scholarly journals Platelet Accumulation in Brain Microvessels in Fatal Pediatric Cerebral Malaria

2003 ◽  
Vol 187 (3) ◽  
pp. 461-466 ◽  
Author(s):  
Georges E. Grau ◽  
Charles D. Mackenzie ◽  
Richard A. Carr ◽  
Mireille Redard ◽  
Giampaolo Pizzolato ◽  
...  
Keyword(s):  
Cerebral Malaria ◽  
Brain Microvessels ◽  
Platelet Accumulation

scholarly journals Suppression of Plasmodium MIF-CD74 Signaling Protects Against Severe Malaria

2021 ◽  
Author(s):  
Alvaro Baeza Garcia ◽  
Edwin Siu ◽  
Xin Du ◽  
Lin Leng ◽  
Blandine Franke-Fayard ◽  
...  
Keyword(s):  
T Cells ◽  
Inflammatory Response ◽  
Cerebral Malaria ◽  
Macrophage Migration Inhibitory Factor ◽  
Molecular Mechanisms ◽  
Macrophage Migration ◽  
Erythrocytic Stage ◽  
Experimental Cerebral Malaria ◽  
Brain Microvessels

AbstractMalaria begins when mosquito-borne Plasmodium sporozoites invade hepatocytes and usurp host pathways to support the differentiation and multiplication of erythrocyte-infective merozoite progeny. The deadliest complication of infection, cerebral malaria, accounts for the majority of malarial fatalities. Although our understanding of the cellular and molecular mechanisms underlying the pathology remains incomplete, recent studies support the contribution of systemic and neuroinflammation as the cause of cerebral edema and blood-brain barrier (BBB) dysfunction. All Plasmodium species encode an orthologue of the innate cytokine, Macrophage Migration Inhibitory Factor (MIF), which functions in mammalian biology to regulate innate responses. Plasmodium MIF (PMIF) similarly signals through the host MIF receptor CD74, leading to an enhanced inflammatory response. We investigated the PMIF-CD74 interaction in the onset of experimental cerebral malaria (ECM) using CD74 deficient (Cd74−/−) mice, which were found to be protected from ECM. The protection was associated with the inability of brain microvessels from Cd74−/− hosts to present parasite antigen to sequestered Plasmodium-specific CD8+ T cells. Infection of mice with PMIF-deficient sporozoites (PbAmif-) also protected mice from ECM, highlighting the pivotal role of PMIF in the pre-erythrocytic stage of the infection. A novel pharmacologic PMIF-selective antagonist reduced PMIF/CD74 signaling and fully protected mice from ECM. These findings reveal a conserved mechanism for Plasmodium usurpation of host CD74 signaling and suggest a tractable approach for new pharmacologic intervention.

IgE deposition in brain microvessels and on parasitized erythrocytes from cerebral malaria patients.

2000 ◽  
Vol 63 (3) ◽  
pp. 128-132 ◽  
Author(s):  
Y Maeno ◽  
T Nakabayashi ◽  
P Perlmann ◽  
K Win ◽  
PerlmannH ◽  
...  
Keyword(s):  
Cerebral Malaria ◽  
Brain Microvessels

scholarly journals Binding Heterogeneity ofPlasmodium falciparumto Engineered 3D Brain Microvessels Is Mediated by EPCR and ICAM-1

mBio ◽  
2019 ◽  
Vol 10 (3) ◽  
Author(s):  
Maria Bernabeu ◽  
Celina Gunnarsson ◽  
Maria Vishnyakova ◽  
Caitlin C. Howard ◽  
Ryan J. Nagao ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Human Brain ◽  
Cerebral Malaria ◽  
Brain Endothelial Cells ◽  
Endothelial Protein C Receptor ◽  
Content Type ◽  
Brain Microvessels ◽  
Tnf Α ◽  
Brain Microvessel ◽  
The Brain

ABSTRACTCerebral malaria is a severe neurological complication associated with sequestration ofPlasmodium falciparum-infected erythrocytes (IE) in the brain microvasculature, but the specific binding interactions remain under debate. Here, we have generated an engineered three-dimensional (3D) human brain endothelial microvessel model and studiedP. falciparumbinding under the large range of physiological flow velocities that occur in both health and disease. Perfusion assays on 3D microvessels reveal previously unappreciated phenotypic heterogeneity in parasite binding to tumor necrosis factor alpha (TNF-α)-activated brain endothelial cells. While clonal parasite lines expressing a group BP. falciparumerythrocyte membrane protein 1 (PfEMP1) present an increase in binding to activated 3D microvessels,P. falciparum-IE expressing DC8-PfEMP1 present a decrease in binding. The differential response to endothelium activation is mediated by surface expression changes of endothelial protein C receptor (EPCR) and intercellular adhesion molecule 1 (ICAM-1). These findings demonstrate heterogeneity in parasite binding and provide evidence for a parasite strategy to adapt to a changing microvascular environment during infection. The engineered 3D human brain microvessel model provides new mechanistic insight into parasite binding and opens opportunities for further studies on malaria pathogenesis and parasite-vessel interactions.IMPORTANCECerebral malaria research has been hindered by the inaccessibility of the brain. Here, we have developed an engineered 3D human brain microvessel model that mimics the blood flow rates and architecture of small blood vessels to study howP. falciparum-infected human erythrocytes attach to brain endothelial cells. By studying parasite lines with different adhesive properties, we show that the malaria parasite binding rate is heterogeneous and strongly influenced by physiological differences in flow and whether the endothelium has been previously activated by TNF-α, a proinflammatory cytokine that is linked to malaria disease severity. We also show the importance of human EPCR and ICAM-1 in parasite binding. Our model sheds new light on howP. falciparumbinds within brain microvessels and provides a powerful method for future investigations of recruitment of human brain pathogens to the blood vessel lining of the brain.

