Neuroimmunological blood brain barrier opening in experimental cerebral malaria.
Neuroimmunological blood brain barrier opening in experimental cerebral malaria.
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DOI：
10.1371/journal.ppat.1002982
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发表时间：
2012
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;Baer K;Mikolajczak SA;Kappe SH;Frevert U
恶性疟原虫疟疾每年在全世界造成近100万人死亡。由于难以监测人类脑型疟疾的发病机制，我们在各种小鼠模型中进行了研究，以更好地了解实验性脑型疟疾（ECM）的疾病进展。我们比较了伯氏疟原虫ANKA（一种已知的ECM模型）、伯氏疟原虫NK 65（通常认为不诱导ECM）、约氏疟原虫17 XL（最初报道诱导人脑疟疾样组织病理学）和约氏疟原虫YM对血脑屏障（BBB）完整性和脑组织病理学的影响。正如预期的那样，伯氏疟原虫ANKA感染引起CBA/CaJ和Swiss韦伯斯特小鼠的神经系统体征、脑损伤和BBB功能障碍，而Balb/c和A/J小鼠具有抗性。令人惊讶的是，PbNK在CBA/CaJ小鼠中诱导ECM，而所有其他小鼠都具有抗性。约氏疟原虫17 XL和约氏疟原虫YM在所有小鼠品系中引起致死性高寄生虫血症;未观察到组织病理学改变、BBB功能障碍或神经学体征。活体成像显示，含有成熟寄生虫的感染红细胞缓慢通过毛细血管，与内皮密切接触，但没有停止。除了相对罕见的微血管病变外，ECM小鼠没有表现出明显的组织病理学改变，这可以解释BBB的广泛破坏。然而，活体成像确实显示，ECM小鼠的毛细血管后小静脉（而非毛细血管或小动脉）（而非高寄生虫血症）表现出血小板边缘化、血管外纤维蛋白沉积、CD 14表达和广泛的血管渗漏。LFA-1介导的细胞相互作用的阻断防止了白细胞粘附、血管渗漏、神经系统体征和ECM导致的死亡。内皮屏障稳定介质伊马替尼和FTY 720抑制血管渗漏和神经系统体征，并延长存活至ECM。因此，看来ECM中的神经体征和昏迷是由于在神经免疫学BBB处的细胞旁连接和跨细胞囊泡液体转运途径的调节开放。 恶性疟原虫是所有人类疟疾寄生虫中最致命的一种，可引起脑型疟疾，这是这种毁灭性疾病的严重且经常致命的并发症。幼儿主要处于危险之中，并且可能从神经系统受累的最初迹象迅速进展到昏迷和死亡。在这里，我们使用了高分辨率的小鼠模型在体内成像，以证明脑疟疾，而不是高寄生虫血症和严重贫血，是与大量的液体从脑血管渗漏到脑组织。这种血管渗漏发生在毛细血管床的下游，在神经免疫血脑屏障处，该部位最近被认为是神经炎症期间免疫细胞进入大脑的入口点。血管渗漏与神经系统体征的出现密切相关，这表明脑型疟疾中脑水肿、昏迷和死亡的最终原因是神经免疫血脑屏障的广泛开放。事实上，血管渗漏，神经系统的迹象，并从ECM死亡可以防止与内皮屏障稳定药物。基于这种解剖特征在神经炎症中的独特作用，我们的研究结果有望对中枢神经系统的其他感染性疾病和自身免疫性疾病产生影响。
Plasmodium falciparum malaria is responsible for nearly one million annual deaths worldwide. Because of the difficulty in monitoring the pathogenesis of cerebral malaria in humans, we conducted a study in various mouse models to better understand disease progression in experimental cerebral malaria (ECM). We compared the effect on the integrity of the blood brain barrier (BBB) and the histopathology of the brain of P. berghei ANKA, a known ECM model, P. berghei NK65, generally thought not to induce ECM, P. yoelii 17XL, originally reported to induce human cerebral malaria-like histopathology, and P. yoelii YM. As expected, P. berghei ANKA infection caused neurological signs, cerebral hemorrhages, and BBB dysfunction in CBA/CaJ and Swiss Webster mice, while Balb/c and A/J mice were resistant. Surprisingly, PbNK induced ECM in CBA/CaJ mice, while all other mice were resistant. P. yoelii 17XL and P. yoelii YM caused lethal hyperparasitemia in all mouse strains; histopathological alterations, BBB dysfunction, or neurological signs were not observed. Intravital imaging revealed that infected erythrocytes containing mature parasites passed slowly through capillaries making intimate contact with the endothelium, but did not arrest. Except for relatively rare microhemorrhages, mice with ECM presented no obvious histopathological alterations that would explain the widespread disruption of the BBB. Intravital imaging did reveal, however, that postcapillary venules, but not capillaries or arterioles, from mice with ECM, but not hyperparasitemia, exhibit platelet marginalization, extravascular fibrin deposition, CD14 expression, and extensive vascular leakage. Blockage of LFA-1 mediated cellular interactions prevented leukocyte adhesion, vascular leakage, neurological signs, and death from ECM. The endothelial barrier-stabilizing mediators imatinib and FTY720 inhibited vascular leakage and neurological signs and prolonged survival to ECM. Thus, it appears that neurological signs and coma in ECM are due to regulated opening of paracellular-junctional and transcellular-vesicular fluid transport pathways at the neuroimmunological BBB. Plasmodium falciparum, the deadliest of all human malaria parasites, can cause cerebral malaria, a severe and frequently fatal complication of this devastating disease. Young children are predominantly at risk and may progress rapidly from the first signs of neurological involvement to coma and death. Here we used a murine model for high-resolution in vivo imaging to demonstrate that cerebral malaria, but not high parasitemia and severe anemia, is associated with extensive leakage of fluid from cerebral blood vessels into the brain tissue. This vascular leakage occurs downstream from the capillary bed, at the neuroimmunological blood brain barrier, a site recently recognized as the immune cell entry point into the brain during neuroinflammation. Vascular leakage is closely associated with the appearance of neurological signs suggesting that the ultimate cause of brain edema, coma and death in cerebral malaria is a widespread opening of the neuroimmunological blood brain barrier. Indeed, vascular leakage, neurological signs, and death from ECM can be prevented with endothelial barrier-stabilizing drugs. Based on the unique role of this anatomical feature in neuroinflammation, our findings are expected to have implications for other infectious diseases and autoimmune disorders of the central nervous system.
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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：
6.4
作者：
Carvalho, Bruna O.;Lopes, Stefanie C. P.;Costa, Fabio T. M.
通讯作者：
Costa, Fabio T. M.
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影响因子：
3
作者：
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通讯作者：
Taylor, TE
影响因子：
15.3
作者：
Beghdadi, Walid;Porcherie, Adeline;Schneider, Bradley S.;Dubayle, David;Peronet, Roger;Huerre, Michel;Watanabe, Takeshi;Ohtsu, Hiroshi;Louis, Jacques;Mecheri, Salaheddine
通讯作者：
Mecheri, Salaheddine
影响因子：
2.2
作者：
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通讯作者：
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