B cells targeting parasites capture spatially linked antigens to secure T cell help
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1145999 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30177105_1.fastq.gz | Fastqsanger.gz | |||
| SRR30177105_2.fastq.gz | Fastqsanger.gz | |||
| SRR30177106_1.fastq.gz | Fastqsanger.gz | |||
| SRR30177106_2.fastq.gz | Fastqsanger.gz | |||
| SRR30177107_1.fastq.gz | Fastqsanger.gz |
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Project description:Our understanding of T-cell-dependent humoral responses has been largely shaped by studies involving model antigens such as recombinant proteins and viruses. In these contexts, B cells internalize the entire antigen or pathogen, and present a range of antigens to helper CD4+ T cells to initiate the humoral response. However, this model does not account for large pathogens (such as parasites) that are too large to be taken up by individual B cells, and the mechanisms by which B cells acquire and present antigens from large complex pathogens to T cells remain poorly understood. Here we used Plasmodium, the causative parasite of malaria, as a model to investigate the requirements for T cell help for B cells targeting the Plasmodium surface circumsporozoite protein (CSP). Upon Plasmodium sporozoite (SPZ) immunization, CSP-specific B cells can form a synapse-like structure with SPZs and take up CSP and non-CSP surface antigens. As a result, CSP-specific B cells can receive help from CD4+ T cells specific to antigens that are located on the surface but not cytosol of the Plasmodium SPZ. Therefore, B cells can obtain help, not only from T cells with the same protein specificity, but also from T cells specific for spatially linked antigens. This flexibility in T cell help may enhance the initiation and maintenance of humoral immune responses to complex pathogens.
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Project description:The malaria parasite Plasmodium falciparum relies on clonally variant gene expression in order to escape immune recognition and secure continuous proliferation during blood stage infection. Here, we studied the role of heterochromatin protein 1 (HP1), an evolutionary conserved regulator of heritable gene silencing, in the biology of P. falciparum blood stage parasites. We demonstrate that conditional PfHP1 depletion de-represses hundreds of heterochromatic virulence genes and disrupts the elusive mechanism underlying mutually exclusive expression and antigenic variation of PfEMP1. Intriguingly, we also discovered that the PfHP1-dependent regulation of an ApiAP2 transcription factor controls the switch from asexual parasite proliferation to sexual differentiation. This uncovers the first mechanistic insight into the unknown pathway triggering gametocyte conversion and establishes a new concept of HP1-dependent cell fate decision in unicellular eukaryotes. P. falciparum 3D7 parasites expressing endogenous PfHP1-GFP-DD were grown in presence of 4nM WR/625nM Shield-1 (3D7/HP1ON) or 4nM WR (3D7/HP1OFF). RNA extracted from these samples at eleven consecutive time points each was processed for microarray analysis.
2014-07-09 | E-GEOD-53176 | biostudies-arrayexpress
Project description:Understanding individual capability to adjust to protracted confinement and isolation may inform adaptive plasticity and disease vulnerability/resilience, and may have long-term implications for operations requiring prolonged presence in distant and restricted environments. Individual coping depends on many different factors encompassing psychological dispositional traits, endocrine reactivity and their underlying molecular mechanisms (e.g. gene expression). A positive view of self and others (secure attachment style) has been proposed to promote individual resilience under extreme environmental conditions. Here, we tested this hypothesis and investigated the underlying molecular mechanisms in 13 healthy volunteers confined and isolated for 12 months in a research station located 1670 km away from the south geographic pole on the Antarctic Plateau at 3233 m above sea level. Study participants, stratified for attachment style, were characterised longitudinally (before, during and after confinement) for their psychological appraisal of the stressful nature of the expedition, diurnal fluctuations in endocrine stress reactivity, and gene expression profiling (Agilent microarray transcriptomics). Predictably, a secure attachment style was associated with reduced psychological distress and endocrine vulnerability to stress. In addition, while prolonged confinement and isolation remarkably altered overall patterns of gene expression, such alteration was largely reduced in individuals characterized by a secure attachment style. Furthermore, increased resilience was associated with a reduced expression of genes involved in energy metabolism (mitochondrial function and oxidative phosphorylation). Ultimately, our data indicate that a secure attachment style may favour individual resilience in extreme environments and that such resilience can be mapped onto identifiable molecular substrates.
2020-04-26 | GSE149321 | GEO
Project description:The malaria parasite Plasmodium falciparum relies on clonally variant gene expression in order to escape immune recognition and secure continuous proliferation during blood stage infection. Here, we studied the role of heterochromatin protein 1 (HP1), an evolutionary conserved regulator of heritable gene silencing, in the biology of P. falciparum blood stage parasites. We demonstrate that conditional PfHP1 depletion de-represses hundreds of heterochromatic virulence genes and disrupts the elusive mechanism underlying mutually exclusive expression and antigenic variation of PfEMP1. Intriguingly, we also discovered that the PfHP1-dependent regulation of an ApiAP2 transcription factor controls the switch from asexual parasite proliferation to sexual differentiation. This uncovers the first mechanistic insight into the unknown pathway triggering gametocyte conversion and establishes a new concept of HP1-dependent cell fate decision in unicellular eukaryotes.
