Inhibition of histamine-mediated signaling confers significant protection against severe malaria in mouse models of disease.
Inhibition of histamine-mediated signaling confers significant protection against severe malaria in mouse models of disease.
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DOI：
10.1084/jem.20071548
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发表时间：
2008-02-18
影响因子：
15.3
通讯作者：
Mecheri, Salaheddine
中科院分区：
文献类型：
--
作者：
Beghdadi, Walid;Porcherie, Adeline;Schneider, Bradley S.;Dubayle, David;Peronet, Roger;Huerre, Michel;Watanabe, Takeshi;Ohtsu, Hiroshi;Louis, Jacques;Mecheri, Salaheddine
从通过按蚊叮咬接种疟原虫子孢子到形成血液期寄生虫，宿主反应的一个标志是炎症反应，其特征是血清和组织中组胺水平升高。鉴于与组胺相关的促炎和免疫抑制活性，我们推测这种血管活性胺参与疟疾发病机制。结合遗传和药理学方法表明，组胺与 H1R 和 H2R 结合，但不与 H3R 和 H4R 结合，会增加小鼠对疟原虫感染的易感性。为了进一步了解组胺在疟疾发病机制中的作用，我们使用了不含组胺的组氨酸脱羧酶缺陷（HDC−/−）小鼠。 HDC−/− 小鼠对严重疟疾具有高度抵抗力，无论是通过蚊虫叮咬感染还是通过注射受感染的红细胞感染。 HDC−/− 小鼠表现出对两种致命菌株的抵抗力：伯氏疟原虫 (Pb) ANKA 会引发脑型疟疾 (CM)，而 Pb NK65 则会导致死亡，但不会出现神经系统症状。 HDC−/− 小鼠对 CM 的抵抗力与保留的血脑屏障完整性、脑血管中不存在受感染的红细胞聚集以及缺乏 CD4 和 CD8 T 细胞的隔离有关。我们证明组胺介导的信号传导有助于疟疾的发病机制。了解感染期间组胺的这些生物学效应的基础可能会导致新的治疗策略来减轻疟疾的严重程度。
From the inoculation of Plasmodium sporozoites via Anopheles mosquito bites to the development of blood-stage parasites, a hallmark of the host response is an inflammatory reaction characterized by elevated histamine levels in the serum and tissues. Given the proinflammatory and immunosuppressive activities associated with histamine, we postulated that this vasoactive amine participates in malaria pathogenesis. Combined genetic and pharmacologic approaches demonstrated that histamine binding to H1R and H2R but not H3R and H4R increases the susceptibility of mice to infection with Plasmodium. To further understand the role of histamine in malaria pathogenesis, we used histidine decarboxylase–deficient (HDC−/−) mice, which are free of histamine. HDC−/− mice were highly resistant to severe malaria whether infected by mosquito bites or via injection of infected erythrocytes. HDC−/− mice displayed resistance to two lethal strains: Plasmodium berghei (Pb) ANKA, which triggers cerebral malaria (CM), and Pb NK65, which causes death without neurological symptoms. The resistance of HDC−/− mice to CM was associated with preserved blood–brain barrier integrity, the absence of infected erythrocyte aggregation in the brain vessels, and a lack of sequestration of CD4 and CD8 T cells. We demonstrate that histamine-mediated signaling contributes to malaria pathogenesis. Understanding the basis for these biological effects of histamine during infection may lead to novel therapeutic strategies to alleviate the severity of malaria.
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DOI：
10.1073/pnas.93.23.13316
发表时间：
1996-11-12
影响因子：
11.1
作者：
Inoue, I;Yanai, K;Watanabe, T
通讯作者：
Watanabe, T
影响因子：
20.3
作者：
Belnoue, E;Kayibanda, M;Rénia, L
通讯作者：
Rénia, L
影响因子：
12.4
作者：
BURY, TB;CORHAY, JL;RADERMECKER, MF
通讯作者：
RADERMECKER, MF
影响因子：
4.4
作者：
Furuta, Takahisa;Kikuchi, Takane;Watanabe, Naohiro
通讯作者：
Watanabe, Naohiro
影响因子：
4.4
作者：
Belnoue, E;Kayibanda, M;Rénia, L
通讯作者：
Rénia, L