Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA103845 | ENA |
REPOSITORIES: ENA
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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:Cerebral malaria is the most deadly manifestation of infection with Plasmodium falciparum. The pathology of cerebral malaria is characterised by the accumulation of infected erythrocytes in the microvasculature of the brain, due to parasite adhesins on the surface of infected erythrocytes binding to human receptors on microvascular endothelial cells. The parasite and host molecules involved in this interaction are unknown. We used the Human Brain Endothelial Cell line HBEC-5i to identify the malaria parasite ligands responsible for binding to human brain endothelial cells. Three P. falciparum strains (HB3, 3D7 and IT/FCR3) were selected for binding to HBEC5i and the whole transcriptome of selected and unselected parasites was analysed using a variant surface antigen-supplemented microarray chip. After selection, the only highly upregulated genes were a subset of group A-like var genes (HB3var3, 3D7_PFD0020c, ITvar7 and ITvar19), that showed 11 to >100-fold higher transcription levels in selected parasites. These genes are highly diverse in sequence, but do however show strong similarities in PfEMP1 architecture. Antibodies raised to the HB3var3 variant recognized the surface of infected erythrocytes and abolished the binding of infected erythrocytes to brain endothelial cells. The subset of Group A PfEMP1 variants identified here provides a new target for interventions to treat or prevent cerebral malaria.
2011-11-01 | GSE32211 | GEO
Project description:Cerebral malaria is the most deadly manifestation of infection with Plasmodium falciparum. The pathology of cerebral malaria is characterised by the accumulation of infected erythrocytes in the microvasculature of the brain, due to parasite adhesins on the surface of infected erythrocytes binding to human receptors on microvascular endothelial cells. The parasite and host molecules involved in this interaction are unknown. We used the Human Brain Endothelial Cell line HBEC-5i to identify the malaria parasite ligands responsible for binding to human brain endothelial cells. Three P. falciparum strains (HB3, 3D7 and IT/FCR3) were selected for binding to HBEC5i and the whole transcriptome of selected and unselected parasites was analysed using a variant surface antigen-supplemented microarray chip. After selection, the only highly upregulated genes were a subset of group A-like var genes (HB3var3, 3D7_PFD0020c, ITvar7 and ITvar19), that showed 11 to >100-fold higher transcription levels in selected parasites. These genes are highly diverse in sequence, but do however show strong similarities in PfEMP1 architecture. Antibodies raised to the HB3var3 variant recognized the surface of infected erythrocytes and abolished the binding of infected erythrocytes to brain endothelial cells. The subset of Group A PfEMP1 variants identified here provides a new target for interventions to treat or prevent cerebral malaria. Unselected Plasmodium falciparum parasites (Uns) only poorly cytoadhere to human brain endothelial cells (HBEC-5i). Plasmodium falciparum HB3, 3D7 and IT/FCR3 strains were selected for binding to HBEC-5i (HB3-HBEC1, HB3-HBEC2, HB3-HBEC-TNF, 3D7-HBEC and IT-HBEC). HBEC-selected and unselected cultures 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 unselected parasites (HB3-Uns, 3D7-Uns or IT-Uns) 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 selected and unselectedparasites were then used for cDNA synthesis. For HB3-HBEC1 (pilot experiment), each HB3-HBEC1 time point (pilot experiment) was hybridised directly with HB3-Uns1 time points. 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.
2011-11-01 | E-GEOD-32211 | biostudies-arrayexpress
Project description:Cerebral malaria is a severe complication of Plasmodium falciparum infection characterized by the loss of blood-brain barrier (BBB) integrity, which is associated with brain swelling and mortality in patients. P. falciparum-infected red blood cells and in!ammatory cytokines, like tumor necrosis factor alpha (TNF-a), have been implicated in the development of cerebral malaria, but it is still unclear how they contribute to the loss of BBB integrity. Here, a combination of transcriptomic analysis and cellular assays detecting changes in barrier integrity and endothelial activation were used to distinguish between the effects of P. falciparum and TNF-a on a human brain microvascular endothelial cell (HBMEC) line and in primary human brain microvascular endothelial cells. We observed that while TNF-a induced high levels of endothelial activation, it only caused a small increase in HBMEC permeability. Conversely, P. falciparum-infected red blood cells (iRBCLs) led to a strong increase in HBMEC permeability that was not mediated by cell death. Distinct transcriptomic pro"les of TNF-a and P. falciparum in HBMECs con"rm the differential effects of these stimuli, with the parasite preferentially inducing an endoplasmic reticulum stress response. Our results establish that there are fundamental differences in the responses induced by TNF-a and P. falciparum on brain endothelial cells and suggest that parasite-induced signaling is a major component driving the disruption of the BBB during cerebral malaria, proposing a potential target for much needed therapeutics.
