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Single nucleotide polymorphisms are associated with strain-specific virulence differences among clinical isolates of Cryptococcus neoformans
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Single nucleotide polymorphisms are associated with strain-specific virulence differences among clinical isolates of Cryptococcus neoformans
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Journal Article
Single nucleotide polymorphisms are associated with strain-specific virulence differences among clinical isolates of Cryptococcus neoformans
2024
Overview
Studies across various pathogens highlight the importance of pathogen genetic differences in disease manifestation. In the human fungal pathogen
Cryptococcus neoformans
, sequence type (ST) associates with patient outcome. We performed a meta-analysis of four genomic studies and identified overlapping gene regions associated with virulence, suggesting the importance of these gene regions in cryptococcal disease in diverse clinical isolates. We explored the relationship between virulence and strain genetic differences using the cryptococcosis mouse model and a closely related library of ST93 clinical isolates. We identified four in vivo virulence phenotypes: hypervirulence, typical virulence with CNS disease, typical virulence with non-CNS disease, and latent disease. Hypervirulent isolates were clade specific and associated with an interferon gamma (IFNγ) dominated immune response. Using a genome wide association study (GWAS), we identified nine genes with polymorphisms associated with IFNγ production, including the inositol sensor
ITR4
. The
itr4Δ
mutant recapitulated the hypervirulence phenotype and
ITR4
affects expression of two IFNγ associated genes. Finally, we showed that IFNγ production is associated with SNPs that downregulate
ITR4
and with SNP accumulation in other IFNγ associated genes. These data highlight the complex role of pathogen genetics in virulence and identify genes associated with hypervirulence and IFNγ in
Cryptococcus neoformans
.
Identification of virulence-associated genes in pathogens is important to understand mechanisms of disease. Here, Jackson et al. use a mouse model and clinical isolates of
Cryptococcus neoformans
to identify novel gene networks that impact virulence.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 38/22
/ 38/23
/ 38/39
/ 38/43
/ 38/91
/ 64/60
/ Animals
/ Cryptococcosis - microbiology
/ Cryptococcus neoformans - genetics
/ Cryptococcus neoformans - isolation & purification
/ Cryptococcus neoformans - pathogenicity
/ Fungal Proteins - metabolism
/ Fungi
/ Gene Expression Regulation, Fungal
/ Genes
/ Genetics
/ Genome-wide association studies
/ Genome-Wide Association Study
/ Humanities and Social Sciences
/ Humans
/ Inositol
/ Mice
/ Polymorphism, Single Nucleotide
/ Science
