In vivo sequestration of Plasmodium falciparum-infected human erythrocytes: a severe combined immunodeficiency mouse model for cerebral malaria.

Abstract

SummaryCerebral malaria is a fatal complication of infection by Plasmodiumfakiparum in man. The neurological symptoms that characterize this form of malarial disease are accompanied by the adhesion of infected erythrocytes to the vasculature of the brain. To study this phenomenon in vivo, an acute phase severe combined immunodeficiency (SCID) mouse model was developed in which sequestration of P.fakiparum-infected human erythrocytes took place. During acute cerebral malaria in humans, the expression of intercellular adhesion molecule-1 (ICAM-1) is induced in vascular endothelium by inflammatory reactions. Acute phase ICAM-1 expression can also be obtained in SCID mice. The endothelium of the midbrain region was the most responsive to such inflammatory stimulus. It is noteworthy that the reticular formation in the midbrain controls the level of consciousness, and loss of consciousness is a symptom of cerebral malaria. We found that infected human erythrocytes were retained 24 times more than normal erythrocytes in ICAM-1-positive mouse brain. Sequestration to the brain was reduced by anti-ICAM-1 antibodies. These in vivo results were confirmed by the binding of P. fakiparum-infected erythrocytes to the ICAM-l-positive endothelium in tissue sections of mouse brain. We conclude that the SCID mouse serves as a versatile in vivo model that allows the study ofP.fakiparum-infected erythrocyte adhesion as it occurs in human cerebral malaria. Upregulation of ICAM-1 expression in the region of the midbrain correlates with increased retention of malaria-infected erythrocytes and with the symptoms of cerebral malaria.p , lasmodium falciparum, one of the four plasmodium spedes that infect man, produces a fulminant disease that can lead to severe cerebral symptoms. Every year, this parasite causes about 250 million clinical cases of malaria (1). Approximately 2 million individuals, mainly children under 5 years of age, die from the main complications, which are cerebral malaria and severe anemia. A special feature of P. falciparum pathology is the absence of mature intraerythrocytic stages of the parasite in the circulating blood. Mature forms are found attached to the lining of microvessels in peripheral organs. This adhesion of infected erythrocytes to the vascular endothelium is called sequestration. Clinically severe neurological symptoms correlate with a much higher frequency of sequestered parasitized erythrocytes in the brain vasculature compared to other organs (2).Sequestration is thought to depend on differences between P.fakiparum strains leading to the expression of different erythrocyte surface molecules mediating adhesion to endothelia, as well as variation in the production of endotoxins eliciting a TNF-ot response by host macrophages (3). Thus, sequestration depends also on the susceptibility of the host to endotoxins, the subsequent regulation of adhesion molecules, and the host's level of immunity (4). A key role is played by TNF. Its plasma concentration levels are elevated in patients with fatal cerebral m...

Differential Binding of Clonal Variants ofPlasmodium falciparumto Allelic Forms of Intracellular Adhesion Molecule 1 Determined by Flow Adhesion Assay

“…Adhesion of infected erythrocytes to endothelial cells is of prime importance in causing sequestration and mediating the pathological effects of cerebral malaria in the brain. Many endothelial ligands are known to mediate binding of PBRC, and a number of studies support a role for ICAM-1 binding in the pathology of cerebral malaria (13,27,31). Recently, an allelic form of this protein (ICAM-1 Kilifi ) (10) which has been associated with increased susceptibility to cerebral malaria in Kenya, but not The Gambia, has been described (3).…”

“…In vivo studies of animals and of humans support a role for ICAM-1 as a sequestration receptor, particularly in the brain, where it is implicated in the pathology of cerebral malaria (13,27,31). The most direct evidence comes from immunohistochemical staining, which has revealed up-regulation of ICAM-1 and colocalization with adherent PRBC in the cerebral vasculature of fatal cases of falciparum malaria (27).…”

ICAM-1: Isoforms and Phenotypes

“…In rodents, innoculation of C567BL/6 mice with Plasmodium berghei ANKA iRBCs has recently become a widely used model for ECM (69–71). Additional evidence to support a role for ICAM-1 in ECM comes from studies demonstrating that anti-ICAM-1 antibody treatment abrogates iRBC adherence and rolling in both in vitro and in vivo model systems (66, 68, 72). However, direct evidence implicating an important role for ICAM-1 and its isoforms in ECM has been lacking until recently.…”

Experimental Cerebral Malaria Develops Independently of Endothelial Expression of Intercellular Adhesion Molecule-1 (ICAM-1)

“…In experimental cerebral malaria (ECM), the animal model of CM, treatment with anti-ICAM-1 antibodies markedly inhibited rolling and iRBC sequestration in the central nervous system (3,4,15). Anti-ICAM-1 antibodies also inhibited adherence and rolling of iRBCs on LPS-primed brain sections or ICAM-1-transfected cells (3). Furthermore, there are reports that ICAM-1 polymorphisms are associated with severe forms of malaria, particularly CM, although this remains controversial (16 -18).…”