Induction of VEGFA and Snail-1 by meningitic Escherichia coli mediates disruption of the blood-brain barrier
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Ruicheng Yang1,2, Wentong Liu1,2, Ling Miao1,2, Xiaopei Yang1,2, Jiyang Fu1,2, Beibei Dou1,2, Aoling Cai1,2, Xin Zong1,2, Chen Tan1,2,3, Huanchun Chen1,2,3, Xiangru Wang1,2,3
1State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei 430070, China
2The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, Hubei 430070, China
3Key Laboratory of development of veterinary diagnostic products of Ministry of Agriculture, Huazhong Agricultural University, Wuhan, Hubei 430070, China
Xiangru Wang, email: [email protected]
Keywords: blood-brain barrier, tight junctions, vascular endothelial growth factor A, Snail-1, bacterial meningitis
Received: April 12, 2016 Accepted: August 24, 2016 Published: August 30, 2016
Escherichia coli is the most common Gram-negative bacterium that possesses the ability to cause neonatal meningitis, which develops as circulating bacteria penetrate the blood-brain barrier (BBB). However, whether meningitic E. coli could induce disruption of the BBB and the underlying mechanisms are poorly understood. Our current work highlight for the first time the participation of VEGFA and Snail-1, as well as the potential mechanisms, in meningitic E. coli induced disruption of the BBB. Here, we characterized a meningitis-causing E. coli PCN033, and demonstrated that PCN033 invasion could increase the BBB permeability through downregulating and remodeling the tight junction proteins (TJ proteins). This process required the PCN033 infection-induced upregulation of VEGFA and Snail-1, which involves the activation of TLR2-MAPK-ERK1/2 signaling cascade. Moreover, production of proinflammatory cytokines and chemokines in response to infection also promoted the upregulation of VEGFA and Snail-1, therefore further mediating the BBB disruption. Our observations reported here directly support the involvement of VEGFA and Snail-1 in meningitic E. coli induced BBB disruption, and VEGFA and Snail-1 would therefore represent the essential host targets for future prevention of clinical E. coli meningitis.
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