Japanese encephalitis virus (JEV) is the leading cause of viral encephalitis in Asia. JEV infection of mice and humans can lead to an uncontrolled inflammatory response in the central nervous system (CNS), resulting in a detrimental outcome. Pigs act as important amplification and reservoir hosts, and JEV infection of pigs is mostly subclinical. Information on virus spread in the CNS and immune responses controlling JEV infection in the CNS of pigs, however remains scarce. Nine-week-old pigs were inoculated intranasal or intradermal with a relevant dose of 105 TCID50 of JEV genotype 3 Nakayama strain. Clinical signs were assessed daily, and viral spread was followed by RT-qPCR. mRNA expression profiles were determined to study immune responses in the CNS. Besides a delay of 2 days to reach the peak viremia upon intranasal compared to intradermal inoculation, the overall virus spread via both inoculation routes was highly similar. JEV appearance in lymphoid and visceral organs was in line with a blood-borne JEV dissemination. JEV showed a particular tropism to the CNS but without the induction of neurological signs. JEV entry in the CNS probably occurred via different hematogenous and neuronal pathways, but replication in the brain was mostly efficiently suppressed and associated with a type I IFN-independent activation of OAS1 expression. In the olfactory bulb and thalamus, where JEV replication was not completely controlled by this mechanism, a short but strong induction of chemokine gene expression was detected. An increased IFNy expression was simultaneously observed, probably originating from infiltrating T cells, correlating with a fast suppression of JEV replication. The chemokine response was however not associated with the induction of a strong inflammatory response, nor was an induction of the NLRP3 inflammasome observed. These findings indicate that an adequate antiviral response and an attenuated inflammatory response contribute to a favorable outcome of JEV infection in pigs and help to explain the limited neurological disease compared to other hosts. We show that the NLRP3 inflammasome, a key mediator of neurologic disease in mice, is not upregulated in pigs, further supporting its important role in JEV infections.

中文翻译：

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在没有明显炎症免疫反应的情况下，有效控制感染猪的中枢神经系统中的日本脑炎病毒

日本脑炎病毒 (JEV) 是亚洲病毒性脑炎的主要原因。小鼠和人类的 JEV 感染可导致中枢神经系统 (CNS) 中不受控制的炎症反应，从而导致不利的结果。猪是重要的扩增宿主和宿主，猪的JEV感染多为亚临床感染。然而，关于病毒在中枢神经系统中传播和控制猪中枢神经系统中 JEV 感染的免疫反应的信息仍然很少。用相关剂量的 105 TCID50 的 JEV 基因型 3 Nakayama 菌株鼻内或皮内接种 9 周龄猪。每天评估临床症状，并通过 RT-qPCR 跟踪病毒传播。确定 mRNA 表达谱以研究 CNS 中的免疫反应。除了与皮内接种相比，鼻内病毒达到峰值病毒血症延迟 2 天外，通过两种接种途径传播的总体病毒高度相似。JEV 在淋巴和内脏器官中的出现与血源性 JEV 传播一致。JEV 对中枢神经系统表现出特殊的趋向性，但没有引起神经系统症状。JEV 进入 CNS 可能通过不同的血源和神经元通路发生，但大脑中的复制大多被有效抑制，并与 I 型 IFN 非依赖性激活 OAS1 表达相关。在嗅球和丘脑中，JEV 复制并未完全受此机制控制，检测到趋化因子基因表达的短暂但强烈诱导。同时观察到 IFNy 表达增加，可能源自浸润性 T 细胞，与 JEV 复制的快速抑制相关。然而，趋化因子反应与强烈炎症反应的诱导无关，也未观察到 NLRP3 炎性体的诱导。这些发现表明，足够的抗病毒反应和减弱的炎症反应有助于猪感染 JEV 的良好结果，并有助于解释与其他宿主相比有限的神经系统疾病。我们表明 NLRP3 炎症小体是小鼠神经系统疾病的关键介质，在猪中没有上调，进一步支持其在 JEV 感染中的重要作用。也没有观察到 NLRP3 炎症小体的诱导。这些发现表明，足够的抗病毒反应和减弱的炎症反应有助于猪感染 JEV 的良好结果，并有助于解释与其他宿主相比有限的神经系统疾病。我们表明 NLRP3 炎症小体是小鼠神经系统疾病的关键介质，在猪中没有上调，进一步支持其在 JEV 感染中的重要作用。也没有观察到 NLRP3 炎症小体的诱导。这些发现表明，足够的抗病毒反应和减弱的炎症反应有助于猪感染 JEV 的良好结果，并有助于解释与其他宿主相比有限的神经系统疾病。我们表明 NLRP3 炎症小体是小鼠神经系统疾病的关键介质，在猪中没有上调，进一步支持其在 JEV 感染中的重要作用。