2022-08-20 | GSE211439 | GEO
Project description:Sequestration of Plasmodium falciparum-infected erythrocytes (IEs) in the brain microcirculation is a hallmark of cerebral malaria (CM), leading to endothelial activation, microvascular occlusion, brain swelling, and death. The inflammatory pathogenesis is however poorly understood, partly due to the lack of suitable in vitro platforms to study CM biology. Here, we used 3D perfusable brain microvessels to investigate combinatorial pathogen and host inflammatory stimuli over the in situ parasite maturation and IE rupture. Whereas tumor necros factor (TNF) potently upregulated adhesion molecules and inflammatory pathways, and uniformly recruited leukocytes throughout the microvessels, P. falciparum-IEs upregulated unique stress response pathways, induced minor junctional disturbances and low levels of endothelial apoptosis, and preferentially recruited leukocytes at IE binding regions. Furthermore, parasites delayed recovery from TNF stimulation and enhanced inflammatory responses. Our findings offer insights into CM biology, and suggest that multiple events intersect to promote brain barrier inflammation in CM.
2023-09-30 | GSE227672 | GEO
Project description:Cerebral malaria is a severe multifactorial condition associated with the interaction of high numbers of infected erythrocytes to human brain endothelium without invasion into the brain. The result is coma and seizures with death in more than 20% of cases. Because the brain endothelium is at the interface of these processes, we investigated the global gene responses of human brain endothelium after the interaction with Plasmodium falciparum–infected erythrocytes with either high- or low-binding phenotypes. The most significantly up-regulated transcripts were found in gene ontology groups comprising the immune response, apoptosis and antiapoptosis, inflammatory response, cell-cell signaling, and signal transduction and nuclear factor B (NF-B) activation cascade. The proinflammatory NF-B pathway was central to the regulation of the P falciparum–modulated endothelium transcriptome. The proinflammatory molecules, for example, CCL20, CXCL1, CXCL2, IL-6, and IL-8, were increased more than 100-fold, suggesting an important role of blood-brain barrier (BBB) endothelium in the innate defense during P falciparum–infected erythrocyte (Pf-IRBC) sequestration. However, some of these diffusible molecules could have reversible effects on brain tissue and thus on neurologic function. The inflammatory pathways were validated by direct measurement of proteins in brain endothelial supernatants. This study delineates the strong inflammatory component of human brain endothelium contributing to cerebral malaria.
2009-11-10 | GSE9861 | GEO
Project description:To study the effect of Plasmodium falciparum-infected erythrocytes on gene expression in NK92 cells, microarray analysis after 6, 12 and 24 hours of co-culture with either uRBC or iRBC was performed. The aim was to identify pathways in NK92 cells that are switched on after iRBC encounter in a time-dependent manner that will help to understand the mechanisms in innate immune defenses against Plasmodium falciparum infection.
2011-11-12 | GSE26876 | GEO
Project description:To study the effect of Plasmodium falciparum-infected erythrocytes on gene expression in NK92 cells, microarray analysis after 6, 12 and 24 hours of co-culture with either uRBC or iRBC was performed. The aim was to identify pathways in NK92 cells that are switched on after iRBC encounter in a time-dependent manner that will help to understand the mechanisms in innate immune defenses against Plasmodium falciparum infection. Variation in gene expression of NK92 cells was determined after 6, 12, and 24 hours of co-culture with either infected or uninfected RBC compared to timepoint 0 (start of co-culture, untreated control). All experiments were done in triplicate, that means that samples were collected in 3 different experiments (A, B, and C) each time after 0, 6, 12 and 24 hours of co-culture.
2011-11-12 | E-GEOD-26876 | biostudies-arrayexpress
Project description:The effect of Mycophenolic acid on primary isolated human dermal microvascular endothelial (HDMVEC) and fibroblast cells as well as human glioblastoma brain tumor cell line (U87).
2008-06-25 | E-TABM-315 | biostudies-arrayexpress
Project description:The effect of Everolimus (RAD001) on primary isolated human dermal microvascular endothelial (HDMVEC) and Fibroblast Cells as well as human glioblastoma brain tumor cell line (U87).
2013-11-12 | E-MEXP-3802 | biostudies-arrayexpress