Street rabies virus (RABV) usually infects hosts at peripheral sites and migrates from motor or sensory nerves to the central nervous system. Several studies have found that inflammation is mild in a mouse model of street RABV infection. However, the pathogenetic mechanisms of street RABV in naturally infected dogs or humans are not well understood. Brain tissues collected from 3 dogs and 3 humans were used; these tissue samples were collected under the natural condition of rabies-induced death. The inflammatory response and pathway activation in the brain tissue samples of dogs and humans were evaluated by HE, IHC, ARY006, WB and ELISA. The clinical isolate street RABV strains CGS-17 and CXZ-15 from 30 six-week-old ICR mice were used to construct the mouse infection model presented here. Neuronal degeneration and increased lymphocyte infiltration in the cerebral cortex, especially marked activation of microglia, formation of glial nodules, and neuronophagy, were observed in the dogs and humans infected with the street RABV strains. The various levels of proinflammatory chemokines, particularly CXCL1, CXCL12, CCL2, and CCL5, were increased significantly in the context of infection with street RABV strains in dogs and humans in relation to healthy controls, and the levels of MAPK and NF-κB phosphorylation were also increased in dogs and humans with natural infection. We also found that the degrees of pathological change, inflammatory response, MAPK and NF-κB signaling pathway activation were obviously increased during natural infection in dogs and humans compared with artificial model infection in mice. The data obtained here provide direct evidence for the RABV-induced activation of the inflammatory response in a dog infection model, which is a relatively accurate reflection of the pathogenic mechanism of human street RABV infection. These observations provide insight into the precise roles of underlying mechanisms in fatal natural RABV infection.

中文翻译：

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自然街头狂犬病病毒感染狗和人脑组织中诱导的炎症反应以及 MAPK 和 NF-κB 通路激活


街头狂犬病病毒（RABV）通常在外周部位感染宿主，并从运动或感觉神经迁移到中枢神经系统。多项研究发现，街头 RABV 感染的小鼠模型中炎症程度较轻。然而，街头 RABV 在自然感染的狗或人类中的发病机制尚不清楚。使用从 3 只狗和 3 名人类身上采集的脑组织；这些组织样本是在狂犬病引起的死亡的自然条件下收集的。通过 HE、IHC、ARY006、WB 和 ELISA 评估狗和人类脑组织样本中的炎症反应和通路激活。使用来自 30 只六周龄 ICR 小鼠的临床分离街道 RABV 毒株 CGS-17 和 CXZ-15 来构建此处介绍的小鼠感染模型。在感染街头 RABV 毒株的狗和人中观察到神经元变性和大脑皮层淋巴细胞浸润增加，特别是小胶质细胞显着激活、胶质结节形成和神经吞噬。与健康对照相比，在感染街道 RABV 株的狗和人类中，促炎趋化因子的各种水平，特别是 CXCL1、CXCL12、CCL2 和 CCL5 显着增加，并且 MAPK 和 NF-κB 磷酸化水平显着增加。在自然感染的狗和人类中也有所增加。我们还发现，与小鼠的人工模型感染相比，狗和人类自然感染时病理变化、炎症反应、MAPK和NF-κB信号通路激活程度明显增加。 这里获得的数据为狗感染模型中RABV诱导的炎症反应激活提供了直接证据，相对准确地反映了人类街头RABV感染的致病机制。这些观察结果让我们深入了解致命的自然 RABV 感染的潜在机制的精确作用。