Willimann K, Matile H, Weiss N A, Imhof B A
Department of Medical Parasitology, Swiss Tropical Institute, Basel.
J Exp Med. 1995 Sep 1;182(3):643-53. doi: 10.1084/jem.182.3.643.
Cerebral malaria is a fatal complication of infection by Plasmodium falciparum 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. falciparum-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. falciparum-infected erythrocytes to the ICAM-1-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 of P. falciparum-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.
脑型疟疾是人类感染恶性疟原虫后的一种致命并发症。这种形式的疟疾疾病所特有的神经症状伴随着受感染红细胞与脑血管系统的黏附。为了在体内研究这一现象，开发了一种急性期严重联合免疫缺陷（SCID）小鼠模型，其中发生了恶性疟原虫感染的人类红细胞的滞留。在人类急性脑型疟疾期间，炎症反应会诱导血管内皮细胞表达细胞间黏附分子-1（ICAM-1）。急性期ICAM-1表达在SCID小鼠中也能获得。中脑区域的内皮细胞对这种炎症刺激反应最为敏感。值得注意的是，中脑的网状结构控制着意识水平，而意识丧失是脑型疟疾的一种症状。我们发现，在ICAM-1阳性的小鼠脑中，受感染的人类红细胞的滞留量比正常红细胞多24倍。抗ICAM-1抗体可减少对脑的滞留。这些体内结果通过恶性疟原虫感染的红细胞与小鼠脑组织切片中ICAM-1阳性内皮细胞的结合得到了证实。我们得出结论，SCID小鼠是一种通用的体内模型，可用于研究人类脑型疟疾中发生的恶性疟原虫感染红细胞的黏附。中脑区域ICAM-1表达的上调与疟疾感染红细胞滞留的增加以及脑型疟疾的症状相关。
