Abstract
Cytoadherence of Plasmodium falciparum-infected red blood cells (IRBCs) on human microvascular endothelium is mediated by synergistic adhesive interactions with different adhesion molecules in vitro. Here, the authors used a unique human/severe combined immunodeficient (SCID) mouse chimeric model to directly visualize IRBC–endothelial interactions in an intact human microvasculature in vivo. Stimulation of human skin grafts with 100 ng TNF-α for 4 h led to a dramatic reduction in the distance rolled by IRBCs before arrest, so that the majority of IRBCs adhered directly to the endothelium with a 1.8-fold increase in the number of adherent cells. The decrease in rolling distance and increase in adhesion could be reversed by anti-ICAM-1. More importantly, the effect of TNF-α could be seen only in the presence of CD36. A further increase in adhesion by 4.9-fold was observed after 24 h of TNF-α stimulation. The increase could be reversed by anti-ICAM-1, but not anti-VCAM-1. In histamine-stimulated grafts, the rolling flux fraction and adhesion increased by 2.8- and 1.6-fold, respectively. The increases were attributable to P-selectin as an inhibitory anti-P-selectin antibody abrogated both the increased rolling flux fraction and firm adhesion. These findings indicate that in addition to CD36, ICAM-1, and P-selectin are major contributors to the dynamic process of IRBC adhesion by different mechanisms in vivo.
The authors thank Robert Lindsay, Department of Surgery, Foothills Hospital, Calgary, Alberta, Canada for providing the skin specimens, and Carol Gwozd for expert help with the immunohistochemistry. This research was supported by a grant (MT14104) from the Canadian Institutes of Health Research (CIHR) and an Alberta Heritage Foundation for Medical Research (AHFMR) Senior Scholar Award (to M.H.), Clinical Investigator Award (to A.M.), postdoctoral fellowship (to M.H. and G.A.), and studentship (to B.Y.). PK is an AHFMR scientist and CRC Chair.