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The transcription factor Pdr802 regulates Titan cell production and Cryptococcus neoformans pathogenicity (RNA-Seq)

ABSTRACT: We report on our study the role of C. neoformans transcription factor Pdr802, whose expression is highly induced under host-like conditions in vitro and is critical for C. neoformans dissemination and virulence in a mouse model of infection. We found that direct targets of Pdr802 include the calcineurin targets Had1 and Pmc1, which are important for C. neoformans virulence, the transcription factor Bzp4, which promotes cryptococcal melanization and capsule thickness, and 35 transmembrane transporters. Notably, a strain engineered to lack Pdr802 showed a dramatically increased population of Titan cells. Since Titan cells are not phagocyted and do not disseminate via the Trojan horse mechanism or via penetration of biological barriers, this likely explains the reduced dissemination of pdr802 cells to the central nervous system and consequently reduced pathogenicity of this strain. The role of Pdr802 as a negative regulator of titanisation is thus critical for cryptococcal virulence.

ORGANISM(S): Cryptococcus neoformans

PROVIDER: GSE162851 | GEO | 2021/02/16

REPOSITORIES: GEO

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The transcription factor Pdr802 regulates Titan cell production and Cryptococcus neoformans pathogenicity

Project description:We report on our study the role of C. neoformans transcription factor Pdr802, whose expression is highly induced under host-like conditions in vitro and is critical for C. neoformans dissemination and virulence in a mouse model of infection. We found that direct targets of Pdr802 include the calcineurin targets Had1 and Pmc1, which are important for C. neoformans virulence, the transcription factor Bzp4, which promotes cryptococcal melanization and capsule thickness, and 35 transmembrane transporters. Notably, a strain engineered to lack Pdr802 showed a dramatically increased population of Titan cells. Since Titan cells are not phagocyted and do not disseminate via the Trojan horse mechanism or via penetration of biological barriers, this likely explains the reduced dissemination of pdr802 cells to the central nervous system and consequently reduced pathogenicity of this strain. The role of Pdr802 as a negative regulator of titanisation is thus critical for cryptococcal virulence.

2021-02-16 | GSE153134 | GEO

Amoeba Predation of Cryptococcus: A Quantitative and Population Genomic Evaluation of the Accidental Pathogen Hypothesis

Project description:The “Amoeboid Predator-Fungal Animal Virulence Hypothesis” posits that interactions with environmental phagocytes shape the evolution of virulence traits in fungal pathogens. In this hypothesis, selection to avoid predation by amoeba inadvertently selects for traits that contribute to fungal escape from phagocytic immune cells. Here, we investigate this hypothesis in the human fungalpathogens Cryptococcus neoformans and Cryptococcus deneoformans. Applying quantitative trait locus (QTL) mapping and comparative genomics, we discovered a cross-species QTL region that is responsible for variation in resistance to amoeba predation. In C. neoformans, this same QTL was found to have pleiotropic effects on melanization, an established virulence factor. Through fine mapping and population genomic comparisons, we identified the gene encoding the transcription factor BZP4 that underlies this pleiotropic QTL and we show that decreased expression of this gene reduces melanization and increases susceptibility to amoeba predation. Despite the joint effects of BZP4 on amoeba resistance and melanin production, we find no relationship between BZP4 genotype and escape from macrophages or virulence in murine models of disease. Our findings provide new perspectives on how microbial ecology shapes the genetic architecture of fungal virulence, and suggests the need for more nuanced models for the evolution of pathogenesis that account for the complexities of both microbe-microbe and microbe-host interactions.

2023-07-25 | GSE238170 | GEO

Transcriptomic profiling of the Cryptococcus neoformans transition to titan-like cells

Project description:We compared the expression profile of titan-like cells with cells of regular size in C. neoformans. This was investigated at different time points of the transition: 7 and 24 h

2018-04-20 | GSE111400 | GEO

Differential and cooperative effects of IL-25 and IL-33 on T helper cells contribute to cryptococcal virulence and brain infection

