MICROVASCULAR HEMODYNAMICS AND IN-VIVO EVIDENCE FOR THE ROLE OF INTERCELLULAR-ADHESION MOLECULE-1 IN THE SEQUESTRATION OF INFECTED RED-BLOOD-CELLS IN A MOUSE MODEL OF LETHAL MALARIA

The cytoadherence of infected red blood cells (IRBCs) to the vascular endothelium is the major cause of IRBC sequestration and vessel blocka ge in the cerebral form of human malaria. Among the rodent models of m alaria, Plasmodium yoelii 17XL-infected mice show many similarities wi th the human cerebral malaria caused by P. falciparum. in both, the se questration of IRBCs in the brain vessels is secondary to the cytoadhe rence of IRBCs to the vascular endothelium. Similar to P. falciparum i nfection in the human but in contrast to P. berghei ANKA infection in mice, P. yoelii 17XL results in Little, if any, accumulation of monocy tes in the brain. In vivo microcirculatory studies reported here were designed to further understand the hemodynamic aspects and mechanisms underlying cytoadherence of IRBCs in the P. yoelii model using the eas ily accessible cremaster muscle vasculature. The results show signific ant decreases in arteriovenous red blood cell velocities (Vrbc) and wa ll shear rates in the microcirculation of P. yoelii-infected mice, wit h a maximal decrease occurring in small-diameter postcapillary venules , the main sites of cytoadherence. This reflects contributions from IR BC cytoadherence as well as from increased rigidity of parasitized red blood cells. No cytoadherence is observed in arterioles of the infect ed mice despite decreased wall shear rates, indicating that endothelia l receptors for cytoadherence are restricted to venules. Infusion of a monoclonal antibody (MAb) against the intercellular adhesion molecule -1 (ICAM-1) resulted in significant increases in both arteriolar and v enular Vrbc and wall shear rates, accompanied by detachment of adhered IRBCs at some venular sites. The peripheral blood smears taken after the MAb infusion showed a distinct increase in the percentage of schiz onts, again indicating detachment and/or prevention of cytoadherence. An MAb against the vascular cell adhesion molecule-1 (VCAM-1) as well as an irrelevant control antibody had no effect on these parameters. T hese results provide the first in vivo microcirculatory evidence indic ating involvement of ICAM-1, but not of VCAM-1, in the sequestration o f IRBCs in a rodent model of cerebral malaria.