Stress-induced inactivation of the Staphylococcus aureus purine biosynthesis repressor leads to hypervirulence
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA514046 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8424702.fastq.gz | Fastqsanger.gz | |||
| SRR8424703.fastq.gz | Fastqsanger.gz | |||
| SRR8424704.fastq.gz | Fastqsanger.gz | |||
| SRR8424705.fastq.gz | Fastqsanger.gz | |||
| SRR8424706.fastq.gz | Fastqsanger.gz |
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Project description:Staphylococcus aureus is a significant cause of human infection. Here, we demonstrate that mutations in the transcriptional repressor of purine biosynthesis, purR, enhance the pathogenic potential of S. aureus. Indeed, systemic infection with purR mutants causes accelerated mortality in mice, which is due to aberrant up-regulation of fibronectin binding proteins (FnBPs). Remarkably, purR mutations can arise upon exposure of S. aureus to stress, such as an intact immune system. In humans, naturally occurring anti-FnBP antibodies exist that, while not protective against recurrent S. aureus infection, ostensibly protect against hypervirulent S. aureus infections. Vaccination studies support this notion, where anti-Fnb antibodies in mice protect against purR hypervirulence. These findings provide a novel link between purine metabolism and virulence in S. aureus.
2019-02-26 | GSE124869 | GEO
Project description:Staphylococcus aureus is a significant cause of human infection. Here, we demonstrate that mutations in the transcriptional repressor of purine biosynthesis, purR, enhance the pathogenic potential of S. aureus. Indeed, systemic infection with purR mutants causes accelerated mortality in mice, which is due to aberrant up-regulation of fibronectin binding proteins (FnBPs). Remarkably, purR mutations can arise upon exposure of S. aureus to stress, such as an intact immune system. In humans, naturally occurring anti-FnBP antibodies exist that, while not protective against recurrent S. aureus infection, ostensibly protect against hypervirulent S. aureus infections. Vaccination studies support this notion, where anti-Fnb antibodies in mice protect against purR hypervirulence. These findings provide a novel link between purine metabolism and virulence in S. aureus.
| S-EPMC6377658 | biostudies-literature
Project description:Senescence-associated secretory phenotype (SASP), an established feature of cellular senescence, mediates the biological effects of senescent cell on tissue microenvironment and contributes to aging-associated disease progression. The metabolic enzyme ACSS2 produces acetyl-CoA from acetate and epigenetically regulates gene expression through histone acetylation. Whether and how ACSS2 regulates cellular senescence through non-histone acetylation mechanisms remain unclear. Here we show that ACSS2 drives SASP by promoting PAlCS acetylation to restrain purine metabolism. Genetic and pharmacological inhibition, as well as deletion of Acss2 in mice blunts SASP gene expression and abrogates the pro-tumorigenic and immune surveillance functions of senescent cells. Mechanistically, ACSS2 directly interacts and promotes acetylation of PAlCS, a key enzyme for purine metabolism. The acetylation of PAlCS promotes autophagy-mediated degradation of PAlCS to limit purine metabolism and reduces dNTP pools for DNA repair, which exacerbates cytoplasmic chromatin fragment (CCF) accumulation and SASP. Altogether, our work links ACSS2-mediated local acetyI-CoA generation to purine metabolism through PAlCS acetylation that dictates the functionality of SASP, and identify ACSS2 as a potential senomorphic target for healthy aging and to prevent senescence-associated diseases.
