Experimental cerebral malaria pathogenesis--hemodynamics at the blood brain barrier.
Experimental cerebral malaria pathogenesis--hemodynamics at the blood brain barrier.
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DOI：
10.1371/journal.ppat.1004528
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发表时间：
2014-12
期刊：
影响因子：
6.7
通讯作者：
Frevert U
中科院分区：
文献类型：
--
作者：
Nacer A;Movila A;Sohet F;Girgis NM;Gundra UM;Loke P;Daneman R;Frevert U
脑型疟疾每年夺去60多万非洲儿童的生命。为了更好地了解这种破坏性疾病的发病机制，我们比较了两种感染模型的细胞动力学，即伯氏疟原虫ANKA （PbA）感染的CBA/CaJ小鼠发生实验性脑型疟疾（ECM），而P. yoelii 17XL （PyXL）感染的小鼠死于疟疾高寄生虫血症，但没有神经损伤。结合活体成像和流式细胞术，我们发现与高寄生虫血症相比，ECM期间有更多的CD8+ T细胞、中性粒细胞和巨噬细胞被招募到毛细血管后小静脉。ECM与巨噬细胞的ICAM-1上调相关，而血管内皮在ECM和高寄生虫血症期间上调ICAM-1。毛细血管后和大静脉中大量白细胞的阻滞引起微流变学改变，显著限制了静脉血流量。FTY720治疗可抑制血管渗漏、神经症状和ECM死亡，可阻止CD45hi、CD8+ T细胞、ICAM-1+巨噬细胞和中性粒细胞聚集到毛细血管后小静脉。FTY720对毛细血管后小静脉中模式识别受体CD14的ecm相关表达无影响，提示内皮活化不足以引起血管病理。与fty720处理的pba感染小鼠或高寄生虫血症的pyxl感染小鼠相比，ECM小鼠的大脑皮层和小脑中内皮紧密连接蛋白claudin-5、occludin和ZO-1的表达没有改变。因此，血脑屏障开放不涉及内皮损伤，并且可能是可逆的，这与许多CM患者的快速恢复一致。我们得出结论，ecm相关的大量活化白细胞，特别是CD8+ T细胞和ICAM+巨噬细胞的募集，导致大脑静脉血流出严重受限，从而加剧血管源性水肿并增加颅内压。因此，颅内高压可能导致ECM死亡。疟疾仍然是全球最严重的健康问题之一，但我们对疟原虫的生物学和严重疾病的发病机制的了解仍然有限。人脑疟疾是一种严重的神经系统并发症，其特点是从头痛迅速发展为抽搐和无法唤醒的昏迷，每年在非洲造成数十万儿童死亡。为了更好地了解脑疟疾的发病机制，我们对实验性脑疟疾（ECM）小鼠与无神经损伤的疟疾高寄生虫血症小鼠的脑微血管免疫细胞进行了成像。与高寄生虫血症相比，ECM的死亡与血浆渗漏、血小板边缘化和向毛细血管后小静脉募集更多白细胞密切相关。毛细血管后小静脉的白细胞阻滞导致静脉血流量严重受限，免疫调节药物FTY720可阻止这种聚集和ECM的死亡。我们提出了一种ECM模型，其中白细胞阻滞，类似于HCM中恶性疟原虫感染的红细胞的隔离，严重限制了静脉血流量，从而加剧了感染的非侧昏迷期脑水肿和肿胀，导致颅内高压和死亡。
Cerebral malaria claims the lives of over 600,000 African children every year. To better understand the pathogenesis of this devastating disease, we compared the cellular dynamics in the cortical microvasculature between two infection models, Plasmodium berghei ANKA (PbA) infected CBA/CaJ mice, which develop experimental cerebral malaria (ECM), and P. yoelii 17XL (PyXL) infected mice, which succumb to malarial hyperparasitemia without neurological impairment. Using a combination of intravital imaging and flow cytometry, we show that significantly more CD8+ T cells, neutrophils, and macrophages are recruited to postcapillary venules during ECM compared to hyperparasitemia. ECM correlated with ICAM-1 upregulation on macrophages, while vascular endothelia upregulated ICAM-1 during ECM and hyperparasitemia. The arrest of large numbers of leukocytes in postcapillary and larger venules caused microrheological alterations that significantly restricted the venous blood flow. Treatment with FTY720, which inhibits vascular leakage, neurological signs, and death from ECM, prevented the recruitment of a subpopulation of CD45hi CD8+ T cells, ICAM-1+ macrophages, and neutrophils to postcapillary venules. FTY720 had no effect on the ECM-associated expression of the pattern recognition receptor CD14 in postcapillary venules suggesting that endothelial activation is insufficient to cause vascular pathology. Expression of the endothelial tight junction proteins claudin-5, occludin, and ZO-1 in the cerebral cortex and cerebellum of PbA-infected mice with ECM was unaltered compared to FTY720-treated PbA-infected mice or PyXL-infected mice with hyperparasitemia. Thus, blood brain barrier opening does not involve endothelial injury and is likely reversible, consistent with the rapid recovery of many patients with CM. We conclude that the ECM-associated recruitment of large numbers of activated leukocytes, in particular CD8+ T cells and ICAM+ macrophages, causes a severe restriction in the venous blood efflux from the brain, which exacerbates the vasogenic edema and increases the intracranial pressure. Thus, death from ECM could potentially occur as a consequence of intracranial hypertension. Malaria remains one of the most serious health problems globally, but our understanding of the biology of the Plasmodium parasite and the pathogenesis of severe disease is still limited. Human cerebral malaria (HCM), a severe neurological complication characterized by rapid progression from headache to convulsions and unrousable coma, causes the death of hundreds of thousands of children in Africa annually. To better understand the pathogenesis of cerebral malaria, we imaged immune cells in brain microvessels of mice with experimental cerebral malaria (ECM) versus mice with malarial hyperparasitemia, which lack neurological impairment. Death from ECM closely correlated with plasma leakage, platelet marginalization, and the recruitment of significantly more leukocytes to postcapillary venules compared to hyperparasitemia. Leukocyte arrest in postcapillary venules caused a severe restriction in the venous blood flow and the immunomodulatory drug FTY720 prevents this recruitment and death from ECM. We propose a model for ECM in which leukocyte arrest, analogous to the sequestration of P. falciparum infected red blood cells in HCM, severely restricts the venous blood flow, which exacerbates edema and swelling of the brain at the agonal comatose stage of the infection, leading to intracranial hypertension and death.
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影响因子：
6.7
作者：
Baer K;Klotz C;Kappe SH;Schnieder T;Frevert U
通讯作者：
Frevert U
影响因子：
2.2
作者：
Becker, MD;Nobiling, R;Rosenbaum, JT
通讯作者：
Rosenbaum, JT
影响因子：
20.3
作者：
Belnoue, E;Kayibanda, M;Rénia, L
通讯作者：
Rénia, L
影响因子：
4.4
作者：
Belnoue, E;Kayibanda, M;Rénia, L
通讯作者：
Rénia, L
DOI：
10.4269/ajtmh.2012.11-0459
发表时间：
2012-12-01
影响因子：
3.3
作者：
Beare, Nicholas A. V.;Glover, Simon J.;Molyneux, Malcolm E.
通讯作者：
Molyneux, Malcolm E.