Biological and Biochemical Characteristics of Cytoadhesion of Plasmodium falciparum-Infected Erythrocytes to Chondroitin-4-Sulfate

ABSTRACT The cytoadhesion of Plasmodium falciparum laboratory strains and clones to Saimiri brain microvascular endothelial cells (SBEC 17), with chondroitin-4-sulfate (CSA) as the only adhesion receptor, was tested. Only one strain had significant cytoadhesion. However, CSA-specific infected erythrocytes (IRBCs) were detected in all strains after selection of a CSA-specific subpopulation by culturing the few adherent IRBCs. This demonstrates the lack of sensitivity of cytoadhesion microassays for detecting small quantities of CSA-specific IRBCs in cultures or field isolates. Cytoadhesion to CSA is maximal at 24 h of the cycle and decreases with the onset of schizogony, reaching a minimum just before reinvasion. This fluctuation must be taken into account in comparisons of the cytoadhesion of different strains or isolates. The minimum size of CSA for active inhibition was 4 kDa, and a mass of 9 kDa was required for inhibition similar to that obtained with the 50-kDa CSA. In contrast to cytoadhesion to CSA, which is pH independent or maximal at physiological pH (depending on the target endothelial cells), adhesion to CD36 and intercellular adhesion molecule 1 was pH dependent, requiring acidic conditions to be maximal in all cases. Cytoadhesion to CSA may trigger the occlusion of microvessels and cause the acidosis necessary for the other receptors to be fully efficient. If this key role in the mechanisms of sequestration were to be confirmed in vivo, prevalence studies of the CSA cytoadhesion phenotype would have to be reevaluated, because simple cytoadhesion assays do not detect CSA-specific parasites present in very low numbers, and these parasites might then be undetected in the peripheral blood but present in organs in which sequestration occurs, such as the placenta (M. Fried and P. E. Duffy, Science 272:1502–1504, 1996).

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CD36 Peptides That Block Cytoadherence Define the CD36 Binding Region for Plasmodium falciparum-Infected Erythrocytes

Blood ◽

10.1182/blood.v94.6.2121 ◽

1999 ◽

Vol 94 (6) ◽

pp. 2121-2127 ◽

Cited By ~ 45

Author(s):

Dror I. Baruch ◽

Xin C. Ma ◽

Brittan Pasloske ◽

Russell J. Howard ◽

Louis H. Miller

Keyword(s):

Endothelial Cells ◽

Plasmodium Falciparum ◽

Scavenger Receptor ◽

Intercellular Adhesion Molecule ◽

Microvascular Endothelial Cells ◽

Binding Region ◽

Intercellular Adhesion Molecule 1 ◽

Severe Pathology ◽

Variant Antigen ◽

Micromolar Range

Abstract Mature Plasmodium falciparum parasitized erythrocytes (PE) sequester from the circulation by adhering to microvascular endothelial cells. PE sequestration contributes directly to the virulence and severe pathology of falciparum malaria. The scavenger receptor, CD36, is a major host receptor for PE adherence. PE adhesion to CD36 is mediated by the malarial variant antigen, P. falciparumerythrocyte membrane protein 1 (PfEMP1), and particularly by its cysteine-rich interdomain region 1 (CIDR-1). Several peptides from the extended immunodominant domain of CD36 (residues 139-184), including CD36 139-155, CD36 145-171, CD36 146-164, and CD36 156-184 interfered with the CD36-PfEMP1 interaction. Each of these peptides affected binding at the low micromolar range in 2 independent assays. Two peptides, CD36 145-171 and CD36 156-184, specifically blocked PE adhesion to CD36 without affecting binding to the host receptor intercellular adhesion molecule-1 (ICAM-1). Moreover, an adhesion blocking peptide from the ICAM-1 sequence inhibits the PfEMP1–ICAM-1 interaction without affecting adhesion to CD36. These results confirm earlier observations that PfEMP1 is also a receptor for ICAM-1. Thus, the region 139-184 and particularly the 146-164 or the 145-171 regions of CD36 form the adhesion region for P. falciparum PE. Adherence blocking peptides from this region may be useful for modeling the PE/PfEMP1 interaction with CD36 and for development of potential anti-adhesion therapeutics.

