Brain-infiltrating CD4 T cells drive inflammatory microglia proliferation during cryptococcal meningitis in mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE262502 | GEO | 2025/03/01
REPOSITORIES: GEO
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Project description:Cryptococcus neoformans is a major cause of fungal meningitis in immunocompromised individuals worldwide. Studies have categorized the transcriptome of Cryptococcus under various stresses, such as temperature, nitric oxide, iron, antifungal drugs and macrophages. However, an accurate and comprehensive transcriptome profiling of C. neoformans in the human host may allow an even better understanding of its survival and disease production. In this study, we isolated RNA from yeast cells taken directly from CSF of two individuals with cryptococcal meningitis. RNA-Seq was used to generate and compare transcriptional profiles from those yeast cells exposed to three environmental conditions. Under same conditions, similar expression patterns were found between the two strains with different genotypes. Yeast cells from in vivo CSF appear to be more metabolically active compared to those exposed to ex vivo CSF. Moreover, genes that were identified as significantly up-regulated in both ex vivo CSF and in vivo CSF conditions compared with growth in YPD appear to be important for the virulence of Cryptococcus. In the central nervous system, differentially expressed genes, single nucleotide variants and novel genes between strains were identified to emphasize that strains have consensus expression patterns but they do have their unique features. Genes with transporter functions were found to be enriched in the regulated transcripts demonstrating this important function of yeasts under host stress. These findings provide the platform for further interrogation into how this yeast survives in humans to provide identification of possible antifungal target(s) and/or genetic signatures to predict outcome. Examination of mRNA expression levels under three different conditions of two different strains with different genotypes
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Project description:Cryptococcus neoformans is a fungal pathogen responsible for hundreds of thousands of deaths per year. Its critical virulence factor is a polysacharride capsule which grows large upon entry into a mammalian host. We previously identified USV101 as a transcription factor whose deletion results in enlarged capsules. Here, we characterize strains lacking or overexpressing USV101 in terms of their virulence-related phenotypes, the altered course of infection by them and immune response to them in a mouse model, the relationship of Usv101 to other transcription factors involved in capsule regulation, and the changes in Usv101 activity during capsule induction. To study the function of Usv101, a key C. neoformans regulator of virulence, and its interactions with downstream capsule-regulating TFs GAT201 and SP1, expression profiles were generated by RNA-seq of a usv101 deletion mutant, a USV101 overexpression mutant, strains expressing GAT201 under various promoters, various double mutants, and wildtype cells grown in a capsule non-inducing condition, a capsule inducing condition for 90 minutes, or a capsule inducing condition for 24 hours.
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