Abstract：
Hepatitis E virus (HEV) is a foodborne zoonotic pathogen that is supposed to be one of the most common causes of acute viral hepatitis. However, HEV infection has been recently associated with a wide spectrum of extrahepatic manifestations, particularly neurological disorders. Previous studies have shown that HEV is able to cross the blood-brain barrier (BBB) and induce inflammatory response of the central nervous system. However, the pathogenesis of HEV-induced neuroinflammation and tissue injury of the central nervous system have yet to be fully elucidated. In this study, activation of NLRP3 inflammasome following HEV infection were investigated. In a gerbil model infected by HEV, brain histopathological changes including gliosis, neuronophagia and neuron injury were observed and expression of NLRP3, caspase-1, IL-1β and IL-18 were elevated. Brain microvascular endothelial cells (BMECs) are key components of the BBB that protects the brain from various challenges. Following HEV infection, virus-like particles range from 30 to 40 nm in diameter were observed in human BMECs (hBMECs). Enhanced expression levels of NLRP3 and subsequent ASC, caspase-1, IL-1β and IL-18 were detected in infected cells. Treatment with MCC950 alleviated HEV infection induced activation of NLRP3 inflammasome, mitochondrial damage and VE-cadherin degradation. The findings provide new insights into HEV-associated neuroinflammation. Moreover, targeting NLRP3 inflammasome signalling is a promising therapeutic in HEV-induced neurological disorder.
摘要：
戊型肝炎病毒（HEV）是一种食源性人畜共患病原体，被认为是急性病毒性肝炎的最常见原因之一。然而,HEV感染最近与广泛的肝外表现有关，特别是神经系统疾病。先前的研究表明，HEV能够穿过血脑屏障（BBB）并诱导中枢神经系统的炎症反应。然而,HEV引起的神经炎症和中枢神经系统组织损伤的发病机制尚未完全阐明。在这项研究中,研究了HEV感染后NLRP3炎性体的激活。在被HEV感染的沙鼠模型中,脑组织病理学改变，包括神经胶质增生，观察到神经元吞噬和神经元损伤，NLRP3，caspase-1，IL-1β和IL-18的表达升高。脑微血管内皮细胞（BMEC）是保护大脑免受各种挑战的BBB的关键成分。HEV感染后,在人BMECs（hBMECs）中观察到直径为30至40nm的病毒样颗粒。NLRP3和随后的ASC的表达水平增强，在感染细胞中检测到caspase-1、IL-1β和IL-18。MCC950治疗可缓解HEV感染诱导的NLRP3炎性体激活，线粒体损伤和VE-钙粘蛋白降解。这些发现为HEV相关的神经炎症提供了新的见解。此外，靶向NLRP3炎性体信号是HEV诱导的神经系统疾病的一种有前景的治疗方法.