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Project description:CD4+ T-cell help creates effector memory CTLs with innate and help-independent recall capacities
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Project description:The ability to sense, respond and adapt to changes in nutrient availability is a survival requisite. This might be particularly important for malaria parasites, which encounter major alterations in nutrients levels throughout infection. How these parasites deal with nutrient fluctuations and maintain infection without killing their hosts before transmission remains unknown. Here, we show that blood-stage malaria parasites respond to dietary-restriction through a rearrangement of their transcriptome accompanied by a significant reduction in their multiplication rate. A kinome analysis combined with chemical and genetic approaches identified KIN, a putative AMP-activated kinase homologue, as a master regulator that senses host nutrients both in vitro and in vivo, and mediates the transcriptional response to the host nutritional status. Diet-responsive genes include the plant-like ApiAP2 transcription regulators, which appear to act as downstream effectors of KIN. Overall, these findings reveal key components of a parasite nutrient-sensing mechanism that is critical to modulate replication and virulence in malaria parasites.
2017-07-14 | GSE69627 | GEO
Project description:Background: The cytoadherence of Plasmodium falciparum is thought to be mediated by variant surface antigens (VSA), encoded by var, rif, stevor and pfmc-2tm genes. The last three families have rarely been studied in the context of cytoadherence. As most VSA genes are unique, the variability among sequences has impeded the functional study of VSA across different P. falciparum strains. However, many P. falciparum genomes have recently been sequenced, allowing the development of specific microarray probes to each VSA gene. Methods: All VSA sequences from the HB3, Dd2 and IT/FCR3 genomes were extracted using HMMer. Oligonucleotide probes were designed with OligoRankPick and added to the 3D7-based microarray chip. As a proof of concept, IT/R29 parasites were selected for and against rosette formation and the transcriptomes of isogenic rosetting and non-rosetting parasites were compared by microarray. Results: From each parasite strain 50-56 var genes, 125-132 rif genes, 26-33 stevor genes and 3-8 pfmc-2tm genes were identified. The ability of the VSA-supplemented microarray chip to detect cytoadherence-related genes was assessed using P. falciparum clone IT/R29, in which rosetting is known to be mediated by PfEMP1 encoded by ITvar9. Whole transcriptome analysis showed that the most highly upregulated gene in rosetting parasites was ITvar9 (19 to 429-fold upregulated over six time points). Only one rif gene (IT4rifA_042) was upregulated by more than 4-fold (5-fold at 12 hours post-invasion), and no stevor or pfmc-2tm genes were upregulated by more than 2-fold. 49 non-VSA genes were upregulated in rosetting parasites by more than 3-fold in at least two time-points, although none as markedly as ITvar9. Conclusions: We demonstrate that the VSA of newly sequenced P. falciparum strains can be added to the 3D7-based microarray chip, allowing the analysis of the entire transcriptome of multiple strains. For the rosetting clone IT/R29, the striking transcriptional upregulation of ITvar9 was confirmed, and the data did not support the involvement of other VSA families in rosette formation. Plasmodium falciparum parasites, strain IT/R29, were selected for (R29R+) or against (R29R-) rosetting. Both cultures (R29R+ and R29R-) were tightly synchronised before a timecourse experiment was performed. 6 samples, named time points 1 to 6, were taken every 8 hours. 12μg of RNA from the R29 non-rosetting parasites at each of the 6 time points was combined together to form the reference pool. The pool and 12μg of each individual time point sample from both rosetting and non-rosetting parasites were then used for cDNA synthesis. For microarray hybridizations,each cDNA sample was coupled to Cy5 (red dye) while Cy3 (green dye) was added to the pool. Cy5-labelled time point samples were mixed with the same amount of Cy3-labelled pool sample. The solution was loaded on a microarray slide and hybridized for 14–16 h.
2011-07-01 | E-GEOD-28990 | biostudies-arrayexpress
Project description:Background: The cytoadherence of Plasmodium falciparum is thought to be mediated by variant surface antigens (VSA), encoded by var, rif, stevor and pfmc-2tm genes. The last three families have rarely been studied in the context of cytoadherence. As most VSA genes are unique, the variability among sequences has impeded the functional study of VSA across different P. falciparum strains. However, many P. falciparum genomes have recently been sequenced, allowing the development of specific microarray probes to each VSA gene. Methods: All VSA sequences from the HB3, Dd2 and IT/FCR3 genomes were extracted using HMMer. Oligonucleotide probes were designed with OligoRankPick and added to the 3D7-based microarray chip. As a proof of concept, IT/R29 parasites were selected for and against rosette formation and the transcriptomes of isogenic rosetting and non-rosetting parasites were compared by microarray. Results: From each parasite strain 50-56 var genes, 125-132 rif genes, 26-33 stevor genes and 3-8 pfmc-2tm genes were identified. The ability of the VSA-supplemented microarray chip to detect cytoadherence-related genes was assessed using P. falciparum clone IT/R29, in which rosetting is known to be mediated by PfEMP1 encoded by ITvar9. Whole transcriptome analysis showed that the most highly upregulated gene in rosetting parasites was ITvar9 (19 to 429-fold upregulated over six time points). Only one rif gene (IT4rifA_042) was upregulated by more than 4-fold (5-fold at 12 hours post-invasion), and no stevor or pfmc-2tm genes were upregulated by more than 2-fold. 49 non-VSA genes were upregulated in rosetting parasites by more than 3-fold in at least two time-points, although none as markedly as ITvar9. Conclusions: We demonstrate that the VSA of newly sequenced P. falciparum strains can be added to the 3D7-based microarray chip, allowing the analysis of the entire transcriptome of multiple strains. For the rosetting clone IT/R29, the striking transcriptional upregulation of ITvar9 was confirmed, and the data did not support the involvement of other VSA families in rosette formation.
2011-07-01 | GSE28990 | GEO