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Selection of Plasmodium falciparum Parasites for Cytoadhesion to Human Brain Endothelial Cells
Published on: January 3, 2012
Pathophysiology of cerebral malaria: role of host cells in the modulation of cytoadhesion
Samuel C Wassmer1, Valéry Combes, Georges E Grau
1Unité de Parasitologie Expérimentale, EA 3282, IFR 48, Faculties of Medicine and Pharmacy, Université de la Méditerranée, F-13 385 Marseille Cedex 05, France.
Abstract:
Cerebral malaria (CM), one of the most serious complications of Plasmodium falciparum infection, is characterized by the sequestration of infected erythrocytes (IEs) in cerebral microvascular beds. The precise mechanisms involved in the onset of neuropathology remain unknown, but parasite sequestration in the brain, metabolic disturbances, and host immune responses all play a role. Studies in a murine model of CM showed a potential role for host cells, especially platelets, in the pathogenesis of CM. Indeed, urokinase plasminogen activator receptor (uPAR; CD87) deficiency attenuates the severity of CM, most likely by its important role in platelet kinetics and trapping. These results led us to evaluate whether platelets have a role in the human disease. By immunostaining of brain samples from Malawian patients, we determined that the surface of platelet accumulation and the proportion of vessels filled with platelets were significantly higher in patients who died of CM than in those who died of other causes. We then investigated the role of platelets in IE cytoadhesion in vitro, using CD36-binding IE (IECD36) and CD36-deficient (CD36DEF) brain microvascular endothelial cells (ECs). Coincubation studies indicated that platelets can induce strong IECD36 binding to CD36DEF ECs and, conversely, can hide constitutively expressed falciparum receptors such as chondroitin sulfate A. Thus, platelets may provide an adhesion receptor to microvascular beds originally devoid of it. This novel mechanism of cytoadhesion may reorient the sequestration of different parasite phenotypes and play an important role in the pathogenesis of severe malaria.
Insights
Platelets play a critical role in severe cerebral malaria (CM) pathogenesis. They enhance infected erythrocyte adhesion to brain vessels and may mediate parasite sequestration, contributing to CM severity in humans.
Area of Science:
- Immunology
- Pathology
- Hematology
Background:
- Cerebral malaria (CM), a severe complication of Plasmodium falciparum infection, involves infected erythrocyte sequestration in brain microvasuclar beds.
- Pathogenesis mechanisms are unclear, but parasite sequestration, metabolic issues, and immune responses are implicated.
- Murine models suggest host cells, particularly platelets, contribute to CM pathogenesis.
Purpose of the Study:
- To investigate the role of platelets in the pathogenesis of human cerebral malaria.
- To determine if platelets influence infected erythrocyte cytoadhesion in the brain.
Main Methods:
- Immunostaining of brain samples from Malawian patients (CM vs. non-CM deaths).
- In vitro cytoadhesion assays using CD36-binding infected erythrocytes (IEs) and endothelial cells (ECs).
- Coincubation studies with platelets and IEs on CD36-deficient ECs.
Main Results:
- Significantly higher platelet accumulation and vessel occupancy in CM patient brains compared to controls.
- Platelets induced strong IE binding to CD36-deficient ECs in vitro.
- Platelets can mask or provide alternative adhesion receptors for IEs.
Conclusions:
- Platelets are implicated in the pathogenesis of human cerebral malaria.
- Platelets may facilitate infected erythrocyte sequestration by providing novel adhesion mechanisms.
- This platelet-mediated cytoadhesion mechanism could be crucial in severe malaria.
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