Rosetting of Plasmodium falciparum-infected red blood cells with uninfected red blood cells enhances microvascular obstruction under flow conditions

Abstract

The occurrence of rosetting of Plasmodium falciparum-infected human red blood cells (IRBC) with uninfected red blood cells (RBC) and its potential pathophysiologic consequences were investigated under flow conditions using the perfused rat mesocecum vasculature. Perfusion experiments were performed using two knobby (K+) lines of P falciparum, ie, rosetting positive (K+R+) and rosetting negative (K+R-). The infusion of K+R+ IRBC resulted in higher peripheral resistance (PRU) than K+R- IRBC (P less than .0012). Video microscopy showed that under conditions of flow, in addition to cytoadherence of K+R+ IRBC to the venular endothelium, rosette formation was also restricted to venules, especially in the areas of slow flow. Rosettes were absent in arterioles and were presumably dissociated by higher wall shear rates. The presence of rosettes in the venules must therefore reflect their rapid reformation after disruption. Cytoadherence of K+R+ IRBC was characterized by formation of focal clusters along the venular wall. In addition, large aggregates of RBC were frequently observed at venular junctions, probably as a result of interaction between flowing rosettes, free IRBC, and uninfected RBC. In contrast, the infusion of K+R+ IRBC resulted in diffuse cytoadherence of these cells exclusively to the venular endothelium but not in rosetting or large aggregate formation. The cytoadherence of K+R+ IRBC showed strong inverse correlation with the venular diameter (r = -.856, P less than .00001). Incubation of K+R+ IRBC with heparin and with monoclonal antibodies to glycoprotein IV/CD36 abolished the rosette formation and resulted in decreased PRU and microvascular blockage. These findings demonstrate that rosetting of K+R+ IRBC with uninfected RBC enhances vasocclusion, suggesting an important in vivo role for rosetting in the microvascular sequestration of P falciparum-infected RBC.

The malaria-infected red blood cell: Structural and functional changes

“…A second possibility is that the rosettes interfere with circulation of the blood, leading to a greater degree of microvascular obstruction, and perhaps increased pathology. Consistent with this is the observation that in the rat ex vivo mesoappendix model, perfusion of rosetting parasites showed higher levels of vascular resistance than with non-rosetting parasites (Kaul et al, 1991). Alternatively, the parasite in a rosette may have less exposure to serum antibodies directed to parasite antigens on the surface of the infected red blood cells, such as PfEMP1, or to surface proteins of the merozoite during invasion.…”

Complement Receptor 1: Disease associations and therapeutic implications

“…The first mechanism suggests microvasular obstruction brought about by rosetting of erythrocytes in the microvasculature of various vital organs. The second mechanism suggested is immune complex mediated (Kaul et al, 1991), Immune complexes, by multiple downstream pathways and complement activation-induced metabolic dysfunction, cause tissue injury and multi-organ failure (June et al, 1979;Nagayasu et al, 2001). None of these suggested mechanisms could explain all the above complications.…”

The role of rosetting in the multiplication of Plasmodium falciparum: rosette formation neither enhances nor targets parasite invasion into uninfected red cells

“…Rosetting might be important in pathogenesis in three ways. Using an ex vivo model it has been suggested that rosetting, by causing aggregates of cells, leads to microvasculature obstruction (Kaul et al, 1991). This in turn raises vascular resistance and assists in the process of sequestration in which mature forms of the parasite bind to specific receptors on endothelial cells in post-capillary venules and fail to circulate.…”