Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients infected with the malaria parasite Plasmodium falciparum may develop a diffuse reversible encephalopathy, termed cerebral malaria. It is unclear how the intraerythrocytic parasite, which sequesters in the cerebral microvasculature but does not enter the brain parenchyma, induces this neurological syndrome. Adhesion of parasitized red blood cells in the brain microvasculature is mediated by specific receptors on the host endothelium, including intercellular adhesion molecule (ICAM)-1, CD36 and CD31. Leucocyte binding to cerebral endothelial cells in culture induces intracellular signalling via ICAM-1. The hypothesis that parasitized red blood cells binding to receptors on cerebral endothelial cells causes changes in the integrity of the blood-brain barrier was tested. Immunohistochemistry was used to examine the blood-brain barrier in human cerebral malaria, with antibodies to macrophage and endothelial activation markers, intercellular junction proteins, and plasma proteins. The distribution of the cell junction proteins occludin, vinculin and ZO-1 were altered in cerebral malaria cases compared to controls. While fibrinogen was the only plasma protein detected in the perivascular space, there was widespread perivascular macrophage activation, suggesting that these cells had been exposed to plasma proteins. It was concluded that functional changes to the blood-brain barrier occur in cerebral malaria, possibly as a result of the binding of parasitized red blood cells to cerebral endothelial cells. These changes require further examination in vitro.
 ...
PMID:Evidence of blood-brain barrier dysfunction in human cerebral malaria. 1047 50

To understand the mechanism of sequestration in the microvasculature of patients with falciparum malaria, we examined the patterns of expression of mRNAs for adhesion molecules (ICAM-1, VCAM-1, and E-selectin) and tight junction molecules (occludin, vinculin, and ZO-1) in human umbilical vein endothelial cells (HUVECs) co-cultured with Plasmodium falciparum-parasitized red blood cells (PRBCs) in vitro. The PRBCs were collected from patients with uncomplicated, severe, or cerebral malaria (CM). Patterns of mRNA expression in HUVECs co-cultured with PRBCs were examined by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR). Levels of mRNAs for all the three adhesion molecules increased with increased culture time within 3 h, regardless of the source of the PRBCs. In contrast, the patterns of mRNA expression for the tight junction molecules varied between the different co-cultures. When HUVECs were cultured with PRBCs from uncomplicated malaria patients, levels of mRNAs for tight junction molecules increased according to the culture time. HUVECs co-cultured with PRBCs from severe malaria patients showed no change in the mRNAs levels during 3 h of observation. When HUVECs were cultured with PRBCs from CM patients, levels of mRNAs for tight junction proteins decreased according to the culture time. Although the mechanisms underlying these phenomena are not clear, our results suggest that PRBCs can alter expression of tight junction proteins in endothelial cells at the site of sequestration and thereby influence disease severity.
 ...
PMID:Down-regulation of tight junction mRNAs in human endothelial cells co-cultured with Plasmodium falciparum-infected erythrocytes. 1638 77

Dysregulation of the blood-brain barrier (BBB) is a hallmark feature of numerous neurologic disorders as diverse as multiple sclerosis, stroke, epilepsy, viral hemorrhagic fevers, cerebral malaria, and acute hemorrhagic leukoencephalitis. CD8 T cells are one immune cell type that have been implicated in promoting vascular permeability in these conditions. Our laboratory has created a murine model of CD8 T cell-mediated CNS vascular permeability using a variation of the Theiler's murine encephalomyelitis virus system traditionally used to study multiple sclerosis. Previously, we demonstrated that CD8 T cells have the capacity to initiate astrocyte activation, cerebral endothelial cell tight junction protein alterations and CNS vascular permeability through a perforin-dependent process. To address the downstream mechanism by which CD8 T cells promote BBB dysregulation, in this study, we assess the role of vascular endothelial growth factor (VEGF) expression in this model. We demonstrate that neuronal expression of VEGF is significantly upregulated prior to, and coinciding with, CNS vascular permeability. Phosphorylation of fetal liver kinase-1 is significantly increased early in this process indicating activation of this receptor. Specific inhibition of neuropilin-1 significantly reduced CNS vascular permeability and fetal liver kinase-1 activation, and preserved levels of the cerebral endothelial cell tight junction protein occludin. Our data demonstrate that CD8 T cells initiate neuronal expression of VEGF in the CNS under neuroinflammatory conditions, and that VEGF may be a viable therapeutic target in neurologic disease characterized by inflammation-induced BBB disruption.
 ...
PMID:CD8 T cell-initiated vascular endothelial growth factor expression promotes central nervous system vascular permeability under neuroinflammatory conditions. 2000 93