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Characterization of Plasmodium falciparum-Infected Erythrocyte and P-Selectin Interaction Under Flow Conditions

Blood ◽

10.1182/blood.v91.12.4803 ◽

1998 ◽

Vol 91 (12) ◽

pp. 4803-4809 ◽

Cited By ~ 45

Author(s):

May Ho ◽

Tineke Schollaardt ◽

Xiaofei Niu ◽

Sornchai Looareesuwan ◽

Kamala D. Patel ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Adhesion Molecule ◽

Sialic Acid Residue ◽

Intercellular Adhesion Molecule ◽

Flow Conditions ◽

Intercellular Adhesion Molecule 1 ◽

Adhesive Interaction ◽

Lectin Domain

Abstract Plasmodium falciparum-infected erythrocytes (IRBC) roll on the adhesion molecule P-selectin in vitro under flow conditions that approximate the shear stress in capillary and postcapillary venules in which cytoadherence occurs in vivo. The pathological significance of this adhesive interaction is currently unknown. In this study, we further investigated the molecular interactions between IRBC and P-selectin by using a laminar flow system that allowed for the direct visualization of IRBC-substratum interactions. The results showed that the IRBC–P-selectin interaction was Ca2+-dependent and involved the lectin domain of P-selectin and a sialic acid residue on IRBC. The sialylated P-selectin ligand was trypsin-sensitive, which suggests that it could be part of the parasite antigen PfEMP1 that interacts with CD36 and intercellular adhesion molecule-1 (ICAM-1), but different from a trypsin-resistant IRBC ligand that adheres selectively to chondroitin sulfate A. Studies on the rolling and adhesion of IRBC on activated platelets that express both CD36 and P-selectin showed that inhibition of rolling on P-selectin reduced the adhesion of some clinical parasite isolates to CD36, whereas other parasite isolates appeared to interact directly with CD36. Thus, cytoadherence under physiological flow conditions may be mediated by multiple IRBC ligands that interact with different adhesion molecules in a cooperative fashion. These findings underscore the complexity of the interactions betweeen IRBC and vascular endothelium.

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SRY gene transferred by extracellular vesicles accelerates atherosclerosis by promotion of leucocyte adherence to endothelial cells

Clinical Science ◽

10.1042/cs20140826 ◽

2015 ◽

Vol 129 (3) ◽

pp. 259-269 ◽

Cited By ~ 14

Author(s):

Jin Cai ◽

Weiwei Guan ◽

Xiaorong Tan ◽

Caiyu Chen ◽

Liangpeng Li ◽

...

Keyword(s):

Endothelial Cells ◽

Extracellular Vesicles ◽

Vascular Endothelial Cells ◽

Umbilical Vein ◽

Gene Copy Number ◽

Intercellular Adhesion Molecule ◽

Gene Copy ◽

Sry Gene ◽

Intercellular Adhesion Molecule 1

We set out to investigate whether and how SRY (sex-determining region, Y) DNAs in plasma EVs (extracellular vesicles) is involved in the pathogenesis of atherosclerosis. PCR and gene sequencing found the SRY gene fragment in plasma EVs from male, but not female, patients; EVs from male patients with CAD (coronary artery disease) had a higher SRY GCN (gene copy number) than healthy subjects. Additional studies found that leucocytes, the major source of plasma EVs, had higher SRY GCN and mRNA and protein expression in male CAD patients than controls. After incubation with EVs from SRY-transfected HEK (human embryonic kidney)-293 cells, monocytes (THP-1) and HUVECs (human umbilical vein endothelial cells), which do not endogenously express SRY protein, were found to express newly synthesized SRY protein. This resulted in an increase in the adherence factors CD11-a in THP-1 cells and ICAM-1 (intercellular adhesion molecule 1) in HUVECs. EMSA showed that SRY protein increased the promoter activity of CD11-a in THP-1 cells and ICAM-1 in HUVECs. There was an increase in THP-1 cells adherent to HUVECs after incubation with SRY-EVs. SRY DNAs transferred from EVs have pathophysiological significance in vivo; injection of SRY EVs into ApoE−/− (apolipoprotein-knockout) mice accelerated atherosclerosis. The SRY gene in plasma EVs transferred to vascular endothelial cells may play an important role in the pathogenesis of atherosclerosis; this mechanism provides a new approach to the understanding of inheritable CAD in men.

