Breaking down the blood–brain barrier: signaling a path to cerebral malaria?

Adams, Sue K.; Brown, Hilary F.; Turner, Gareth D. H.

doi:10.1016/s1471-4922(02)02353-x

Cited by 106 publications

(81 citation statements)

References 54 publications

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“…Such effects may be intensified due to the enhanced cytoadherence of Pf-RBCs to the vascular endothelium (3)(4)(5)(6). This adherence of Pf-RBCs is believed to be the main cause of bleeding complications in cerebral malaria due to blockages of small vessels in the brain (7). Unlike the extensive research on leukocytes, very few in vitro experiments (8)(9)(10)(11) have examined the adhesive dynamics of Pf-RBCs.…”

mentioning

confidence: 99%

Quantifying the biophysical characteristics of Plasmodium-falciparum -parasitized red blood cells in microcirculation

Fedosov

Caswell

Suresh

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

169

141

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The pathogenicity of Plasmodium falciparum (Pf) malaria results from the stiffening of red blood cells (RBCs) and its ability to adhere to endothelial cells (cytoadherence). The dynamics of Pf-parasitized RBCs is studied by three-dimensional mesoscopic simulations of flow in cylindrical capillaries in order to predict the flow resistance enhancement at different parasitemia levels. In addition, the adhesive dynamics of Pf-RBCs is explored for various parameters revealing several types of cell dynamics such as firm adhesion, very slow slipping along the wall, and intermittent flipping. The parasite inside the RBC is modeled explicitly in order to capture phenomena such as "hindered tumbling" motion of the RBC and the sudden transition from firm RBC cytoadherence to flipping on the endothelial surface. These predictions are in quantitative agreement with recent experimental observations, and thus the three-dimensional modeling method presented here provides new capabilities for guiding and interpreting future in vitro and in vivo studies of malaria.adhesion | erythrocyte | malaria | mechanical properties | dissipative particle dynamics R ed blood cells parasitized by Plasmodium falciparum (Pf-RBCs) undergo irreversible changes in structure and biophysical characteristics, which can lead to drastically altered blood circulation. The membrane shear modulus of infected RBCs may increase up to ten-fold causing capillary occlusions (1, 2), thereby resulting in substantial increase in resistance to blood flow. Such effects may be intensified due to the enhanced cytoadherence of Pf-RBCs to the vascular endothelium (3-6). This adherence of Pf-RBCs is believed to be the main cause of bleeding complications in cerebral malaria due to blockages of small vessels in the brain (7). Unlike the extensive research on leukocytes, very few in vitro experiments (8-11) Recent progress in multiscale numerical modeling (12-14) allows us to model soft matter, and RBCs in particular, at sufficient detail, i.e., simulating nanometer scales while simultaneously capturing the large scale dynamics. We have developed and validated a Dissipative Particle Dynamics (DPD) model (12, 14-16) that can accurately simulate the properties and dynamic behavior of healthy RBCs as well as Pf-RBCs. The multiscale model can represent a RBC at the spectrin level with 30,000 points (17) or at a coarser level with 500 points by proper scaling of the physiologically correct parameters (12, 14, 15); hence, no ad hoc calibration is required. The predictive capability of the DPD model has been demonstrated in comparisons with microfluidic experiments that probe controlled pressure-velocity relationships of (healthy) RBC flow through microchannels whose inner openings mimic the smallest dimensions for RBC passage in the microvasculature (16). In addition, we have extended the adhesive dynamics model of (18,19) to the DPD framework, and validated it by simulating the adhesive dynamics of leukocytes for which extensive experimental results exist (20,21). In summary, ...

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confidence: 99%

Quantifying the biophysical characteristics of Plasmodium-falciparum -parasitized red blood cells in microcirculation

Fedosov

Caswell

Suresh

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

169

141

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“…PRBC cytoadherence in the microvasculature of organs, such as the brain and lungs is modulated by platelets 6,7 and mediated by endothelial cell-surface receptors such as thrombospondin, CD36, intracellular adhesion molecule-1, vascular cellular adhesion molecule-1, CD31, integrins and hyaluronic acid. 8 PRBC adhesion to endothelial cell receptors can induce (1) over-production of various inflammatory cytokines, such as interferon-γ, tumor necrosis factor-α, transforming growth factor-β, interleukin-1 (IL-1), IL-6, IL-10 and IL-18 by endothelial cells, 3,7 (2) phosphorylation and activation of endothelial cell cytosketal proteins such as cortactin, which increases junctional permeability through cytoskeleton changes, 9 and (3) caspase activation and apoptosis. 10 Most studies of interactions between PRBC and endothelial cell receptors have been done in vitro.…”

mentioning

confidence: 99%

Cytoadherence and Genotype of Plasmodium falciparum Strains from Symptomatic Children in Franceville, Southeastern Gabon

Touré¹,

Ouwe-Missi-Oukem-Boyer²,

Mezui-Me-Ndong³

et al. 2007

Clinical Medicine & Research

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“…More recently, Adams et al (2002) have suggested that the adherence of the PRBC to cerebral endothelium activates secondary signalling events (see Figure 1) similar to leucocytes, which cause functional changes to the BBB, allowing passage of compounds that alter neuronal function. Unlike the leucocytes, the PRBC remain attached to the endothelium, and thus do not enter the brain parenchyma, except with haemorrhages.…”

Section: Pathogenesis Of the Neurological Complications Of Falciparummentioning

confidence: 99%

“…Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP-1)-mediated parasite adhesion to ICAM-1 might mimic these events. Alterations to paracellular permeability would allow leakage of plasma proteins and mediators into the perivascular space, causing activation of pericytes, astrocytes and microglia (see Figure 2; Adams et al 2002). membrane.…”

Section: Morphological Vs Functional Blood-brain Barriermentioning

confidence: 99%

Review Article: Blood-brain barrier in falciparum malaria*

Gitau

Newton

2005

Trop Med Int Health

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SummaryPlasmodium falciparum malaria is the most important parasitic disease infecting the central nervous system of humans worldwide. The pathogenesis of the neurological complications of falciparum malaria remains unclear. In particular, how do asexual parasites confined to the vascular space of the brain cause neuronal impairment? The evidence for a breakdown in the blood-brain barrier (BBB) is conflicting. In some animal models of malaria, there is evidence of breakdown of the BBB, but the data from humans suggests the BBB is mildly impaired only, with few morphological changes. Whether these changes in the BBB are sufficient to account for the neurological complications remains to be determined.keywords falciparum malaria, blood-brain barrier impairment

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Breaking down the blood–brain barrier: signaling a path to cerebral malaria?

Cited by 106 publications

References 54 publications

Quantifying the biophysical characteristics of Plasmodium-falciparum -parasitized red blood cells in microcirculation

Quantifying the biophysical characteristics of Plasmodium-falciparum -parasitized red blood cells in microcirculation

Cytoadherence and Genotype of Plasmodium falciparum Strains from Symptomatic Children in Franceville, Southeastern Gabon

Review Article: Blood-brain barrier in falciparum malaria*

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