Introduction

The adhesion of infected erythrocytes containing mature stages of the parasite Plasmodium falciparum (IRBCs) to host endothelium is a key pathogenic process of the infection. The resulting sequestration of IRBCs in the microvas-culature leads to tissue hypoxia, metabolic disturbances, multiorgan dysfunction, and ultimately the death of 1 to 2 million patients worldwide annually. Under physiological flow conditions, the process of cytoadherence is mediated by the parasite protein Plasmodium falciparum erythrocyte membrane protein 1 (PfEMPl) expressed on the surface of IRBCs, and its synergistic interactions with a number of endothelial receptor molecules, mimicking the adhesive events in the leukocyte recruitment cascade. In previous studies, we demonstrated that although IRBCs from clinical parasite isolates can tether and roll on intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and P-selectin, they adhere preferentially to CD36 on microvascular endothelial cells.

In addition to serving as points of attachment, adhesion molecules are known to serve as receptor signaling molecules capable of transducing an extracellular signal leading to cellular activation. Such signaling activities have been reported for a number of adhesion molecules including the selectins, the immunoglobulin superfamily of adhesion molecules, and integrins, all of which play critical roles in leukocyte recruitment to sites of inflammation.

In this review, we will discuss recent experimental data that indicate that the adhesion of IRBCs to CD36 can also lead to endothelial intracellular signaling. Furthermore, the evidence suggests that there are both outside-in and inside-out signaling mechanisms that modulate the affinity of the

IRBC-CD36 interaction through a change in the phosphorylation state of endothelial CD36. Vascular endothelium thus has a much more dynamic role in cytoadherence than previously recognized. The proposed novel intracellular signaling mechanism involving CD36, Src-family kinases, and an ecto-alkaline phosphatase could potentially be exploited to inhibit the pathophysiological chain of events seen in patients with severe falciparum malaria.

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