Cerebral malaria claims the lives of over 600,000 African children every year. To better understand the pathogenesis of this devastating disease, we compared the cellular dynamics in the cortical microvasculature between two infection models, Plasmodium berghei ANKA (PbA) infected CBA/CaJ mice, which develop experimental cerebral malaria (ECM), and P. yoelii 17XL (PyXL) infected mice, which succumb to malarial hyperparasitemia without neurological impairment. Using a combination of intravital imaging and flow cytometry, we show that significantly more CD8(+) T cells, neutrophils, and macrophages are recruited to postcapillary venules during ECM compared to hyperparasitemia. ECM correlated with ICAM-1 upregulation on macrophages, while vascular endothelia upregulated ICAM-1 during ECM and hyperparasitemia. The arrest of large numbers of leukocytes in postcapillary and larger venules caused microrheological alterations that significantly restricted the venous blood flow. Treatment with FTY720, which inhibits vascular leakage, neurological signs, and death from ECM, prevented the recruitment of a subpopulation of CD45(hi) CD8(+) T cells, ICAM-1(+) macrophages, and neutrophils to postcapillary venules. FTY720 had no effect on the ECM-associated expression of the pattern recognition receptor CD14 in postcapillary venules suggesting that endothelial activation is insufficient to cause vascular pathology. Expression of the endothelial tight junction proteins claudin-5, occludin, and ZO-1 in the cerebral cortex and cerebellum of PbA-infected mice with ECM was unaltered compared to FTY720-treated PbA-infected mice or PyXL-infected mice with hyperparasitemia. Thus, blood brain barrier opening does not involve endothelial injury and is likely reversible, consistent with the rapid recovery of many patients with CM. We conclude that the ECM-associated recruitment of large numbers of activated leukocytes, in particular CD8(+) T cells and ICAM(+) macrophages, causes a severe restriction in the venous blood efflux from the brain, which exacerbates the vasogenic edema and increases the intracranial pressure. Thus, death from ECM could potentially occur as a consequence of intracranial hypertension.
 ...
PMID:Experimental cerebral malaria pathogenesis--hemodynamics at the blood brain barrier. 2547 13

Human cerebral malaria (HCM) is a serious complication of Plasmodium falciparum infection. The most severe outcomes for patients include coma, permanent neurological deficits, and death. Recently, a large-scale magnetic resonance imaging (MRI) study in humans identified brain swelling as the most prominent predictor of fatal HCM. Therefore, in this study, we sought to define the mechanism controlling brain edema through the use of the murine experimental cerebral malaria (ECM) model. Specifically, we investigated the ability of CD8 T cells to initiate brain edema during ECM. We determined that areas of blood-brain barrier (BBB) permeability colocalized with a reduction of the cerebral endothelial cell tight-junction proteins claudin-5 and occludin. Furthermore, through small-animal MRI, we analyzed edema and vascular leakage. Using gadolinium-enhanced T1-weighted MRI, we determined that vascular permeability is not homogeneous but rather confined to specific regions of the brain. Our findings show that BBB permeability was localized within the brainstem, olfactory bulb, and lateral ventricle. Concurrently with the initiation of vascular permeability, T2-weighted MRI revealed edema and brain swelling. Importantly, ablation of the cytolytic effector molecule perforin fully protected against vascular permeability and edema. Furthermore, perforin production specifically by CD8 T cells was required to cause fatal edema during ECM. We propose that CD8 T cells initiate BBB breakdown through perforin-mediated disruption of tight junctions. In turn, leakage from the vasculature into the parenchyma causes brain swelling and edema. This results in a breakdown of homeostatic maintenance that likely contributes to ECM pathology.
 ...
PMID:Perforin Expression by CD8 T Cells Is Sufficient To Cause Fatal Brain Edema during Experimental Cerebral Malaria. 2826 5

Schistosomiasis remains the second most prevalent zoonotic disease after malaria in veterinary medicine. The egg lodgement in target host tissue plays important roles in pathogenesis of this disease, but the process prior to egg-laying is still elusive. Surely, investigation of how this parasite invades and moves inside corresponding host will probably improve our understanding of homeostasis and maintenance of animal health, further, of related pathogenesis and thus potential intervention against schistosomiasis. TNT-coupled transcription/translation-expressed Sj serpin was employed for the protease inhibition assay. Transendothelial resistance (TER), its charge selectivity and size selectivity, were measured by the ussing chamber technique in serpin-transfected or recombinant serpin-treated HUVEC monolayer. The expressions of junction proteins were assayed using real-time PCR, Western blot and immunostaining. Sj serpin blocks the protease activity of elastase in a time-dependent manner; and Sj serpin can increase TER ofendothelial monolayer by decreasing its paracellular size selectivity, but not by interfere with the charge selectivity. Altered expression of tight junction protein claudin-2 was not observed at either RNA or protein levels; however, we found a marked increase in the expression of occludin, ZO-1,VE-cadherin and beta-catenin. Sj serpin can increase the transendothelial barrier function by decreasing the transendothelial permeability, implying serpin as a potential target to limit the invasion of schistosome into animal blood vessel.
 ...
PMID:Schistosoma japonicum serine protease inhibitor increases endothelial barrier function. 3196 71