2025-02-10 | GSE275173 | GEO
Project description:Senescence-associated secretory phenotype (SASP), an established feature of cellular senescence, mediates the biological effects of senescent cell on tissue microenvironment and contributes to aging-associated disease progression. The metabolic enzyme ACSS2 produces acetyl-CoA from acetate and epigenetically regulates gene expression through histone acetylation. Whether and how ACSS2 regulates cellular senescence through non-histone acetylation mechanisms remain unclear. Here we show that ACSS2 drives SASP by promoting PAlCS acetylation to restrain purine metabolism. Genetic and pharmacological inhibition, as well as deletion of Acss2 in mice blunts SASP gene expression and abrogates the pro-tumorigenic and immune surveillance functions of senescent cells. Mechanistically, ACSS2 directly interacts and promotes acetylation of PAlCS, a key enzyme for purine metabolism. The acetylation of PAlCS promotes autophagy-mediated degradation of PAlCS to limit purine metabolism and reduces dNTP pools for DNA repair, which exacerbates cytoplasmic chromatin fragment (CCF) accumulation and SASP. Altogether, our work links ACSS2-mediated local acetyl-CoA generation to purine metabolism through PAlCS acetylation that dictates the functionality of SASP, and identify ACSS2 as a potential senomorphic target for healthy aging and to prevent senescence-associated diseases.
2025-02-10 | GSE274295 | GEO
Project description:Upon axenic cultivation in presence of the mycotoxin inducing nitrogen source L- ornithine the HEP1 deletion mutant showed an altered secondary metabolite profile including reduced levels of deoxynivalenol (DON). This finding was contrasted with a 1.5 fold increased infection rate on the susceptible wheat cv. Remus which was accompanied by increased production of DON. Transcriptome analysis of the HEP1 deletion versus the PH-1 wildtype strain during pathogenic growth state as well as during saprophytic growth on dead (non-responding) wheat heads and axenic samples allows to distinguish gene response of the pathogen reacting on signals from the active, defending plant from those regulated by plant substrate effects or in vitro mimicked mycotoxin inducing conditions, providing insights into gene regulation underlying the observed hypervirulence.
2019-09-30 | GSE96705 | GEO
Project description:The ability of Leishmania to survive in their insect or mammalian host is dependent upon an ability to sense and adapt to changes in the microenvironment. However, little is known about the molecular mechanisms underlying the parasite response to environmental changes, such as nutrient availability. To elucidate nutrient stress response pathways in Leishmania donovani, we have used purine starvation as the paradigm. The salvage of purines from the host milieu is obligatory for parasite replication; nevertheless, purine-starved parasites can persist in culture without supplementary purine for over 3 months, indicating that the response to purine starvation is robust and engenders parasite survival under conditions of extreme scarcity. To understand metabolic reprogramming during purine starvation we have employed global approaches. Whole proteome comparisons between purine-starved and purine-replete parasites over a 6-48 h span have revealed a temporal and coordinated response to purine starvation. Purine transporters and enzymes involved in acquisition at the cell surface are upregulated within a few hours of purine removal from the media, while other key purine salvage components are upregulated later in the time-course and more modestly. After 48 h, the proteome of purine-starved parasites is extensively remodeled and adaptations to purine stress appear tailored to deal with both purine deprivation and general stress. To probe the molecular mechanisms affecting proteome remodeling in response to purine starvation, comparative RNA-seq analyses, qRT-PCR, and luciferase reporter assays were performed on purine-starved versus purine-replete parasites. While the regulation of a minority of proteins tracked with changes at the mRNA level, for many regulated proteins it appears that proteome remodeling during purine stress occurs primarily via translational and post-translational mechanisms. One mRNA sample from each of Purine-Starved and Purine-Replete cells were analyzed using SL RNA-Seq methodology
2014-02-01 | E-GEOD-48394 | biostudies-arrayexpress
Project description:Ionophores are antibacterial compounds that affect bacterial growth by changing intracellular concentrations of the essential cations, sodium and potassium. They are extensively used in animal husbandry to increase productivity and reduce infectious diseases. Given their widespread usage, it is important to determine the potential negative consequences of ionophore use on human and animal health. In this study, we demonstrate that exposure to the ionophore monensin can select for resistant mutants in the human and animal pathogen Staphylococcus aureus, with a majority of the resistant mutants showing increased growth rates in vitro and/or in mice. Whole-genome sequencing and proteomics analysis of the resistant mutants show that the resistance phenotype is associated with de-repression of de novo purine synthesis, which could be achieved through mutations in different transcriptional regulators including mutations in the gene purR, the repressor of the purine de novo synthesis pathway. This study shows that mutants with reduced susceptibility to the ionophore monensin can be readily selected and highlights an unexplored link between ionophore resistance, purine metabolism and fitness in pathogenic bacteria.
