Interferon-mediated innate immune responses against malaria parasite liver stages
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Wonjong Moon
PROVIDER: E-GEOD-44831 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:MalariaM-bM-^@M-^Ys cycle of infection requires parasite transmission between a mosquito vector and a vertebrate host. Plasmodium regulates transmission by translationally repressing specific mRNAs until their products are needed. We demonstrate that the Plasmodium yoelii Pumilio-FBF family member Puf2 allows the sporozoite to retain its infectivity in the mosquito salivary glands while awaiting transmission. Puf2 mediates this critical feature solely through its RNA-Binding Domain (RBD) likely by protecting and silencing specific mRNAs. Puf2 storage granules are distinct from stress granules and P-bodies and dissolve rapidly after infection of hepatocytes, likely releasing the protected and silenced transcripts for M-bM-^@M-^Xjust-in-timeM-bM-^@M-^Y translation by early exoerythrocytic forms (EEFs). Further corroborating this model, pypuf2- sporozoites have no apparent defect in host infection early after invading the salivary glands, but become progressively noninfectious and subsequently prematurely transform into EEFs during prolonged salivary gland residence. In contrast, the premature overexpression of Puf2 in oocysts causes striking deregulation of sporozoite maturation, resulting in fewer oocyst sporozoites that are non-infectious and unable to colonize the salivary glands. Maintenance of Puf2 expression in liver stage parasites produces no phenotype, suggesting that a window of permissive expression exists. Finally, by conducting the first comparative RNAseq analysis of Plasmodium sporozoites, we have uncovered that Puf2 may play a role in both the protection of specific transcripts as well as RNA turnover via the CCR4/Not complex. These findings uncover requirements for maintaining a window of opportunity for the malaria parasite to accommodate the unpredictable moment of transmission from mosquito to vertebrate host. Wild-type (Py17XNL) and pypuf2 -salivary gland sporozoites
2012-10-27 | E-GEOD-41873 | biostudies-arrayexpress
Project description:STING gain-of-function (GOF) mutations lead to T cell lymphopenia, in the context of severe combined immunodeficiency (SCID) for STING GOF V154M mice. This T cell lymphopenia, which is of central origin, has been described as type I IFN independent and associated with dysfunctions of the rare mature T cells found in the periphery. To better describe the biological mechanisms of these dysfunctions, we performed a transcriptomic analysis by RNA-seq on sorted splenic CD4+ and CD8+ mature T cells from STING GOF mice. We highlighted an unexpected T cell exhaustion phenotype that could partly explain their dysfunctions. Acquired very early in life, but only once the peripheral environment is reached, the phenotype appeared to depend neither on type I IFNs, nor on the intrinsic activation of STING in T or stromal cells. Mechanistically, the few mature T cells reaching the periphery seem to be rapidly impacted by the lymphopenic environment through increased antigenic and IL-7 stimulations that could lead to their exhaustion. By using STING GOF long term-hematopoietic stem cells (LT-HSC) transplantations with supportive wild-type bone marrow (BM) cells, we prevented the T cell exhaustion of STING GOF T cells in the resulting non lymphopenic context. With the support of lymphopenic RAG1 hypomorphic mice developing the phenotype, our data uncover a lymphopenia-mediated T cell exhaustion mechanism in STING GOF mice, for which a synergistic effect of the mutation is also envisaged.
2024-01-07 | E-MTAB-13658 | biostudies-arrayexpress
Project description:Cells have been collected by limited dilution and mRNA from 3 consequtive passages of cells cultured in Dulbecco’s modified Eagle’s medium (DMEM Dutscher L0104-500) containing 4.5 g/L glucose, L-glutamine, sodium pyruvate supplemented with 10% of inactivated fetal bovine serum (FBS, Dutscher S1510-500), penicillin (10 000 U/mL), streptomycin (10 mg/mL) (Dutscher P06-07100) were used for RNA seq analysis.
