the CLSI microdilution reference method. Nine A. fumigatus sensu stricto and six Fumigati cryptic isolates showed high minimal inhibitory concentrations to itraconazole, voriconazole, and/or posaconazole. Real-time PCR to detect cyp51A mutations and sequencing of cyp51A gene and its promoter were performed. The overall frequency of resistance to azoles in A. fumigatus sensu stricto was 3.0%. With this retrospective analysis, we were able to detect one azole-resistant G54R mutant A. fumigatus environmental isolate, collected in 2015. The TR34/L98H mutation, linked to environmental transmission route of azole resistance, was the most frequently detected mutation (N = 4; 1.4%). Our findings underline the demand for correct identification and susceptibility testing of Aspergillus isolates.

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Section: Discussionmentioning

confidence: 89%

Trends on Aspergillus Epidemiology—Perspectives from a National Reference Laboratory Surveillance Program

Sabino

Gonçalves

Melo

et al. 2021

JoF

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“…Several studies have previously analyzed genomic data of A. fumigatus strains (Abdolrasouli et al, 2015;Takahashi-Nakaguchi et al, 2015), uncovering cyp51A mutations in A. fumigatus populations (Abdolrasouli et al, 2015). Some studies have also used population genomic data for strains of A. fumigatus to gain insights on antifungal drug susceptibility (Garcia-Rubio et al, 2018) or virulence potential (Puértolas-Balint et al, 2019). Correlations between phenotypic traits, such as antifungal susceptibility or virulence and genetic traits have been also studied in other well-studied pathogens, such as the opportunistic yeast Candida albicans (Hirakawa et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Genomic and Phenotypic Heterogeneity of Clinical Isolates of the Human Pathogens Aspergillus fumigatus, Aspergillus lentulus, and Aspergillus fumigatiaffinis

et al. 2020

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Fungal pathogens are a global threat to human health. For example, fungi from the genus Aspergillus cause a spectrum of diseases collectively known as aspergillosis. Most of the >200,000 life-threatening aspergillosis infections per year worldwide are caused by Aspergillus fumigatus. Recently, molecular typing techniques have revealed that aspergillosis can also be caused by organisms that are phenotypically similar to A. fumigatus but genetically distinct, such as Aspergillus lentulus and Aspergillus fumigatiaffinis. Importantly, some of these so-called cryptic species are thought to exhibit different virulence and drug susceptibility profiles than A. fumigatus, however, our understanding of their biology and pathogenic potential has been stymied by the lack of genome sequences and phenotypic profiling of multiple clinical strains. To fill this gap, we phenotypically characterized the virulence and drug susceptibility of 15 clinical strains of A. fumigatus, A. lentulus, and A. fumigatiaffinis from Spain and sequenced their genomes. We found heterogeneity in drug susceptibility across species and strains. We further found heterogeneity in virulence within each species but no significant differences in the virulence profiles between the three species. Genes known to influence drug susceptibility (cyp51A and fks1) vary in paralog number and sequence among these species and strains and correlate with differences in drug susceptibility. Similarly, genes known to be important for virulence in A. fumigatus showed variability in number of paralogs across strains and across species. Characterization of the genomic similarities and differences of clinical strains of A. lentulus, A. fumigatiaffinis, and A. fumigatus that vary in disease-relevant traits will advance our understanding of the variance in pathogenicity between Aspergillus species and strains that are collectively responsible for the vast majority of aspergillosis infections in humans.

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“…Our analysis above focused only on SCOs; therefore, many secretory, membrane proteion coding genes and virulence associcated genes were involuntarily excluded by this criterion. To overcome this limitation, we collected multi-gene families from the literature (Puertolas-Balint, et al 2019;Vivek-Ananth, et al 2018) and analysed the positive selection for these genes. We focused on virulence associated genes in multi-gene families.…”

Section: Positive Selection In a Fumigatus In Multi-gene Familiesmentioning

confidence: 99%

“…See Table S9for the complete list of PSGs in multi-gene family secretory, membrane protein coding genes and virulence associated genes (as defined byPuertolas-Balint, et al 2019).…”

mentioning

confidence: 99%

Aspergillus fumigatusversus GenusAspergillus: Conservation, adaptive evolution and specific virulence genes

Gupta¹,

Srivastava²,

Osmanoğlu³

et al. 2020

Preprint

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Aspergillus is an important fungal genus containing economically important species, as well as pathogenic species of animals and plants. Using eighteen fungal species of the genus Aspergillus, we conducted a comprehensive investigation of conserved genes and their evolution. This also allows to investigate the selection pressure driving the adaptive evolution in the pathogenic species A. fumigatus. Among single-copy orthologs (SCOs) for A. fumigatus and the closely related species A. fischeri, we identified 122 versus 50 positively selected genes (PSGs), respectively. Moreover, twenty conserved genes of unknown function were established to be clearly positively selected and thus important for adaption. A. fumigatus PSGs interacting with human host proteins show over-representation of adaptive, symbiosis-related, immunomodulatory, and virulence related pathways such as the TGF-β pathway, insulin receptor signaling, IL1 pathway and interfering with phagosomal of GTPase signaling. Additionally, among the virulence factor coding genes, secretory and membrane protein coding genes in multi-copy gene families, 212 genes underwent positive selection and also suggest increased adaptation such as fungal immune evasion mechanisms (aspf2), siderophore biosynthesis (sidD), fumarylalanine production (sidE), stress tolerance (atfA) and thermotolerance (sodA). These genes presumably contribute to host adaptation strategies. Genes for the biosynthesis of gliotoxin are shared among all the close relatives of A. fumigatus as ancient defense mechanism. Positive selection plays a crucial role in the adaptive evolution of A. fumigatus. The genome-wide profile of PSGs provides valuable targets for further research on the mechanisms of immune evasion, for antimycotic targeting and understanding fundamental processes of virulence.

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Revealing the Virulence Potential of Clinical and Environmental Aspergillus fumigatus Isolates Using Whole-Genome Sequencing

Cited by 21 publications

References 49 publications

Trends on Aspergillus Epidemiology—Perspectives from a National Reference Laboratory Surveillance Program

Trends on Aspergillus Epidemiology—Perspectives from a National Reference Laboratory Surveillance Program

Genomic and Phenotypic Heterogeneity of Clinical Isolates of the Human Pathogens Aspergillus fumigatus, Aspergillus lentulus, and Aspergillus fumigatiaffinis

Aspergillus fumigatusversus GenusAspergillus: Conservation, adaptive evolution and specific virulence genes

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