2024-01-09 | PXD047199 | Pride
Project description:The ability of Leishmania to survive in their insect or mammalian host is dependent upon an ability to sense and adapt to changes in the microenvironment. However, little is known about the molecular mechanisms underlying the parasite response to environmental changes, such as nutrient availability. To elucidate nutrient stress response pathways in Leishmania donovani, we have used purine starvation as the paradigm. The salvage of purines from the host milieu is obligatory for parasite replication; nevertheless, purine-starved parasites can persist in culture without supplementary purine for over 3 months, indicating that the response to purine starvation is robust and engenders parasite survival under conditions of extreme scarcity. To understand metabolic reprogramming during purine starvation we have employed global approaches. Whole proteome comparisons between purine-starved and purine-replete parasites over a 6-48 h span have revealed a temporal and coordinated response to purine starvation. Purine transporters and enzymes involved in acquisition at the cell surface are upregulated within a few hours of purine removal from the media, while other key purine salvage components are upregulated later in the time-course and more modestly. After 48 h, the proteome of purine-starved parasites is extensively remodeled and adaptations to purine stress appear tailored to deal with both purine deprivation and general stress. To probe the molecular mechanisms affecting proteome remodeling in response to purine starvation, comparative RNA-seq analyses, qRT-PCR, and luciferase reporter assays were performed on purine-starved versus purine-replete parasites. While the regulation of a minority of proteins tracked with changes at the mRNA level, for many regulated proteins it appears that proteome remodeling during purine stress occurs primarily via translational and post-translational mechanisms.
2014-02-01 | GSE48394 | GEO
Project description:Purine nucleoside phosphorylase (PNP) enables the breakdown and recycling of guanine nucleosides. PNP insufficiency in humans is paradoxically associated with both immunodeficiency and autoimmunity, but the mechanistic basis for these outcomes is incompletely understood. Here we identify two immune lineage-dependent consequences of PNP inactivation dictated by distinct gene interactions. During T cell development, PNP inactivation is synthetically lethal with down-regulation of the dNTP triphosphohydrolase SAMHD1. This interaction requires deoxycytidine kinase activity and is antagonized by microenvironmental deoxycytidine. In B lymphocytes and macrophages, PNP regulates Toll like receptor 7 signaling by controlling the levels of its (deoxy)guanosine nucleoside ligands. Overriding this regulatory mechanism promotes germinal center formation in the absence of exogenous antigen and accelerates disease in a mouse model of autoimmunity. This work reveals that one purine metabolism gene protects against immunodeficiency and autoimmunity via independent mechanisms operating in distinct immune lineages and identifies PNP as a novel metabolic immune checkpoint.
2022-06-02 | GSE203003 | GEO
Project description:Staphylococcus aureus is a noted human and animal pathogen. Despite decades of research on this important bacterium, there are still many unanswered questions regarding the pathogenic mechanisms it uses to infect the mammalian host. This can be attributed to it possessing a plethora of virulence factors and complex virulence factor and metabolic regulation. PurR, the purine biosynthesis regulator, was recently also shown to regulate virulence factors in S. aureus, and mutations in purR result in derepression of fibronectin binding proteins (FnBPs) and extracellular toxins, required for a so-called hypervirulent phenotype. Here, we show that hypervirulent strains containing purR mutations can be attenuated with the addition of purine biosynthesis mutations, implicating the necessity for de novo purine biosynthesis in this phenotype and indicating that S. aureus in the mammalian host experiences purine limitation. Using cell culture, we showed that while purR mutants are not altered in epithelial cell binding, compared to that of wild-type (WT) S. aureus, purR mutants have enhanced invasion of these nonprofessional phagocytes, consistent with the requirement of FnBPs for invasion of these cells. This correlates with purR mutants having increased transcription of fnb genes, resulting in higher levels of surface-exposed FnBPs to promote invasion. These data provide important contributions to our understanding of how the pathogenesis of S. aureus is affected by sensing of purine levels during infection of the mammalian host.
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