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Single nucleotide polymorphisms are associated with strain-specific virulence differences among clinical isolates of Cryptococcus neoformans

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dc.contributor.authorJackson, Katrina M.en
dc.contributor.authorKono, Thomasen
dc.contributor.authorBetancourt, Jovany J.en
dc.contributor.authorWang, Yinaen
dc.contributor.authorKabbale, Kisakye D.en
dc.contributor.authorDing, Minnaen
dc.contributor.authorKezh, Perryen
dc.contributor.authorHa, Graceen
dc.contributor.authorYoder, J. Marinaen
dc.contributor.authorFulton, Sophie R.en
dc.contributor.authorMukaremera, Lilianeen
dc.contributor.authorTiffin, Peteren
dc.contributor.authorGusa, Asiyaen
dc.contributor.authorMeya, David B.en
dc.contributor.authorBillmyre, R. Blakeen
dc.contributor.authorXue, Chaoyangen
dc.contributor.authorNielsen, Kirstenen
dc.date.accessioned2024-12-16T14:43:26Zen
dc.date.available2024-12-16T14:43:26Zen
dc.date.issued2024-12-02en
dc.description.abstractStudies 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.en
dc.description.sponsorshipFunding was provided by National Institutes of Health grants F31AI148047 to KMJ, R21NS108715, R01NS118538, and R01AI134636 to KN, and R01AI123315 and R01AI155647 to CX.en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1038/s41467-024-54729-6en
dc.identifier.urihttps://hdl.handle.net/10919/123809en
dc.identifier.volume15en
dc.language.isoenen
dc.publisherNature Researchen
dc.rightsCreative Commons Attribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.titleSingle nucleotide polymorphisms are associated with strain-specific virulence differences among clinical isolates of <i>Cryptococcus neoformans</i>en
dc.title.serialNature Communicationsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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