Cognitive Deficits Found in a Pro-inflammatory State are Independent of ERK1/2 Signaling in the Murine Brain Hippocampus Treated with Shiga Toxin 2 from Enterohemorrhagic Escherichia coli

Shiga toxin 2 (Stx2) from enterohemorrhagic Escherichia coli (EHEC) produces hemorrhagic colitis, hemolytic uremic syndrome (HUS) and acute encephalopathy. The mortality rate in HUS increases significantly when the central nervous system (CNS) is involved. Besides, EHEC also releases lipopolysaccharide (LPS). Many reports have described cognitive dysfunctions in HUS patients, the hippocampus being one of the brain areas targeted by EHEC infection. In this context, a translational murine model of encephalopathy was employed to establish the deleterious effects of Stx2 and the contribution of LPS in the hippocampus. The purpose of this work is to elucidate the signaling pathways that may activate the inflammatory processes triggered by Stx2, which produces cognitive alterations at the level of the hippocampus. Results demonstrate that Stx2 produced depression-like behavior, pro-inflammatory cytokine release and NF-kB activation independent of the ERK1/2 signaling pathway, while co-administration of Stx2 and LPS reduced memory index. On the other hand, LPS activated NF-kB dependent on ERK1/2 signaling pathway. Cotreatment of Stx2 with LPS aggravated the pathologic state, while dexamethasone treatment succeeded in preventing behavioral alterations. Our present work suggests that the use of drugs such as corticosteroids or NF-kB signaling inhibitors may serve as neuroprotectors from EHEC infection.

志贺毒素2型（Stx2）由肠出血性大肠杆菌（EHEC）产生，可引发出血性结肠炎、溶血性尿毒症综合征（HUS）及急性脑病。当中枢神经系统（CNS）受累时，HUS的死亡率显著升高。此外，EHEC还会释放脂多糖（LPS）。众多报道描述了HUS患者在认知功能障碍方面的表现，海马体是EHEC感染所靶向的脑区之一。在此背景下，采用转化性小鼠模型来探究Stx2的毒性效应以及LPS在海马体中的贡献。本研究的目的是阐明可能激活由Stx2触发的炎症过程的信号通路，这些通路在神经元水平上产生认知改变。结果显示，Stx2诱导出抑郁样行为、促炎细胞因子释放和NF-kB激活，且与ERK1/2信号通路无关，而Stx2与LPS的共给药降低了记忆指数。另一方面，LPS依赖于ERK1/2信号通路激活NF-kB。Stx2与LPS的联合治疗加剧了病理状态，而地塞米松治疗成功预防了行为改变。我们的研究工作表明，使用如皮质类固醇或NF-kB信号通路抑制剂等药物可能作为EHEC感染的神经保护剂。