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ICAM-1 recycling in endothelial cells: a novel pathway for sustained intracellular delivery and prolonged effects of drugs

Blood ◽

10.1182/blood-2004-05-1714 ◽

2005 ◽

Vol 105 (2) ◽

pp. 650-658 ◽

Cited By ~ 86

Author(s):

Silvia Muro ◽

Christine Gajewski ◽

Michael Koval ◽

Vladimir R. Muzykantov

Keyword(s):

Drug Delivery ◽

Endothelial Cells ◽

Fluid Phase ◽

Therapeutic Agents ◽

Intercellular Adhesion Molecule ◽

Major Fraction ◽

Intercellular Adhesion Molecule 1 ◽

Lysosomal Trafficking ◽

Fluid Phase Endocytosis

AbstractIntercellular adhesion molecule-1 (ICAM-1) is a target for drug delivery to endothelial cells (ECs), which internalize multivalent anti-ICAM nanocarriers (anti-ICAM/NCs) within 15 to 30 minutes. The concomitant ICAM-1 disappearance from the EC surface transiently inhibited subsequent binding and uptake of anti-ICAM/NCs. Within 1 hour, internalized ICAM-1 diverged from anti-ICAM/NCs into prelysosomal vesicles, resurfaced, and enabled uptake of a subsequent anti-ICAM/NC dose. Thus, internalized ICAM-1 was able to recycle back to the plasma membrane. In vivo pulmonary targeting of a second anti-ICAM/NC dose injected 15 minutes after the first dose was decreased by 50% but recovered between 30 minutes and 2.5 hours, comparable to cultured ECs. Anti-ICAM/NCs affected neither EC viability nor fluid-phase endocytosis and traffic to lysosomes. However, lysosomal trafficking of the second dose of anti-ICAM/NCs was decelerated at least 2-fold versus the first dose; hence the major fraction of anti-ICAM/NCs resided in prelysosomal vesicles for at least 5 hours without degradation. Two successive doses of anti-ICAM/NC/catalase protected ECs against H2O2 for at least 8 hours versus 2 hours afforded by a single dose, suggesting that recurrent targeting to ICAM-1 affords longer effects. ICAM-1 recycling and inhibited lysosomal traffic/degradation of subsequent doses may help to prolong activity of therapeutic agents delivered into ECs by anti-ICAM/NCs.

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Chronic excessive erythrocytosis induces endothelial activation and damage in mouse brain

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00246.2005 ◽

2006 ◽

Vol 290 (3) ◽

pp. R678-R684 ◽

Cited By ~ 16

Author(s):

O. O. Ogunshola ◽

V. Djonov ◽

R. Staudt ◽

J. Vogel ◽

M. Gassmann

Keyword(s):

Endothelial Cells ◽

Vascular Permeability ◽

Morphological Characteristics ◽

Microscopic Analysis ◽

Endothelial Activation ◽

Endothelial Damage ◽

Intercellular Adhesion Molecule ◽

Intercellular Adhesion Molecule 1 ◽

Electron Microscopic

Excessive erythrocytosis results in severely increased blood viscosity, which may have significant detrimental effects on endothelial cells and, ultimately, function of the vascular endothelium. Because blood-brain barrier stability is crucial for normal physiological function, we used our previously characterized erythropoietin-overexpressing transgenic (tg6) mouse line (which has a hematocrit of 0.8–0.9) to investigate the effect of excessive erythrocytosis on vessel number, structure, and integrity in vivo. These mice have abnormally high levels of nitric oxide (NO), a potent proinflammatory molecule, suggesting altered vascular permeability and function. In this study, we observed that brain vessel density of tg6 mice was significantly reduced (16%) and vessel diameter was significantly increased (15%) compared with wild-type mice. Although no significant increases in vascular permeability under normoxic or acute hypoxic conditions (8% O2for 4 h) were detected, electron-microscopic analysis revealed altered morphological characteristics of the tg6 endothelium. Tg6 brain vascular endothelial cells appeared to be activated, with increased luminal protrusions reminiscent of ongoing inflammatory processes. Consistent with this observation, we detected increased levels of intercellular adhesion molecule-1 and von Willebrand factor, markers of endothelial activation and damage, in brain tissue. We propose that chronic excessive erythrocytosis and sustained high hematocrit cause endothelial damage, which may, ultimately, increase susceptibility to vascular disease.

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Knob-independent cytoadherence of Plasmodium falciparum to the leukocyte differentiation antigen CD36.