Project description:Cryptococcal disease pathogenesis is associated with the induction of type 2 immune response which is largely mediated by adaptive T helper cells. Recently, epithelial cell-derived IL-33 and IL-25 are recognized as key mediators in driving pathogenic type 2 inflammation during C. neoformans infection. Although IL-25 and IL-33 exhibit a combinatorial and closely related function, the differential effect of these cytokines in the regulation of host immune response against C. neoformans infection is still elusive. We observed a predominantly increase of IL-25/IL-33 responsive Th cells within the lung after infection, especially at the chronic infection phase. The ex vivo stimulation of cryptococcal-specific Th cells demonstrated combinatorial effect of IL-25 and IL-33 in promoting the production of type 2 cytokines. A comparative transcriptomic analysis revealed coordinatel effects of these cytokines in promoting activation, survival, and homeostasis of adaptive Th cells during C. neoformans infection. The expression of type 2 cytokines and chemokine was absent in Th cells of Il17rb-/- mice, indicating the requirement of IL-25-mediated Th2-type immune responses during C. neoformans infection. Further analysis of the degree of virulence indicated a positive correlation between the frequency of IL-17RB/ST2-expressing Th cells and cryptococcal brain dissemination in vivo.

2023-06-18 | GSE229703 | GEO

Arginase 1 expression by macrophages promotes Cryptococcus neoformans proliferation and invasion into brain microvascular endothelial cells.

Project description:Cryptococcal meningoencephalitis caused by C. neoformans infection is the most common cause of death in HIV/AIDS patients. Macrophages are recognized as key players in promoting the growth, proliferation, and dissemination of Cryptococcus. However, macrophage-derived factors that underlie these pathogenic responses remain unclear. Thus, the aim of this study is to investigate the permissive factors of macrophages that support the pathogenicity of Cryptococcus infection. We generated mRNA expression profiles of alveolar macrophage isolated from BALB/c mice intranasally treated with PBS or infected with C. neoformans H99 at 7 and 14 days postinfection and performed a comparative transcriptomic analysis to investigate the transcriptomic changes of macrophages during infection. Alveolar macrophages isolated from C. neoformans-infected mice showed dynamic gene expression patterns which were altered from a protective M1-like cells to a pathogenic M2-like phenotype. Interestingly, Arg1, encoded for enzyme arginase-1, was a predominant up-regulated gene observed in alveolar macrophages after infection at 14 days and the activation of macrophage arginase activity is required for the development of M2 macrophages that supports cryptococcal growth, proliferation, and dissemination.

2022-11-30 | GSE214001 | GEO

Differentiated protein extracts from freshwater and terrestrial mollusks inhibit virulence factor production in Cryptococcus neoformans

Project description:Cryptococcus neoformans is a fungal pathogen responsible for an increased mortality among immunocompromised individuals. Long antifungal therapies to treat cryptococcal infections have compounded the occurrence of resistant strains that threaten the efficacy of current treatments. In this senseDue to resistance mechanisms, discovery of compounds that inhibit virulence factors, rather than kill the fungus, have emerged as potential new strategies to combat infection and reduce the rate of resistance due to lower selective pressure. Invertebrates rely solely on an effective innate immune system to prevent infections, provide providing a potential one health approach for discovery of novel antifungal and antibacterial compounds. Here, we demonstrate a differentiated extraction of proteins from three mollusks (freshwater and terrestrial) and evaluate extract their effects against the growth and virulence factor production (thermotolerance, melanin, capsule, and biofilm) in C. neoformans. We show that clarified extracts of Planorbella pilsbryi have a fungicidal effect on cryptococcal cells in a comparable way to Fluconazolefluconazole. Similarly, crude and clarifiedall extracts of Cipangopaludina chinensis not only affects cryptococcal thermotolerance but also impairs biofilm and capsule production. In addition, incubation of C. neoformans with clarified extracts of Cepaea nemoralis extracts reduced capsule production. Using inhibitory activity of extracts against peptidases related with virulence factors and Quantitative quantitative proteomics arose distinct proteome signatures for each extract and proposed proteins driving the observed anti-virulence properties. Overall, this work demonstratesproves the potential of compounds derived from natural sources to inhibit virulence factor production in a clinically important fungal pathogen.