2024-07-13 | E-MTAB-14200 | biostudies-arrayexpress
Project description:The S. cerevisiae Forkhead Box (FOX) proteins, Fkh1 and Fkh2, regulate diverse cellular processes including transcription, long-range DNA interactions during homologous recombination, and replication origin timing and long-range origin clustering. As stimulators of early origin activation, we hypothesized that Fkh1 and Fkh2 abundance limits the rate of origin activation genome-wide. Existing methods, however, were not well suited to quantitative, genome-wide measurements of origin firing between strains and conditions. To overcome this limitation, we developed qBrdU-seq, a quantitative method for BrdU incorporation analysis of replication dynamics, and applied it to show that overexpression of Fkh1 and Fkh2 advance the initiation timing of many origins throughout the genome resulting in a higher total level of origin initiations in early S phase. The higher initiation rate is accompanied by slower replication fork progression, thereby maintaining a normal length of S phase without causing detectable Rad53 checkpoint kinase activation. The advancement of origin firing time, including that of origins in heterochromatic domains, was established in late G1 phase, indicating that origin timing can be reset subsequently to origin licensing. These results provide novel insights into the mechanisms of origin timing regulation by identifying Fkh1 and Fkh2 as rate-limiting factors for origin firing that determine the ability of replication origins to accrue limiting factors and have the potential to reprogram replication timing late in G1 phase. 5 total experiments with replicates
2015-12-18 | E-GEOD-71050 | biostudies-arrayexpress
Project description:Purpose: Aim of the study is to identify changes in hepatic gene expression induced by either a 40kcal% coconut oil rich high fat diet (HFD), a 40kcal% soybean oil plus coconut oil high fat diet (SO-HFD) or a low fat vivarium chow diet (Viv). Methods: Livers from mice that had been fed one of the above mentioned diets for 35 weeks, were used to make cDNA libraries that were then sent for deep sequencing, using the Illumina TruSeq RNA. Result: Many genes involved in metabolism, lipid binding, transport and storage and many Cyp genes are dysregulated in the two high fat diets as compared to Viv HFDs in SO-HFD mice. Comparing the two HFDs shows more metabolism and disease related genes dysregulated in SO-HFD vs HFD. Conclusion: A diet high in soybean oil may be more detrimental to metabolic health than a diet high in saturated fats. cDNA isolated from livers from mice fed HFD, SO-HFD or Viv for 35 weeks, were 50bp pair-ended sequenced in triplicate using Illumina TruSeq RNA Sample Prep v2 Kit.
2015-08-28 | E-GEOD-68360 | biostudies-arrayexpress
Project description:To unravel CFTR function in endothelial cells (HUVECs), we used two complementary approaches to induce CFTR blockade: (i) the allosteric CFTR inhibitor CFTRinh-(172) which is commonly used in CF research, and (ii) CFTR-specific short hairpin RNAs (shRNA).
2020-10-31 | E-MTAB-8599 | biostudies-arrayexpress
Project description:Purpose: The current study tests the hypothesis that peroxisome proliferator-activated receptor β (PPARβ) has a role in liver regeneration due to its effect in regulating energy homeostasis and cell proliferation. Methods: Wild-type (WT) and PPARβ-null mice (KO) male mice (3-5 month, C57BL/6) were kept in steel microisolator cages at 22°C with a 14-hr/10-hr light/dark cycle. Food and water were provided ad libitum throughout the entire feeding period. Standard PH was performed. All the animal experiments were conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals under protocols approved by the University of California Davis Animal Care and Use Committee.Mouse liver RNA was prepared using TRIzol (Invitrogen, Carlsbad, CA). RNA concentration and integrity were determined by the Agilent 2100 Bioanalyzer using a RNA Nano Bioanalysis Chip. RNA-sequencing library preparation and sequencing was carried out by the Genome Sequencing Facility at University of Kansas Medical Center (Kansas City, KS). cDNA libraries were prepared with 2 µg of total RNA using the TruSeq RNA Sample Preparation Kit (Illumina). The libraries were clustered and sequenced on an Illumina HiSeq 2000 instrument with 100 bp paired end reads. Results: Differential gene expression profiling revealed the inhibition of expression in genes and pathways that are involved in metabolism and proliferation in regenerating KO livers. Specifically, PPARβ deficiency affected the activation of Akt and the expression of E2fs. Pathways that control glycolysis, FA synthesis as well as cell proliferation were de-regulated in regenerating PPARβ KO livers. Conclusions: The data suggest a role for PPARβ in regulating liver regeneration that is mediated at least in part through Akt and E2f-regulated pathways. mRNA profiles of 3-month old wild type (WT) and PPARbeta mice were generated by deep sequencing, one simple, using Illumina HiSeq 2000 instrument with 100 bp paired end reads
