Pathogenic Mechanism of Mouse Brain Damage Caused by Oral Infection with Shiga Toxin-Producing Escherichia coliO157:H7
Pathogenic Mechanism of Mouse Brain Damage Caused by Oral Infection with Shiga Toxin-Producing Escherichia coliO157:H7
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口腔感染产志贺毒素大肠杆菌O157:H7引起小鼠脑损伤的致病机制
DOI：
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发表时间：
2000
影响因子：
3.1
通讯作者：
Nobutaka Higashi
中科院分区：
文献类型：
--
作者：
E. Kita;Y. Yunou;Takaaki Kurioka;Hiroko Harada;S. Yoshikawa;K. Mikasa;Nobutaka Higashi
摘要：在之前的一项研究中，我们发现，产生志贺毒素 (Stx) 的大肠杆菌 O157:H7（菌株 SmrN-9）的感染会导致脑组织中 Stx2 免疫反应呈阳性的营养不良小鼠出现神经系统症状。本研究探讨Stx如何损伤血管内皮进入小鼠中枢神经系统的机制。 SmrN-9 菌株的口腔感染最早在感染后 2 天就在血液中引发了肿瘤坏死因子 α (TNF-α) 反应，而 Stx 在感染后 3 天首次被检测到。在大脑中，第 3 天检测到 TNF-α，并且其数量在接下来的 3 天内增加。垂死小鼠的大脑冰冻切片含有大量凋亡细胞。从大脑中提取了抗 Gb3 单克隆抗体识别的糖脂，纯化的 Stx2 能够与糖脂结合。在用荧光素标记的 Stx2 (100 ng/ml) 培养的人脐血管内皮细胞 (HUVEC) 中，TNF-α (20 U/ml) 在孵育 24 小时期间显着促进细胞内荧光区室化，表明 Stx2 的细胞内处理增强。因此，48 小时时发现 HUVEC 细胞凋亡水平较高。 HUVEC 短期暴露于 Stx2 会消除其随后与单独 TNF-α 或 TNF-α 和 Stx2 一起孵育的细胞凋亡反应。相比之下，将 HUVEC 初次暴露于 TNF-α，然后单独暴露于 Stx2，或暴露于 TNF-α 和 Stx2，诱导细胞凋亡，其水平与用这两种药物孵育 48 小时后获得的水平相同。这些结果表明，感染后循环中TNF-α的快速产生会诱导血管内皮细胞进入凋亡状态，最终通过随后血液中Stx的升高来实现。在这种协同作用中，靶细胞必须首先暴露于 TNF-α。这种细胞损伤可能是感染产生 Stx 的大肠杆菌 O157:H7 后脑损伤的先决条件。
ABSTRACT In a previous study, we showed that infection with Shiga toxin (Stx)-producing Escherichia coli O157:H7 (strain SmrN-9) caused neurologic symptoms in malnourished mice with positive immunoreactions of Stx2 in brain tissues. The present study explores the mechanism of how Stx injures the vascular endothelium to enter the central nervous system in mice. Oral infection with strain SmrN-9 elicited a tumor necrosis factor alpha (TNF-α) response in the blood as early as 2 days after infection, while Stx was first detected at 3 days postinfection. In the brain, TNF-α was detected at day 3, and its quantity was increased over the next 3 days. Frozen sections of the brains from moribound mice contained high numbers of apoptotic cells. Glycolipids recognized by an anti-Gb3 monoclonal antibody were extracted from the brain, and purified Stx2 was able to bind to the glycolipids. In human umbilical vascular endothelial cells (HUVEC) cultured with fluorescein-labeled Stx2 (100 ng/ml), TNF-α (20 U/ml) significantly facilitated the intracellular compartmentalization of fluorescence during 24 h of incubation, suggesting the enhanced intracellular processing of Stx2. Consequently, higher levels of apoptosis in HUVEC were found at 48 h. Short-term exposure of HUVEC to Stx2 abrogated their apoptotic response to subsequent incubation with TNF-α alone or TNF-α and Stx2. In contrast, primary exposure of HUVEC to TNF-α followed by exposure to Stx2 alone or TNF-α and Stx2 induced apoptosis at the same level as obtained after 48-h incubation with these two agents. These results suggest that the rapid production of circulating TNF-α after infection induces a state of competence in vascular endothelial cells to undergo apoptosis, which would be finally achieved by subsequent elevation of Stx in the blood. In this synergistic action, target cells must be first exposed to TNF-α. Such cell injury may be a prerequisite to brain damage after infection with Stx-producing E. coliO157:H7.
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DOI：
10.1016/s0021-9258(18)82282-7
发表时间：
1993-07
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
T. Obrig;C. B. Louise;C. Lingwood;B. Boyd;L. Barley-Maloney;T. Daniel
通讯作者：
T. Obrig;C. B. Louise;C. Lingwood;B. Boyd;L. Barley-Maloney;T. Daniel
影响因子：
2.9
作者：
LADISCH, S;GILLARD, B
通讯作者：
GILLARD, B
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DOI：
--
发表时间：
1986
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Weinberg,DS;Ault,KA;Gurley,M;Pinkus,GS
通讯作者：
Pinkus,GS
手术手套粉末颗粒对成人血管内皮细胞培养物的细胞毒性作用：对组织培养技术临床应用的影响。
DOI：
10.1016/0022-4804(86)90163-0
发表时间：
1986
期刊：
The Journal of surgical research
影响因子：
--
作者：
Sharefkin,JB;Fairchild,KD;Albus,RA;Cruess,DF;Rich,NM
通讯作者：
Rich,NM