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Prepublished online as a Blood First Edition Paper on November 27, 2002; DOI 10.1182/blood-2002-09-2841.
Submitted September 20, 2002
Accepted November 6, 2002
Src-family kinase signaling modulates the adhesion of Plasmodium falciparum on human microvascular endothelium under flow
Bryan G Yipp, Stephen M Robbins, Mary E Resek, Dror I Baruch, Sornchai Looareesuwan, and May Ho*
Microbiology & Infectious Diseases, University of Calgary, Calgary, Alberta, Canada
Oncology/Molecular Biology & Biochemistry, University of Calgary, Calgary, Alberta, Canada
Laboratory for Parasitic Diseases, National Institutes of Health, Bethesda, MD, USA
Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
* Corresponding author; email: mho{at}ucalgary.ca.
The pathogenicity of Plasmodium falciparum is due to the unique ability of infected erythrocytes (IRBCs) to adhere to vascular endothelium. We investigated whether adhesion of IRBCs to CD36, the major cytoadherence receptor on dermal microvascular endothelial cells (HDMECs), induces intracellular signaling and regulates adhesion. A recombinant peptide corresponding to the minimal CD36 binding domain from Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), as well as an anti-CD36 mAb that inhibits IRBC binding, activated the MAP kinase pathway that was dependent on Src-family kinase activity. Treatment of HDMECs with a Src-family kinase selective inhibitor (PP1) inhibited adhesion of IRBCs in a flow chamber assay by 72% (p < 0.001). More importantly, Src-family kinase activity was also required for cytoadherence to intact human microvessels in a human/SCID mouse model in vivo. The effect of PP1 could be mimicked by levamisole, a specific alkaline phosphatase inhibitor. Firm adhesion to PP1-treated endothelium was restored by exogenous alkaline phosphatase. In contrast, inhibition of the ERK 1/2 and p38 MAP kinase pathways had no immediate effect on IRBC adhesion. These results suggest a novel mechanism for the modulation of cytoadherence under flow conditions through a signaling pathway involving CD36, Src-family kinases and an ecto-alkaline phosphatase. Targeting endothelial ecto-alkaline phosphatases and/or signaling molecules may constitute a novel therapeutic strategy against severe falciparum malaria.
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