Sphingosine 1-Phosphate Activation of EGFR As a Novel Target for Meningitic Escherichia coli Penetration of the Blood-Brain Barrier.
Sphingosine 1-Phosphate Activation of EGFR As a Novel Target for Meningitic Escherichia coli Penetration of the Blood-Brain Barrier.
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1-磷酸鞘氨醇激活 EGFR 作为脑膜炎大肠杆菌穿透血脑屏障的新靶点
DOI：
10.1371/journal.ppat.1005926
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发表时间：
2016-10
期刊：
影响因子：
6.7
通讯作者：
Kim KS
中科院分区：
文献类型：
--
作者：
Wang X;Maruvada R;Morris AJ;Liu JO;Wolfgang MJ;Baek DJ;Bittman R;Kim KS
中枢神经系统（CNS）感染仍然是死亡和发病的重要原因，需要新的方法来研究其发病机制，预防和治疗。大肠杆菌是引起脑膜炎的最常见的革兰氏阴性杆菌，其在穿透血脑屏障（BBB）后发展。通过化学文库筛选，我们确定表皮生长因子受体（EGFR）是大肠杆菌的一个贡献者。coli侵袭血脑屏障的能力。在此，我们获得了感染CNS的E。coli利用鞘氨醇1-磷酸（S1 P）在体外和体内穿透血脑屏障中激活EGFR。我们发现S1 P位于EGFR的上游，通过S1 P受体以及S1 P介导的EGFR相关配体HB-EGF的上调参与EGFR的活化，通过靶向鞘氨醇激酶和S1 P受体阻断S1 P功能抑制EGFR的活化，E.大肠杆菌侵入血脑屏障。我们进一步发现，S1 P和EGFR激活都发生在对相同的E. coli蛋白（OmpA、FimH、NlpI）的表达，S1 P和EGFR对大肠杆菌蛋白的表达具有促进作用。大肠杆菌通过激活下游c-Src入侵血脑屏障。这些发现表明S1 P和EGFR是脑膜炎E.大肠杆菌渗透血脑屏障并抵消这些靶点提供了一种控制大肠杆菌的新方法。在对传统抗生素的耐药性不断增加的时代，
Central nervous system (CNS) infection continues to be an important cause of mortality and morbidity, necessitating new approaches for investigating its pathogenesis, prevention and therapy. Escherichia coli is the most common Gram-negative bacillary organism causing meningitis, which develops following penetration of the blood–brain barrier (BBB). By chemical library screening, we identified epidermal growth factor receptor (EGFR) as a contributor to E. coli invasion of the BBB in vitro. Here, we obtained the direct evidence that CNS-infecting E. coli exploited sphingosine 1-phosphate (S1P) for EGFR activation in penetration of the BBB in vitro and in vivo. We found that S1P was upstream of EGFR and participated in EGFR activation through S1P receptor as well as through S1P-mediated up-regulation of EGFR-related ligand HB-EGF, and blockade of S1P function through targeting sphingosine kinase and S1P receptor inhibited EGFR activation, and also E. coli invasion of the BBB. We further found that both S1P and EGFR activations occurred in response to the same E. coli proteins (OmpA, FimH, NlpI), and that S1P and EGFR promoted E. coli invasion of the BBB by activating the downstream c-Src. These findings indicate that S1P and EGFR represent the novel host targets for meningitic E. coli penetration of the BBB, and counteracting such targets provide a novel approach for controlling E. coli meningitis in the era of increasing resistance to conventional antibiotics.
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在LDLR - / - 小鼠中，分泌性鞘磷脂酶活性，脂蛋白鞘脂含量和LDL聚集的表征。
影响因子：
4
作者：
Deevska GM;Sunkara M;Morris AJ;Nikolova-Karakashian MN
通讯作者：
Nikolova-Karakashian MN
DOI：
10.1083/jcb.200106148
发表时间：
2001-10-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hoffmann I;Eugène E;Nassif X;Couraud PO;Bourdoulous S
通讯作者：
Bourdoulous S
影响因子：
7.3
作者：
Baek DJ;MacRitchie N;Anthony NG;Mackay SP;Pyne S;Pyne NJ;Bittman R
通讯作者：
Bittman R
影响因子：
3.7
作者：
Blumenberg M
通讯作者：
Blumenberg M
影响因子：
8
作者：
Gschwind, A;Zwick, E;Ullrich, A
通讯作者：
Ullrich, A