Journal of Experimental Medicine ◽

10.1084/jem.171.6.1883 ◽

1990 ◽

Vol 171 (6) ◽

pp. 1883-1892 ◽

Cited By ~ 46

Author(s):

B A Biggs ◽

L Goozé ◽

K Wycherley ◽

D Wilkinson ◽

A W Boyd ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Peripheral Circulation ◽

Melanoma Cells ◽

Intercellular Adhesion Molecule ◽

Intercellular Adhesion Molecule 1 ◽

Differentiation Antigen ◽

Erythrocyte Surface ◽

Falciparum Erythrocyte Membrane Protein

The survival of Plasmodium falciparum-infected erythrocytes is enhanced by the sequestration of mature trophozoites and schizonts from the peripheral circulation. Cytoadherence of infected erythrocytes in vivo is associated with the presence of knobs on the erythrocyte surface, but we and others have shown recently that cytoadherence to C32 melanoma cells may occur in vitro in the absence of knobs. We show here that a knobless clone of P. falciparum adheres to the leukocyte differentiation antigen, CD36, suggesting that binding to CD36 is independent of the presence of knobs on the surface of the infected erythrocyte. This clone showed little cytoadherence to immobilized thrombospondin or to endothelial cells expressing the intercellular adhesion molecule 1. Furthermore, an Mr approximately 300-kD trypsin-sensitive protein doublet was immunoprecipitated from knobless trophozoite-infected erythrocytes. Finding a P. falciparum erythrocyte membrane protein 1 (PfEMP1)-like molecule on these infected erythrocytes is consistent with a role for PfEMP1 in cytoadherence to CD36 and C32 melanoma cells.

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The Nucleolar Protein Nucleophosmin Is Physiologically Secreted by Endothelial Cells in Response to Stress Exerting Proangiogenic Activity Both In Vitro and In Vivo

International Journal of Molecular Sciences ◽

10.3390/ijms22073672 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3672

Author(s):

Anna Di Carlo ◽

Sara Beji ◽

Silvia Palmerio ◽

Mario Picozza ◽

Marco D’Agostino ◽

...

Keyword(s):

Endothelial Cells ◽

Growth Factor ◽

Biological Effects ◽

Intercellular Adhesion Molecule ◽

Serum Starvation ◽

Cell Necrosis ◽

Intercellular Adhesion Molecule 1 ◽

First Time

Nucleophosmin (NPM), a nucleolar multifunctional phosphoprotein, acts as a stress sensor in different cell types. NPM can be actively secreted by inflammatory cells, however its biology on endothelium remains unexplored. In this study, we show for the first time that NPM is secreted by human vein endothelial cells (HUVEC) in the early response to serum deprivation and that NPM acts as a pro-inflammatory and angiogenic molecule both in vitro and in vivo. Accordingly, 24 h of serum starvation condition induced NPM relocalization from the nucleus to cytoplasm. Interestingly, NPM was increasingly excreted in HUVEC-derived conditioned media in a time dependent fashion upon stress conditions up to 24 h. The secretion of NPM was unrelated to cell necrosis within 24 h. The treatment with exogenous and recombinant NPM (rNPM) enhanced migration as well as the Intercellular Adhesion Molecule 1 (ICAM-1) but not Vascular cell adhesion protein 1 (VCAM-1) expression and it did not affect cell proliferation. Notably, in vitro tube formation by Matrigel assay was significantly increased in HUVEC treated with rNPM compared to controls. This result was confirmed by the in vivo injection of Matrigel plug assay upon stimulation with rNPM, displaying significant enhanced number of functional capillaries in the plugs. The stimulation with rNPM in HUVEC was also associated to the increased expression of master genes regulating angiogenesis and migration, including Vascular Endothelial Growth Factor-A (VEGF-A), Hepatocyte Growth Factor (HGF), Stromal derived factor-1 (SDF-1), Fibroblast growth factor-2 (FGF-2), Platelet Derived Growth Factor-B (PDGF-B), and Matrix metallopeptidase 9 (MMP9). Our study demonstrates for the first time that NPM is physiologically secreted by somatic cells under stress condition and in the absence of cell necrosis. The analysis of the biological effects induced by NPM mainly related to a pro-angiogenic and inflammatory activity might suggest an important autocrine/paracrine role for NPM in the regulation of both phenomena.

