CCR5 deficiency decreases susceptibility to experimental cerebral malaria
CCR5 deficiency decreases susceptibility to experimental cerebral malaria
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DOI：
10.1182/blood-2002-05-1493
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发表时间：
2003-06-01
期刊：
影响因子：
20.3
通讯作者：
Rénia, L
中科院分区：
文献类型：
--
作者：
Belnoue, E;Kayibanda, M;Rénia, L
伯氏疟原虫ANKA （PbA）易感小鼠感染是一种有价值的脑型疟疾（CM）实验模型。CM的两个主要病理特征是受感染的红细胞和白细胞在脑微血管内的血管内隔离。我们最近的研究表明，只有这些脑隔离白细胞的CD8(+) t细胞亚群对CM的进展至关重要。趋化因子受体-5 （CCR5）是脑内对真菌和病毒感染的白细胞运输的重要调节因子。因此，我们研究CCR5是否在实验性CM的发病机制中发挥作用。感染PbA的野生型和CCR5（+/-）小鼠中约有70%至85%发展为CM，而感染PbA的CCR5缺陷小鼠中只有约20%表现出CM的特征性神经体征。患有CM的野生型小鼠的大脑显示CCR5（+）白细胞，特别是CCR5(+) CD8(+) T细胞的显著增加，以及T辅助1 （Th1）细胞因子的产生增加。少数受pba感染的ccr5缺陷小鼠发生CM，表现出类似的CD8(+) T细胞增加。在未发生CM的pba感染的ccr5缺陷小鼠中，脑中没有显著的白细胞积累和Th1细胞因子的产生。此外，用骨髓嵌合小鼠进行的实验表明，移植了CCR5（+）骨髓的缺陷小鼠发生CM的比例减少但显著，这表明CCR5在抗辐射脑细胞群上的表达是CM发生的必要条件。综上所述，这些结果表明CCR5是实验性CM发展的重要因素。(C) 2003年由美国血液病学会出版。
Infection of susceptible mouse strains with Plasmodium berghei ANKA (PbA) is a valuable experimental model of cerebral malaria (CM). Two major pathologic features of CM are the intravascular sequestration of infected erythrocytes and leukocytes inside brain microvessels. We have recently shown that only the CD8(+) T-cell subset of these brain-sequestered leukocytes is critical for progression to CM. Chemokine receptor-5 (CCR5) is an important regulator of leukocyte trafficking in the brain in response to fungal and viral infection. Therefore, we investigated whether CCR5 plays a role in the pathogenesis of experimental CM. Approximately 70% to 85% of wild-type and CCR5(+/-) mice infected with PbA developed CM, whereas only about 20% of PbA-infected CCR5-deficient mice exhibited the characteristic neurologic signs of CM. The brains of wild-type mice with CM showed significant increases in CCR5(+) leukocytes, particularly CCR5(+) CD8(+) T cells, as well as increases in T-helper 1 (Th1) cytokine production. The few PbA-infected CCR5-deficient mice that developed CM exhibited a similar increase in CD8(+) T cells. Significant leukocyte accumulation in the brain and Th1 cytokine production did not occur in PbA-Infected CCR5-deficient mice that did not develop CM. Moreover, experiments using bone marrow (BM)-chimeric mice showed that a reduced but significant proportion of deficient mice grafted with CCR5(+) BM develop CM, indicating that CCR5 expression on a radiation-resistant brain cell population is necessary for CM to occur. Taken together, these results suggest that CCR5 is an important factor in the development of experimental CM. (C) 2003 by The American Society of Hematology.