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WT vs gcn5 mutant gene expression under capsule inducing conditions

ABSTRACT: Cryptococcus neoformans is an environmental fungus and an opportunistic human pathogen. Previous studies have demonstrated major alterations in its transcriptional profile as this microorganism enters the hostile environment of the human host. To assess the role of chromatin remodeling in host-induced transcriptional responses, we identified the C. neoformans Gcn5 histone acetyltransferase and demonstrated its function by complementation studies of Saccharomyces cerevisiae. The C. neoformans gcn5Δ mutant strain has defects in high-temperature growth and capsule attachment to the cell surface, in addition to increased sensitivity to FK506 and oxidative stress. Treatment of wild-type cells with the histone acetyltransferase inhibitor garcinol mimics cellular effects of the gcn5Δ mutation. Gcn5 regulates the expression of many genes that are important in responding to the specific environmental conditions encountered by C. neoformans inside the host. Accordingly, the gcn5Δ mutant is avirulent in animal models of cryptococcosis. Our study demonstrates the importance of chromatin remodeling by the conserved histone acetyltransferase Gcn5 in regulating the expression of specific genes that allow C. neoformans to respond appropriately to the human host.

ORGANISM(S): Cryptococcus neoformans Cryptococcus neoformans var. grubii

PROVIDER: GSE23948 | GEO | 2010/09/04

SECONDARY ACCESSION(S): PRJNA130413

REPOSITORIES: GEO

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WT vs rim101 mutant gene expression under capsule inducing conditions

Project description:Cryptococcus neoformans is a prevalent human fungal pathogen that must survive within various tissues in order to establish a human infection. We have identified the C. neoformans Rim101 transcription factor, a highly conserved pH-response regulator in many fungal species. The rim101- mutant strain displays growth defects similar to other fungal species in the presence of alkaline pH, increased salt concentrations, and iron limitation. However, the rim101- strain is also characterized by a striking defect in capsule, an important virulence-associated phenotype. This capsular defect is likely due to alterations in polysaccharide attachment to the cell surface, not in polysaccharide biosynthesis. In contrast to many other C. neoformans capsule-defective strains, the rim101- mutant is hypervirulent in animal models of cryptococcosis. Whereas Rim101 activation in other fungal species occurs through the conserved Rim pathway, we demonstrate that C. neoformans Rim101 is also activated by the cAMP/PKA pathway. We report here that C. neoformans uses PKA and the Rim pathway to regulate the localization, activation, and processing of the Rim101 transcription factor. We also demonstrate specific host- relevant activating conditions for Rim101 cleavage, showing that C. neoformans has co-opted conserved signaling pathways to respond to the specific niche within the infected host. These results establish a novel mechanism for Rim101 activation and the integration of two conserved signaling cascades in response to host environmental conditions.

2010-09-04 | GSE23929 | GEO

Isolated Iliac Cryptococcosis in an Immunocompetent Patient

Project description:Cryptococcal osteomyelitis is an infrequent infection which is usually associated with disseminated cryptococcosis or underlying immunocompromised conditions. Here we described a rare case with isolated iliac cryptococcosis in an immunocompetent patient. Through histological, microbial, and molecular biological examinations, the pathogen was finally identified as C. neoformans VNI genotype, which likely originated from environmental bird droppings. The clinical isolate was hypomelanized but fully virulent in mouse infection model. The patient displayed lower CD4+-T lymphocyte ratio, reduced serum IFN-γ and IL-12, and dysregulated transcriptional profile of blood leukocytes compare with healthy host. After surgical excision and 34 weeks’ antifungal treatment, the patient got clinical cured. Our study suggested that cryptococcosis development was closely associated with the interaction of fungal agent and host immunity. Accurate diagnosis of bone cryptococcosis depends mainly on histological and fungal examinations. A combination of antifungal agent treatment regimen and surgery were quite effective for resolving bone cryptococcosis.

2018-04-17 | GSE108534 | GEO

Immunization with a heat-killed Prm1 deletion strain protects the host from Cryptococcus neoformans infection

Project description:Systemic infection with Cryptococcus neoformans, a dangerous and contagious pathogen found throughout the world, frequently results in lethal cryptococcal pneumonia and meningoencephalitis, and no effective treatments of cryptococcosis are available. Here, we describe Prm1, a novel regulator of virulence in C. neoformans. C. neoformans prm1 cells exhibit extreme sensitivity to various environmental stress conditions. Furthermore, prm1 cells show deficiencies in the biosynthesis of chitin, chitosan, and mannoprotein, which in turn result in impairment of cell wall integrity. Treatment of mice with heat-killed prm1 cells was found to facilitate the host immunological defence against infection with wild-type C. neoformans. Further investigation demonstrated that prm1 cells strongly promote pulmonary production of interferon- and Th1 responses, leading to activation of macrophage M1 differentiation and inhibition of M2 polarization. Therefore, our findings suggest that C. neoformans Prm1 may be a viable target for the development of anti-cryptococcosis medications and, cells lacking Prm1 represent a promising candidate for a vaccine.