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Stringent Selection of Knobby Plasmodium falciparum-Infected Erythrocytes during Cytoadhesion at Febrile Temperature

Microorganisms ◽

10.3390/microorganisms8020174 ◽

2020 ◽

Vol 8 (2) ◽

pp. 174 ◽

Cited By ~ 1

Author(s):

Michael Dörpinghaus ◽

Finn Fürstenwerth ◽

Lisa K. Roth ◽

Philip Bouws ◽

Maximilian Rakotonirinalalao ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Erythrocyte Membrane ◽

Malaria Infection ◽

Binding Capacity ◽

Intercellular Adhesion Molecule ◽

Intercellular Adhesion Molecule 1 ◽

Var Genes ◽

Stringent Selection ◽

Falciparum Erythrocyte Membrane Protein ◽

Selection Of

Changes in the erythrocyte membrane induced by Plasmodium falciparum invasion allow cytoadhesion of infected erythrocytes (IEs) to the host endothelium, which can lead to severe complications. Binding to endothelial cell receptors (ECRs) is mainly mediated by members of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family, encoded by var genes. Malaria infection causes several common symptoms, with fever being the most apparent. In this study, the effects of febrile conditions on cytoadhesion of predominately knobless erythrocytes infected with the laboratory isolate IT4 to chondroitin-4-sulfate A (CSA), intercellular adhesion molecule 1 (ICAM-1), and CD36 were investigated. IEs enriched for binding to CSA at 40 °C exhibited significantly increased binding capacity relative to parasites enriched at 37 °C. This interaction was due to increased var2csa expression and trafficking of the corresponding PfEMP1 to the IE surface as well as to a selection of knobby IEs. Furthermore, the enrichment of IEs to ICAM-1 at 40 °C also led to selection of knobby IEs over knobless IEs, whereas enrichment on CD36 did not lead to a selection. In summary, these findings demonstrate that knobs are crucial for parasitic survival in the host, especially during fever episodes, and thus, that selection pressure on the formation of knobs could be controlled by the host.

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Synergism of multiple adhesion molecules in mediating cytoadherence of Plasmodium falciparum–infected erythrocytes to microvascular endothelial cells under flow

Blood ◽

10.1182/blood.v96.6.2292.h8002292_2292_2298 ◽

2000 ◽

Vol 96 (6) ◽

pp. 2292-2298 ◽

Cited By ~ 1

Author(s):

Bryan G. Yipp ◽

Samantha Anand ◽

Tineke Schollaardt ◽

Kamala D. Patel ◽

Sornchai Looareesuwan ◽

...

Keyword(s):

Endothelial Cells ◽

Plasmodium Falciparum ◽

Adhesion Molecules ◽

Adhesion Molecule ◽

Oncostatin M ◽

Intercellular Adhesion Molecule ◽

Microvascular Endothelial Cells ◽

Intercellular Adhesion Molecule 1 ◽

Microvascular Endothelium ◽

Microvascular Endothelial

Plasmodium falciparum–infected erythrocytes (IRBCs) have been shown to interact with a number of endothelial adhesion molecules expressed on transfectants, on cell lines, and as immobilized purified receptor proteins under flow conditions. However, the experiments were designed in such a way that maximal numbers of adhesion molecules were provided as substratum. Whether the interactive events actually occur on microvascular endothelium, where the distribution and expression of adhesion molecules may be less, remains undetermined. In this study, the cytoadherance of IRBCs on human dermal microvascular endothelial cells (HDMECs) as a model of human microvasculature was examined. IRBCs were observed to tether, roll, and adhere on resting HDMECs, which constitutively expressed CD36 and intercellular adhesion molecule-1 (ICAM-1) at an optimal shear stress of 1 dyne/cm2. Stimulation of HDMECs with tumor necrosis factor–α for 5 and 24 hours, which resulted in up-regulation of ICAM-1 and induction of vascular cell adhesion molecule-1 expression, significantly increased the percentage of rolling cells that adhered without affecting the rolling flux. In contrast, P-selectin expression on HDMECs induced by oncostatin M led to an increase in both rolling flux and adhesion. Inhibition studies with receptor-specific monoclonal antibodies revealed that adhesion of IRBCs on HDMECs was largely CD36 dependent, whereas rolling could be mediated by any of the adhesion molecules studied. Collectively, these findings indicate that IRBCs interact synergistically with multiple adhesion molecules on vascular endothelium. The rolling of IRBCs may be the rate-limiting step in cytoadherance, since it can be modulated by cytokines to enhance CD36-mediated IRBC adhesion.

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