scholarly journals Plasmodium falciparum picks (on) EPCR

Blood ◽  
2014 ◽  
Vol 123 (2) ◽  
pp. 163-167 ◽  
Author(s):  
William C. Aird ◽  
Laurent O. Mosnier ◽  
Rick M. Fairhurst
Keyword(s):  
Plasmodium Falciparum ◽  
Cerebral Malaria ◽  
Protein C ◽  
Falciparum Infection ◽  
Endothelial Protein C Receptor ◽  
Virulence Proteins ◽  
Brain Microvessels ◽  
Specific Syndrome ◽  
Organ Specific ◽  
Specific Virulence

Abstract Of all the outcomes of Plasmodium falciparum infection, the coma of cerebral malaria (CM) is particularly deadly. Malariologists have long wondered how some patients develop this organ-specific syndrome. Data from two recent publications support a novel mechanism of CM pathogenesis in which infected erythrocytes (IEs) express specific virulence proteins that mediate IE binding to the endothelial protein C receptor (EPCR). Malaria-associated depletion of EPCR, with subsequent impairment of the protein C system promotes a proinflammatory, procoagulant state in brain microvessels.

Thrombin Stimulated Platelet Accumulation on Protein Coated Glass Capillaries: Role of Adhesive Platelet α-Granule Proteins

1989 ◽  
Vol 62 (03) ◽  
pp. 989-995 ◽  
Author(s):  
Juliette N Mulvihill ◽  
J Andrew Davies ◽  
Florence Toti ◽  
Jean-Marie Freyssinet ◽  
Jean-Pierre Cazenave
Keyword(s):  
Human Platelets ◽  
Capillary Perfusion ◽  
Coated Glass ◽  
Bovine Collagen ◽  
Glass Capillaries ◽  
Human Thrombin ◽  
Platelet Accumulation ◽  
Granule Proteins ◽  
Von Willebrand

SummaryThe generation of trace amounts of thrombin at artificial surfaces in contact with blood is likely to be a contributing factor in thrombosis on biomaterials. Using an in vitro capillary perfusion system, platelet accumulation on glass surfaces, uncoated or precoated with purified bovine collagen or human plasma proteins, was determined in the presence or absence of preadsorbed purified human thrombin. Static adsorption for 15 min at 22° C from solutions of thrombin 100 NIH units (33 μg)/ml gave surface concentrations in the range 0.019-0.101 μg/cm2. Protein coated capillaries, thrombin treated or untreated, were perfused for 2 min at 37° C with suspensions of washed 111In-labeled human platelets in Tyrode's-albumin buffer containing 40% washed red blood cells, under conditions of controlled, non pulsatile laminar flow (50 s−1 or 2,000 s−1). Platelet accumulation was increased in the presence of surface adsorbed thrombin on uncoated and albumin or fibrinogen coated glass but little affected on fibronectin or collagen coated glass. On von Willebrand factor (vWF) coated glass, thrombin enhancement was observed only at high shear forces. In experiments using antibodies against human platelet α-granule proteins, thrombin stimulated platelet deposition in uncoated glass capillaries was inhibited at 2,000 s−1 by anti-vWF and to a lesser extent by anti-fibrinogen but not by antithrombospondin antibodies.

Platelet Accumulation on Fibrin-coated Polyethylene: Role of Platelet Activation and Factor XIII

1995 ◽  
Vol 73 (05) ◽  
pp. 850-856 ◽  
Author(s):  
F D Rubens ◽  
D W Perry ◽  
M W C Hatton ◽  
P D Bishop ◽  
M A Packham ◽  
...  
Keyword(s):  
Factor Xiii ◽  
Cross Linking ◽  
Internal Diameter ◽  
Static System ◽  
Graft Occlusion ◽  
Platelet Binding ◽  
Coated Surface ◽  
Platelet Accumulation ◽  
Polyethylene Tubing