2023-10-11 | PXD038840 | Pride

The fungal pathogen Cryptococcus neoformans adapts to the host environment through TOR-mediated remodeling of phospholipid asymmetry

Project description:Cryptococcus spp. are environmental fungi that first must adapt to the host environment before they can cause life-threatening meningitis in immunocompromised patients. Host CO2 concentrations are 100-fold higher than the external environment and strains unable to grow at host CO2 concentrations are not pathogenic. Using a genetic screening and transcriptional profiling approach, we found that the TOR pathway is critical for C. neoformans adaptation to host CO2 partly through Ypk1-dependent remodeling of phosphatidylserine asymmetry at the plasma membrane. We also identified a C. neoformans ABC/PDR transporter (PDR9) that is highly expressed in CO2-sensitive environmental strains, suppresses CO2-induced phosphatidylserine remodeling, and increases susceptibility to host concentrations of CO2. Interestingly, regulation of plasma membrane lipid asymmetry by the TOR-Ypk1 axis is distinct in C. neoformans compared to S. cerevisiae. Finally, host CO2 concentrations suppress the C. neoformans pathways that respond to host temperature (Mpk1) and pH (Rim101), indicating that host adaptation requires a stringent balance among distinct stress responses.

2023-10-24 | GSE241788 | GEO

Nitrogen source-dependent capsule induction in human pathogenic Cryptococcus species.

Project description:Cryptococcus neoformans causes meningoencephalitis and is an increasing human health threat. C. neoformans is neurotropic, and persists in the cerebrospinal fluid (CSF) of the mammalian host during infection. In order to survive in the host, pathogenic fungi must procure nutrients such as carbon and nitrogen. To enhance our understanding of nutrient acquisition during infection by Cryptococcus species, we examined utilization of nitrogen sources available in CSF. We screened for growth and capsule production of 817 global environmental and clinical isolates on various sources of nitrogen. Capsule production was assessed using ammonium and urea in the presence or absence of benomyl to determine the relationship of urea exposure to capsule production. Since urea is metabolized to ammonia and CO2 (a known signal for capsule induction), we examined urea metabolism mutants for their response to urea regarding capsule production. Non-preferred nitrogen sources were found to greatly affect capsule production in pathogenic species of Cryptococcus. Urea induced the greatest magnitude of capsule production. Capsule induction by urea was greater in Cryptococcus gattii strains than in C. neoformans strains. In addition, both environmental and clinical strains grew robustly on uric acid, casamino acids, creatinine, and asparagine as sole nitrogen sources. While substantial growth on nitrate was not apparent at day 3, growth was apparent by day 6 for all serotypes. In this study, transcription profiles of urea pathway mutants (ure1 and amt1/2) and WT Cryptococcus neoformans strains were compared in a dye-swap experiment following 1hr exposure to proline or proline + urea (.25g/L).

2013-09-25 | E-GEOD-46829 | biostudies-arrayexpress

Nitrogen source-dependent capsule induction in human pathogenic Cryptococcus species.

2013-09-25 | GSE46829 | GEO

Deletion of Clr3 restores expression of a subset of genes in gcn5- mutant cells

Project description:Histone acetylation and deacetylation is important for gene regulation. The histone acetyltransferase, Gcn5, is a known activator of transcriptional initiation that is recruited to gene promoters. Here we map genome-wide levels of Gcn5 occupancy and histone H3K14ac at high resolution. Gcn5 is predominantly localized to coding regions of highly transcribed genes where it antagonistically collaborates with the class II histone deacetylase, Clr3, to regulate histone H3K14ac levels. Regulation of histone H3k14ac levels is critical for regulation of many genes during stress adaptation. Our findings suggest a novel role for Gcn5 during transcriptional elongation in addition to its known role in transcriptional initiation. The related data for this are GSE13790 and GSE5227 Data showed expression pattern of gcn5- vs gcn5-clr3- and clr3- vs wild type under KCl stress in S. pombe. Two biological replicates are used with dye-swap labeling.

2010-06-24 | E-GEOD-13817 | biostudies-arrayexpress

ChIP Seq analysis of the Cu metalloregulatory transcription factor Cuf1 in Cryptococcus neoformans in response to Cu availability

Project description:The essential yet toxic nature of Cu ions in living cells requires exquisite control of Cu homeostasis. The fungal pathogen C. neoformans regulates Cu homeostasis for survival during a complex host colonization process. During pulmonary infection host innate immune cells use Cu in an attempt to toxify C. neoformans, which responds by activating expression of Cu detoxifying proteins. However, during brain colonization expression of the fungal Cu import machinery is activated and required for virulence. To achieve the genetic plasticity required for adaptation to a continuum of distinct Cu environments within the host, C. neoformans utilizes the Cu-responsive transcription factor, Cuf1. Cuf1 is unique as it senses and responds to both high and low Cu environments, activating different sets of genes dependent on environmental Cu status. Cells lacking Cuf1 are compromised for colonization of the lungs and brain, highlighting Cuf1 as an important virulence factor. A genome-wide assessment of the Cuf1 binding sites in the genome of C. neoformans driven by Cu status identified novel genes required for adaptation to high and low Cu environments. These genes and their regulation provide new insights with respect to adaptive responses to changes in host Cu availability and could reveal new targets for therapeutic intervention in cryptococcosis.

2018-10-29 | GSE110120 | GEO

Chromatin Binding of Gcn5 in Drosophila is Largely Mediated by CP190 [ChIP-seq]

Project description:80% of the genomic binding sites of the histone acetyltransferase Gcn5 are colocalizing with CP190 binding. Depletion of CP190 reduces the number of Gcn5 binding sites and binding strength to chromatin. Binding dependency was further supported by Gcn5 mediated co-precipitation of CP190

2016-12-05 | GSE83408 | GEO

Chromatin Binding of Gcn5 in Drosophila is Largely Mediated by CP190 [RNA-seq]

2016-12-05 | GSE83406 | GEO

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