Src-family kinase signaling modulates the adhesion of Plasmodium falciparum on human microvascular endothelium under flow.
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 human dermal microvascular endothelial cells (HDMECs), induces intracellular signaling and regulates adhesion. A recombinant peptide corresponding to the minimal CD36-binding domain from P falciparum erythrocyte membrane protein 1 (PfEMP1), as well as an anti-CD36 monoclonal antibody (mAb) that inhibits IRBC binding, activated the mitogen-activated protein (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 <.001). More importantly, Src-family kinase activity was also required for cytoadherence to intact human microvessels in a human/severe combined immunodeficient (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 extracellular signal-regulated kinase 1/2 (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 ectoalkaline phosphatase. Targeting endothelial ectoalkaline phosphatases and/or signaling molecules may constitute a novel therapeutic strategy against severe falciparum malaria.
Yipp
Bryan G
BG
Immunology Research Group, Department of Microbiology and Infectious Diseases, University of Calgary, AB, Canada.
Robbins
Stephen M
SM
Resek
Mary E
ME
Baruch
Dror I
DI
Looareesuwan
Sornchai
S
Ho
May
M
D000469:Alkaline Phosphatase / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D018955:CD36 Antigens / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D002448:Cell Adhesion / Q000187:drug effects; D004730:Endothelium, Vascular / Q000737:chemistry / Q000166:cytology*; D004912:Erythrocytes / Q000469:parasitology / Q000473:pathology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D016513:Mice, SCID; D008833:Microcirculation; D010446:Peptide Fragments / Q000494:pharmacology; D010477:Perfusion; D010963:Plasmodium falciparum / Q000166:cytology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D019061:src-Family Kinases / Q000502:physiology*
D018955:CD36 Antigens; D010446:Peptide Fragments; D019061:src-Family Kinases; D000469:Alkaline Phosphatase