SummaryPlatelet accumulation on small- and medium-calibre vascular grafts plays a significant role in graft occlusion. We examined platelet accumulation on the surface of fibrin-coated polyethylene tubing (internal diameter 0.17 cm) during 10 min of flow (l0ml/min) at high wall shear rate (764 s-1). Washed platelets labelled with 51Cr were resuspended in Tyrode solution containing albumin, apyrase and red blood cells (hematocrit 40%). When the thrombin that was used to form the fibrin-coated surface was inactivated with FPRCH2C1 before perfusion of the tubes with the platelet:red blood cell suspension, the accumulation of platelets was 59,840 ± 27,960 platelets per mm2, whereas accumulation on fibrin with residual active thrombin was 316,750 ± 32,560 platelets per mm2 (n = 4). When the fibrin on the surface was cross-linked by including recombinant factor XIII (rFXIII) in the fibrinogen solution used to prepare the fibrin-coated surface, platelet accumulation, after thrombin neutralization, was reduced by the cross-linking from 46,974 ± 9702 to 36,818 ± 7964 platelets per mm2 (n = 12, p <0.01). Platelet accumulation on tubes coated with D-dimer was ten times less than on tubes coated with D-domain; this finding also supports the observation that cross-linking of fibrin with the formation of γ-γ dimers reduces platelet accumulation on the fibrin-coated surface. Thrombin-activated platelets themselves were shown to cross-link fibrin when they had adhered to it during perfusion, or in a static system in which thrombin was used to form clots from FXIII-free fibrinogen in the presence of platelets. Thus, cross-linking of fibrin by FXIII in plasma or from platelets probably decreases the reactivity of the fibrin-containing thrombi to platelets by altering the lysine residue at or near the platelet-binding site of each of the γ-chains of the fibrinogen which was converted into the fibrin of these thrombi.

Intrathoracic Platelet Accumulation in the Guinea-Pig Induced by Intravenous Administration of Arachidonic Acid - Effect of Cyclooxygenase and Thromboxane Synthetase Inhibitors

1986 ◽  
Vol 56 (03) ◽  
pp. 311-317 ◽  
Author(s):  
P A Barrett ◽  
K D Butler ◽  
R A Shand ◽  
R B Wallis
Keyword(s):  
Arachidonic Acid ◽  
Blood Volume ◽  
Intravenous Administration ◽  
Guinea Pigs ◽  
Human Albumin ◽  
Thromboxane Synthetase ◽  
Acid Effect ◽  
Rapid Accumulation ◽  
Platelet Accumulation ◽  
High Doses

SummaryIntravenous administration of arachidonic acid to guinea-pigs caused a dose-related, rapid accumulation of 51Cr-labelled platelets in the thorax. Inhibitors of cyclooxygenase inhibited the platelet accumulation, induced by arachidonic acid (30 mg/kg), at doses which did not alter the thoracic blood volume (as measured by 131I-labelled human albumin). Thromboxane synthetase inhibitors had different effects on platelet accumulation depending on the dose. CGS 12970 (3 mg/kg) and N(1-carboxyheptyl) imidazole (100 mg/kg) reduced platelet accumulation. High doses of CGS 12970 and CGS 13080 caused an apparent enhancement of platelet accumulation which was associated with pooling of blood in the thorax, as measured by either 131I-labelled human albumin or 51Cr-labelled erythrocytes. This increase in thoracic blood volume was abolished if the guinea-pigs were also pretreated with diclofenac (1 mg/kg) in addition to the thromboxane synthetase inhibitor. Increases in thoracic blood volume were also obtained following infusions of PGI2 but not PGD2 or PGE2.

The Effects of Modulation of Prostanoid Metabolism on the Thoracic Platelet Accumulation Induced by Intravenous Administration of Collagen in the Guinea-Pig

1986 ◽  
Vol 56 (03) ◽  
pp. 263-267
Author(s):  
K D Butler ◽  
R A Shand ◽  
R B Wallis
Keyword(s):  
Platelet Count ◽  
Guinea Pig ◽  
Intravenous Administration ◽  
Cyclooxygenase Inhibitors ◽  
Concomitant Increase ◽  
Thromboxane Synthetase ◽  
Platelet Accumulation ◽  
Related Increase

SummaryThe effects of intravenously administered collagen on the circulatory platelet count, TxB2, 6-keto PGF1α and 51Cr-labelled platelet accumulation in the thorax have been evaluated in the guinea-pig. Administration of collagen induced a dose-related peripheral thrombocytopenia and a concomitant increase in 51Cr-labelled platelets in the thorax. There was also a transient dose-related increase in plasma TxB2 but no change in plasma 6-keto PGF1α levels.The thromboxane synthetase inhibitors tested, reduced the platelet accumulation, but only CGS 13080 significantly inhibited TxB2 production. In contrast all the cyclooxygenase inhibitors tested impaired the elevation of plasma TxB2 after collagen, but only diclofenac inhibited the 51Cr-labelled platelet accumulation.The greater effect of thromboxane synthetase inhibitors compared to cyclooxygenase inhibitors on platelet accumulation in this system cannot be completely explained by the changes measured in the circulating prostanoids.

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