Activated neutrophils are associated with pediatric cerebral malaria vasculopathy in Malawian children
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE72058 | GEO | 2015/10/30
SECONDARY ACCESSION(S): PRJNA292833
REPOSITORIES: GEO
Similar Datasets
Project description:We used microarrays to characterize the whole blood global gene expression profiles in 98 children with P. falciparum cerebral malaria We associated retinopathy status with host genes and pathways to explore mechanisms of infected red sequestration to the microvasculature in CM Cross sectional study of chidlren with CM, expression profiling derived from study enrollment whole blood sample RNA isolated from sample stored in Tri-Reagent BD; hybridization with Affymetrix Gene Chip Human Gene 1.0 ST Array.
2015-10-30 | E-GEOD-72058 | biostudies-arrayexpress
Project description:UnlabelledMost patients with cerebral malaria (CM) sustain cerebral microvascular sequestration of Plasmodium falciparum-infected red blood cells (iRBCs). Although many young children are infected with P. falciparum, CM remains a rare outcome; thus, we hypothesized that specific host conditions facilitate iRBC cerebral sequestration. To identify these host factors, we compared the peripheral whole-blood transcriptomes of Malawian children with iRBC cerebral sequestration, identified as malarial-retinopathy-positive CM (Ret+CM), to the transcriptomes of children with CM and no cerebral iRBC sequestration, defined as malarial-retinopathy-negative CM (Ret-CM). Ret+CM was associated with upregulation of 103 gene set pathways, including cytokine, blood coagulation, and extracellular matrix (ECM) pathways (P < 0.01; false-discovery rate [FDR] of <0.05). Neutrophil transcripts were the most highly upregulated individual transcripts in Ret+CM patients. Activated neutrophils can modulate diverse host processes, including the ECM, inflammation, and platelet biology to potentially facilitate parasite sequestration. Therefore, we compared plasma neutrophil proteins and neutrophil chemotaxis between Ret+CM and Ret-CM patients. Plasma levels of human neutrophil elastase, myeloperoxidase, and proteinase 3, but not lactoferrin or lipocalin, were elevated in Ret+CM patients, and neutrophil chemotaxis was impaired, possibly related to increased plasma heme. Neutrophils were rarely seen in CM brain microvasculature autopsy samples, and no neutrophil extracellular traps were found, suggesting that a putative neutrophil effect on endothelial cell biology results from neutrophil soluble factors rather than direct neutrophil cellular tissue effects. Meanwhile, children with Ret-CM had lower levels of inflammation, higher levels of alpha interferon, and upregulation of Toll-like receptor pathways and other host transcriptional pathways, which may represent responses that do not favor cerebral iRBC sequestration.ImportanceThere were approximately 198 million cases of malaria worldwide in 2013, with an estimated 584,000 deaths occurring mostly in sub-Saharan African children. CM is a severe and rare form of Plasmodium falciparum infection and is associated with high rates of mortality and neurological morbidity, despite antimalarial treatment. A greater understanding of the pathophysiology of CM would allow the development of adjunctive therapies to improve clinical outcomes. A hallmark of CM is cerebral microvasculature sequestration of P. falciparum-infected red blood cells (iRBCs), which results in vasculopathy in some patients. Our data provide a global analysis of the host pathways associated with CM and newly identify an association of activated neutrophils with brain iRBC sequestration. Products of activated neutrophils could alter endothelial cell receptors and coagulation to facilitate iRBC adherence. Future studies can now examine the role of neutrophils in CM pathogenesis to improve health outcomes.
| S-EPMC4791846 | biostudies-literature
Project description:Paper: Transcriptional Profiling of Plasmodium falciparum Parasites from Patients with Severe Malaria Identifies Distinct Low vs. High Parasitemic Clusters Milner et al Plos One July 18, 2012 Plasmodium falciparum Parasites from Patients with Severe Malaria
2016-06-24 | E-GEOD-83667 | biostudies-arrayexpress
Project description:Whole blood transcriptomes from a longitudinal study of 5 Malawian children who first present with severe Plasmodium falciparum malaria, and return in one month with mild malaria We used microarrays to identify transcripts that were associated with each clinical presentation.
2012-01-11 | GSE33811 | GEO
Project description:We sequenced the RNA content of circulating extracellular vesicles obtained from retinopathy- positive (CM-R⁺) and negative cerebral malaria (CM-R⁻) patients and community controls (CC) without Plasmodium falciparum infection. We found that some of the transcripts enriched in circulating extracellular vesicles are highly expressed in the brain compared to other tissues and could have a diagnostic potential in the cerebral malaria context.
