Bacterial meningitis is a life-threatening infectious disease with severe neurological sequelae and a high mortality rate, in which Escherichia coli is one of the primary Gram-negative etiological bacteria. Meningitic E. coli infection is often accompanied by an elevated blood–brain barrier (BBB) permeability. BBB is the structural and functional barrier composed of brain microvascular endothelial cells (BMECs), astrocytes, and pericytes, and we have previously shown that astrocytes-derived TGFβ1 physiologically maintained the BBB permeability by triggering a non-canonical hedgehog signaling in brain microvascular endothelial cells (BMECs). Here, we subsequently demonstrated that meningitic E. coli infection could subvert this intercellular communication within BBB by attenuating TGFBRII/Gli2-mediated such signaling. By high-throughput screening, we identified E. coli α-hemolysin as the critical determinant responsible for this attenuation through Sp1-dependent TGFBRII reduction and triggering Ca2+ influx and protein kinase A activation, thus leading to Gli2 suppression. Additionally, the exogenous hedgehog agonist SAG exhibited promising protection against the infection-caused BBB dysfunction. Our work revealed a hedgehog-targeted pathogenic mechanism during meningitic E. coli-caused BBB disruption and suggested that activating hedgehog signaling within BBB could be a potential protective strategy for future therapy of bacterial meningitis.

中文翻译：

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脑膜炎大肠杆菌α-溶血素通过靶向TGFβ1触发的hedgehog信号加重血脑屏障破坏

细菌性脑膜炎是一种危及生命的传染病，具有严重的神经系统后遗症和高死亡率，其中大肠杆菌是主要的革兰氏阴性病原菌之一。脑膜炎大肠杆菌感染通常伴有血脑屏障 (BBB) 通透性升高。BBB 是由脑微血管内皮细胞 (BMECs)、星形胶质细胞和周细胞组成的结构和功能屏障，我们之前已经表明，星形胶质细胞衍生的 TGFβ1 通过触发脑微血管内皮细胞中的非典型刺猬信号在生理上维持 BBB 通透性（BMEC）。在这里，我们随后证明脑膜炎大肠杆菌感染可以通过减弱 TGFBRII/Gli2 介导的这种信号传导来破坏 BBB 内的这种细胞间通讯。通过高通量筛选，我们将大肠杆菌α-溶血素鉴定为通过 Sp1 依赖性 TGFBRII 减少和触发 Ca2+ 流入和蛋白激酶 A 激活，从而导致 Gli2 抑制的关键决定因素。此外，外源性刺猬激动剂 SAG 对感染引起的 BBB 功能障碍表现出有希望的保护作用。我们的工作揭示了在脑膜炎大肠杆菌引起的 BBB 破坏期间以刺猬为目标的致病机制，并表明激活 BBB 内的刺猬信号可能是未来治疗细菌性脑膜炎的潜在保护策略。外源性刺猬激动剂 SAG 对感染引起的 BBB 功能障碍表现出有希望的保护作用。我们的工作揭示了在脑膜炎大肠杆菌引起的 BBB 破坏期间以刺猬为目标的致病机制，并表明激活 BBB 内的刺猬信号可能是未来治疗细菌性脑膜炎的潜在保护策略。外源性刺猬激动剂 SAG 对感染引起的 BBB 功能障碍表现出有希望的保护作用。我们的工作揭示了在脑膜炎大肠杆菌引起的 BBB 破坏期间以刺猬为目标的致病机制，并表明激活 BBB 内的刺猬信号可能是未来治疗细菌性脑膜炎的潜在保护策略。