2013-05-18 | E-GEOD-47062 | biostudies-arrayexpress
Project description:The androgen receptor (AR) is overexpressed and hyperactivated in human castration-resistant prostate cancer (CRPC). However, the determinants of AR overexpression in CRPC are poorly defined. Here we show that retinoic acid receptorârelated orphan receptor γ (ROR-γ) is overexpressed and amplified in metastatic CRPC tumors, and that ROR-γ drives AR expression in the tumors. ROR-γ recruits nuclear receptor coactivator 1 and 3 (NCOA1 and NCOA3, also known as SRC-1 and SRC-3) to an ARâROR response element (RORE) to stimulate AR gene transcription. ROR-γ antagonists suppress the expression of both AR and its variant AR-V7 in prostate cancer (PCa) cell lines and tumors. ROR-γ antagonists also markedly diminish genome-wide AR binding, H3K27ac abundance and expression of the AR target gene network. Finally, ROR-γ antagonists suppressed tumor growth in multiple AR-expressing, but not AR-negative, xenograft PCa models, and they effectively sensitized CRPC tumors to enzalutamide, without overt toxicity in mice. Taken together, these results establish ROR-γ as a key player in CRPC by acting upstream of AR and as a potential therapeutic target for advanced PCa. A total of 6 samples were analyzed in this study. The study included one cell line C4-2B. C4-2B cells were cultured in medium containing vehicle control and/or SR2211 and/or XY011 and/or Enzalutamide (ENZ). The untreated C4-2B cells served as controls for the study.
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Project description:Illumina HiSeq 2000 was conducted on the mRNA fraction of fourth instar Cx. quinquefasciatus from a highly permethrin resistant strain (HAmCqG8) and its parental low resistance strain (HAmCqG0). After aligning reads to the Johannesburg genome using the GTF annotations file from Ensembl Metazoa, we found that 367 genes were upregulated in the high resistant strain and 3982 were downregulated. The upregulated genes were associated with cytochrome P450s and proteases while the downregulated genes were mostly found in the “no annotation” category for the Structural Classification of Proteins classifications for Cx. quinquefasciatus. This study identified the upregulated genes in the highly resistant HAmCqG8 strain that may be involved in resistance to permethrin. RNA Seq profiling of the mRNA of fourth instar HAmCqG0 and HAmCqG8 Cx. quinquefasciatus (whole insect pooled samples)
2012-03-13 | E-GEOD-33736 | biostudies-arrayexpress
Project description:Pathways that stimulate β-cell regeneration remain of great clinical interest, yet effective therapeutic avenues that promote survival or reconstitution of β-cell mass remain elusive. Utilizing a mouse model with inducible β-cell apoptosis followed by adiponectin-mediated regeneration, we aimed to identify key molecules boosting β-cell viability. Within the regenerating pancreatic islets, we examined changes within the transcriptome, and observed an extensive upregulation of genes encoding proteins involved in lipid transport and metabolism. The most prominent targets were further confirmed by quantitative PCR and immunofluorescence. Among the upstream regulators predicted by pathway analysis of the transcriptome, we detected enhanced levels of two key transcription factors, HNF4α and PPARα. Enhanced leptin levels in circulation may also contribute to the anti-lipotoxic program in islets. In summary, our data suggest that improving local lipid metabolism as an important anti-lipotoxic phenomenon to boost β-cell regeneration, primarily mediated by adiponectin’s action on the β-cells directly as well as on the adipocyte. RNA profiles of pancreatic islets isolated from PANIC-ATTAT mice crossed with adiponectin wild-type (P-Adn+/+) or the overexpressing transgene (P-AdnTg/+) at 5 weeks after initial dimerizer administration.
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