2024-08-02 | GSE242856 | GEO
Project description:Paper: Transcriptional Profiling of Plasmodium falciparum Parasites from Patients with Severe Malaria Identifies Distinct Low vs. High Parasitemic Clusters Milner et al Plos One July 18, 2012
2016-06-24 | GSE83667 | GEO
Project description:Whole blood transcriptomes from a longitudinal study of 5 Malawian children who first present with severe Plasmodium falciparum malaria, and return in one month with mild malaria We used microarrays to identify transcripts that were associated with each clinical presentation. A blood sample was taken upon presentation during the severe and mild malaria episodes in 5 Malawian children (total n=5 pairs) followed by RNA extraction and hybridization on Affymetrix GeneChip Human Gene 1.0 ST Array, using a paired analysis
2012-01-11 | E-GEOD-33811 | biostudies-arrayexpress
Project description:Epigenetic processes are the main conductors of phenotypic variation in eukaryotes. The malaria parasite Plasmodium falciparum employs antigenic variation of the major surface antigen PfEMP1, encoded by 60 var genes, to evade acquired immune responses. PfEMP1 also mediates sequestration of infected erythrocytes in the microvasculature, which is directly linked to severe malaria outcomes. Antigenic variation of PfEMP1 occurs through in situ switches in mono-allelic var gene transcription, which is PfSIR2-dependent and associated with the presence of repressive H3K9me3 marks at silenced loci. Here, we show that the P. falciparum ortholog of heterochromatin protein 1 (PfHP1) binds to H3K9me3 and constitutes a major component of heterochromatin in perinuclear chromosome end clusters. High-resolution genome-wide chromatin immuno-precipitation demonstrates the striking association of PfHP1 with non-syntenic virulence gene arrays in subtelomeric and chromosome-internal islands. These include not only var genes but the majority of P. falciparum lineage-specific gene families coding for exported proteins involved in host-parasite interactions. Over-expression of PfHP1 resulted in decreased expression of a small number of (virulance) genes and indicated the presence of well-defined heterochromatic boundaries.. In summary, we uncover an unprecedented function of HP1 as a mayor regulator of virulence gene silencing and phenotypic variation, which will be instrumental for our understanding of this widely used survival strategy of unicellular pathogens. one experimental sample
2010-05-06 | E-GEOD-17029 | biostudies-arrayexpress
Project description:The pathogenesis of severe malaria is complex and involves several pathways that influence host inflammation and endothelial function. The human malaria parasite Plasmodium falciparum is responsible for the majority of mortality and morbidity caused by malaria infection and differs from other human malaria species in the degree of accumulation of parasite-infected red blood cells in the microvasculature, known as cytoadherence or sequestration. In P. falciparum, cytoadherence is mediated by a protein called PfEMP1 which, due to its exposure to the host immune system, undergoes antigenic variation resulting in the expression of different PfEMP1 variants on the infected erythrocyte membrane. These PfEMP1s contain various combinations of adhesive domains, which allow for the differential engagement of a repertoire of endothelial receptors on the host microvasculature, with specific receptor usage associated with severe disease. Cytoadherence results in perturbation of the micro-circulation as well as direct effects on endothelial cells promoted by receptor-mediated signalling. We used a co-culture model of cytoadherence incubating human brain microvascular endothelial cells with erythrocytes infected with two parasite lines expressing different PfEMP1s; IT4var14 (long-form; ups B) that binds strongly to human brain microvascular endothelial cells mainly via ICAM-1, and IT4var 37 (short-form; ups C) that does not bind brain endothelium but shows high levels of binding to human dermal microvascular endothelial cells via CD36. We determined the transcriptional profile of the endothelial cells following different incubation periods with infected erythrocytes, identifying different transcriptional profiles of pathways involved in the pathology of severe malaria, such as inflammation, apoptosis and barrier integrity, induced by the two PfEMP1 variants.
2023-11-01 | E-MTAB-12730 | biostudies-arrayexpress
Project description:The changes occurring in the T cell repertoire during clinical malaria infection in children remain unknown. In this study, we undertook the first detailed comparative study of the T cell repertoire in African children with and without clinical malaria to test the hypothesis that clonotypic expansions that occur during P. falciparum infection will contribute to the generation of a T cell repertoire that is unique to each disease state. We profiled the complementarity-determining region 3 (CDR3) of the TCRβ chain sequences from children with Plasmodium falciparum infections (asymptomatic, uncomplicated and severe malaria) and compared these with sequences from healthy children. Strikingly, we discovered that children with symptomatic malaria has a lower TCR diversity and frequency of shared (or “public”) TCR sequences compared to asymptomatic children. Also, TCR diversity was inversely associated with parasitemia. Furthermore, by clustering TCR sequences based on their predicted antigen specificities, we identified a specificity cluster, with a 4-mer amino acid motif, that is overrepresented in the asymptomatic group compared to the diseased groups. Further investigations into this finding may help in delineating important antigenic targets for vaccine and therapeutic development. The results show that the T cell repertoire in children is altered during malaria, suggesting that exposure to P. falciparum antigens disrupts the adaptive immune response, which is an underlying feature of the disease.
2022-09-11 | GSE212894 | GEO