2023-03-06 | PXD038987 | Pride

Dietary intervention improves health metrics and life expectancy of the genetically obese Titan mouse

Project description:Suitable animal models are essential for translational research, especially in the case of complex, multifactorial conditions, such as obesity. The non-inbred mouse (Mus musculus) line Titan, also known as DU6, is one of the world’s longest selection experiments for high body mass and was previously described as a model for metabolic healthy (benign) obesity. The present study further characterizes the geno- and phenotypes of this non-inbred mouse line and testes its suitability as an interventional obesity model. In contrast to previous findings, our data suggest that Titan mice are metabolically unhealthy obese and short-lived. Line-specific patterns of genetic invariability are in accordance with observed phenotypic traits. Titan mice also show modifications in the liver transcriptome, proteome, and epigenome linked to metabolic (dys)regulations. Importantly, dietary intervention partially reversed the metabolic phenotype in Titan mice and significantly extended their life expectancy. Therefore, the Titan mouse line is a valuable resource for translational and interventional obesity research.

2022-05-01 | GSE150073 | GEO

Unraveling capsule biosynthesis and signaling networks in Cryptococcus neoformans

Project description:Cryptococcus neoformans is an opportunistic basidiomycete pathogen that is a major etiological agent of fungal meningoencephalitis leading to more than 180,000 deaths worldwide annually. For this pathogen, the polysaccharide capsule is a key virulence factor, which interferes with the phagocytosis by host innate immune cells, but its complex signaling networks remain elusive. In this study, we systematically analyzed capsule biosynthesis and signaling networks by using C. neoformans transcription factor (TF) and kinase mutant libraries under diverse capsule-inducing conditions, such as Dulbecco’s Modified Eagle’s (DME), Littman’s medium (LIT) and fetal bovine serum (FBS) medium. We found that deletion of GAT201, YAP1, BZP4, and ADA2 consistently causes capsule production defects in all tested media, indicating that they are capsule-regulating core TFs. Epistatic and expression analysis showed that Yap1 and Ada2 control Gat201 upstream, whereas Bzp4 and Gat201 regulate capsule production independently. We next searched for potential upstream kinases and found that mutants deleted of PKA1, BUD32, POS5, IRE1 or CDC2801 showed reduced capsule production under all three capsule induction conditions, whereas mutants deleted of HOG1 and IRK5 displayed enhanced capsule production. Notably, Pka1 and Irk5 controls induction of GAT201 and BZP4, respectively, under capsule induction condition. Finally, we monitored transcriptome profiles governed by Bzp4, Gat201, and Ada2 under capsule-inducing condition and demonstrated that these TFs regulate redundant and unique sets of downstream target genes. In conclusion, this study provides further insight into the complex regulatory mechanism of capsule production related signaling pathways in C. neoformans.

2022-10-18 | GSE208163 | GEO

Transcriptomic profiling of the Cryptococcus neoformans transition to titan-like cells

Project description:Transcriptomic profiling of the Cryptococcus neoformans transition to titan-like cells

| PRJNA436917 | ENA

Secretome profiling of Cryptococcus neoformans reveals regulation of a subset of virulence-associated proteins and potential biomarkers by protein kinase A

Project description:Background: The pathogenic yeast Cryptococcus neoformans causes life-threatening meningoencephalitis in individuals suffering from HIV/AIDS. The cyclic-AMP/protein kinase A (PKA) signal transduction pathway regulates the production of extracellular virulence factors in C. neoformans, but the influence of the pathway on the secretome has not been investigated. In this study, we performed quantitative proteomics using galactose-inducible and glucose-repressible expression of the PKA1 gene encoding the catalytic subunit of PKA to identify regulated proteins in the secretome. Results: We identified 61 secreted proteins and found that changes in PKA1 expression influenced the extracellular abundance of five proteins, including the Cig1 and Aph1 proteins with known roles in virulence. We also observed a change in the secretome profile upon induction of Pka1 from proteins primarily involved in catabolic and metabolic processes to an expanded set that included proteins for translational regulation and the response to stress. We further characterized the secretome data using enrichment analysis and by predicting conventional versus non-conventional secretion. Targeted proteomics of the Pka1-regulated proteins allowed us to identify the secreted proteins in lysates of phagocytic cells containing C. neoformans, and in samples from infected mice. This analysis also revealed that modulation of PKA1 expression influences the intracellular survival of cryptococcal cells upon phagocytosis. Conclusions: Overall, we found that the cAMP/PKA pathway regulates specific components of the secretome including proteins that affect the virulence of C. neoformans. The detection of secreted cryptococcal proteins from infected phagocytic cells and tissue samples suggests their potential utility as biomarkers of infection.

2015-10-13 | PXD002731 | Pride

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