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The human host comprises a range of specific niche environments. In order to successfully persist, pathogens such as Aspergillus fumigatus must adapt to these environments. One key example of in-host adaptation is the development of resistance to azole antifungals. Azole resistance in A. fumigatus is increasingly reported worldwide and the most commonly reported mechanisms are cyp51A mediated. Using a unique series of A. fumigatus isolates, obtained from a patient suffering from persistent and recurrent invasive aspergillosis over 2 years, this study aimed to gain insight into the genetic basis of in-host adaptation. Single nucleotide polymorphisms (SNPs) unique to a single isolate in this series, which had developed multi-azole resistance in-host, were identified. Two nonsense SNPs were recreated using CRISPR-Cas9; these were 213* in svf1 and 167* in uncharacterised gene AFUA_7G01960. Phenotypic analyses including antifungal susceptibility testing, mycelial growth rate assessment, lipidomics analysis and statin susceptibility testing were performed to associate genotypes to phenotypes. This revealed a role for svf1 in A. fumigatus oxidative stress sensitivity. In contrast, recapitulation of 167* in AFUA_7G01960 resulted in increased itraconazole resistance. Comprehensive lipidomics analysis revealed decreased ergosterol levels in strains containing this SNP, providing insight to the observed itraconazole resistance. Decreases in ergosterol levels were reflected in increased resistance to lovastatin and nystatin. Importantly, this study has identified a SNP in an uncharacterised gene playing a role in azole resistance via a non-cyp51A mediated resistance mechanism. This mechanism is of clinical importance, as this SNP was identified in a clinical isolate, which acquired azole resistance in-host.
Pubmed ID: 31128273 RIS Download
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Database of genetic and molecular biological information about the filamentous fungi of the genus Aspergillus including information about genes and proteins of Aspergillus nidulans and Aspergillus fumigatus; descriptions and classifications of their biological roles, molecular functions, and subcellular localizations; gene, protein, and chromosome sequence information; tools for analysis and comparison of sequences; and links to literature information; as well as a multispecies comparative genomics browser tool (Sybil) for exploration of orthology and synteny across multiple sequenced Sgenus species. Also available are Gene Ontology (GO) and community resources. Based on the Candida Genome Database, the Aspergillus Genome Database is a resource for genomic sequence data and gene and protein information for Aspergilli. Among its many species, the genus contains an excellent model organism (A. nidulans, or its teleomorph Emericella nidulans), an important pathogen of the immunocompromised (A. fumigatus), an agriculturally important toxin producer (A. flavus), and two species used in industrial processes (A. niger and A. oryzae). Search options allow you to: *Search AspGD database using keywords. *Find chromosomal features that match specific properties or annotations. *Find AspGD web pages using keywords located on the page. *Find information on one gene from many databases. *Search for keywords related to a phenotype (e.g., conidiation), an allele (such as veA1), or an experimental condition (e.g., light). Analysis and Tools allow you to: *Find similarities between a sequence of interest and Aspergillus DNA or protein sequences. *Display and analyze an Aspergillus sequence (or other sequence) in many ways. *Navigate the chromosomes set. View nucleotide and protein sequence. *Find short DNA/protein sequence matches in Aspergillus. *Design sequencing and PCR primers for Aspergillus or other input sequences. *Display the restriction map for a Aspergillus or other input sequence. *Find similarities between a sequence of interest and fungal nucleotide or protein sequences. AspGD welcomes data submissions.
View all literature mentionsCollection of data of protein sequence and functional information. Resource for protein sequence and annotation data. Consortium for preservation of the UniProt databases: UniProt Knowledgebase (UniProtKB), UniProt Reference Clusters (UniRef), and UniProt Archive (UniParc), UniProt Proteomes. Collaboration between European Bioinformatics Institute (EMBL-EBI), SIB Swiss Institute of Bioinformatics and Protein Information Resource. Swiss-Prot is a curated subset of UniProtKB.
View all literature mentionsAn online resource which helps researchers manage and organize labs and experimental results by supplying molecular biology software tools for experimental design and data analysis. Benchling provides tools for functions such as primer design and colony counting as well as CRISPR guide design and automated Gibson and Golden Gate cloning. Users can take notes in line with data, link data across entries, keep files and data in one place, and manage and keep track of team progress. An enterprise version of Benchling is available for scientists working within an organization with additional administrative, compliance, and security protocols.
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