A Quantitative Analysis of the Microvascular Sequestration of Malaria Parasites in the Human Brain

Abstract

Microvascular sequestration was assessed in the brains of 50 Thai and Vietnamese patients who died from severe malaria (Plasmodium falciparum, 49; P. vivax, 1). Malaria parasites were sequestered in 46 cases; in 3 intravascular malaria pigment but no parasites were evident; and in the P. vivax case there was no sequestration. Cerebrovascular endothelial expression of the putative cytoadherence receptors ICAM-1 , VCAM-1 , E-selectin , and chondroitin sulfate and also HLA class II was increased. The median (range) ratio of cerebral to peripheral blood parasitemia was 40 (1.8 to 1500). Within the same brain different vessels had discrete but different populations of parasites, indicating that the adhesion characteristics of cerebrovascular endothelium change asynchronously during malaria and also that significant recirculation of parasitized erythrocytes following sequestration is unlikely. The median (range) ratio of schizonts to trophozoites (0.15:1; 0.0 to 11.7) was significantly lower than predicted from the parasite life cycle (P < 0.001). Antimalarial treatment arrests development at the trophozoite stages which remain sequestered in the brain. There were significantly more ring form parasites (age < 26 hours) in the cerebral microvasculature (median range: 19%; 0 -90%) than expected from free mixing of these cells in the systemic circulation (median range ring parasitemia: 1.8%; 0 -36.2%). All developmental stages of P. falciparum are sequestered in the brain in severe malaria. (Am J Pathol 1999, 155:395-410)Severe falciparum malaria remains one of the most important causes of death in the tropics. Cerebral malaria is the major lethal manifestation of this infection. The sequestration of red blood cells containing mature forms of Plasmodium falciparum in the cerebral microvasculature is considered to be the essential underlying pathological process, although how this leads to coma and death remains unresolved.

On the Pathogenic Role of Brain-Sequestered αβ CD8+ T Cells in Experimental Cerebral Malaria

“…The other striking difference concerned leukocytes in the microvessels, which were relatively more numerous in CM brain sections as compared with NCM ones. The distribution of the leukocytes in the capillaries was observed to be uneven, reflecting observations in humans for both leukocytes (22) and sequestered infected RBCs (23). Therefore, we widened our investigations to include the total number of adherent immune cells present in the whole brain.…”

Febrile temperatures induce cytoadherence of ring-stage Plasmodium falciparum -infected erythrocytes

“…To accommodate dependence on parasitaemia, the results were normalized to 1% infected red blood cells of each isolate. To compare the effects of different febrile temperatures, five different parasite isolates with parasites of similar maturation, estimated morphologically to be between 5 and 10 h after red blood cell invasion (9), were incubated at 37°, 38°, 39°, and 40°C for 6 h and tested in the same way.…”

“…All thin films were stained with Giemsa. The stage of development of 100 parasites in the thin blood films was assessed and the size and development of the parasites compared by using computerized image processing (9). The differences in maturation of the parasites from both cultures were compared by using ANOVA.…”

“…It is thought to involve a multistep interaction between parasite derived molecules expressed on the red blood cell surface (1)(2)(3)(4) and receptor molecules present on the surface of endothelial cells (5,6) or other red blood cells (7,8). Although some sequestration of ring-stage-infected red blood cells has been observed in the brain of fatal cases of severe malaria (9), and ring-stage parasites, which bind to chondroitin sulfate A (CS-A), have been shown to cytoadhere in vitro (10), all red blood cells containing more mature parasites cytoadhere to vascular endothelium. Several ligands have been identified as potential receptors for parasitized red blood cell cytoadherence.…”

Review Article: Blood-brain barrier in falciparum malaria*

“…One of the first pathological studies demonstrated the capillaries packed with parasitized red blood cells (PRBCs) (Thomson & Annecke 1926), and led to the hypothesis that CM was caused by 'mechanical obstruction' of the cerebral microvasculature, leading to impaired perfusion of the brain resulting in coma. The removal of the PRBCs from the peripheral circulation and sequestration within the vital organs, particularly the brain, is thought to be mediated by a specific interaction between PRBCs and the vascular endothelium cells (cytoadherence) (MacPherson et al 1985;Pongponratn et al 1991;Silamut et al 1999). In vitro studies have shown that this is mediated by the interaction of parasite proteins such as P. falciparum erythrocyte membrane protein-1 (Pf EMP-1) expressed on the surface of the PRBC and endothelial ligands such as intracellular adhesion molecule (Berendt et al 1998;Dietrich 2002).…”