Influenza-associated encephalopathy (IAE) is extremely acute in onset, with high lethality and morbidity within a few days, while the direct pathogenesis by influenza virus in this acute phase in the brain is largely unknown. Here we show that influenza virus enters into the cerebral endothelium and thereby induces IAE. Three-weeks-old young mice were inoculated with influenza A virus (IAV). Physical and neurological scores were recorded and temporal-spatial analyses of histopathology and viral studies were performed up to 72 h post inoculation. Histopathological examinations were also performed using IAE human autopsy brains. Viral infection, proliferation and pathogenesis were analyzed in cell lines of endothelium and astrocyte. The effects of anti-influenza viral drugs were tested in the cell lines and animal models. Upon intravenous inoculation of IAV in mice, the mice developed encephalopathy with brain edema and pathological lesions represented by micro bleeding and injured astrocytic process (clasmatodendrosis) within 72 h. Histologically, massive deposits of viral nucleoprotein were observed as early as 24 h post infection in the brain endothelial cells of mouse models and the IAE patients. IAV inoculated endothelial cell lines showed deposition of viral proteins and provoked cell death, while IAV scarcely amplified. Inhibition of viral transcription and translation suppressed the endothelial cell death and the lethality of mouse models. These data suggest that the onset of encephalopathy should be induced by cerebral endothelial infection with IAV. Thus, IAV entry into the endothelium, and transcription and/or translation of viral RNA, but not viral proliferation, should be the key pathogenesis of IAE.

流感相关脑病（IAE）起病极其急性，在几天内具有很高的致死率和发病率，而流感病毒在这一急性期在大脑中的直接发病机制在很大程度上尚不清楚。在这里，我们发现流感病毒进入大脑内皮，从而诱发 IAE。三周大的幼鼠接种了甲型流感病毒（IAV）。记录身体和神经学评分，并在接种后 72 小时内进行组织病理学和病毒研究的时空分析。还使用 IAE 人体尸检大脑进行了组织病理学检查。在内皮细胞和星形胶质细胞细胞系中分析病毒感染、增殖和发病机制。在细胞系和动物模型中测试了抗流感病毒药物的效果。小鼠静脉注射IAV后，72小时内小鼠出现脑病，伴有脑水肿和以微出血和星形细胞突起受损（纤细树突）为代表的病理病变。组织学上，早在感染后 24 小时，就在小鼠模型和 IAE 患者的脑内皮细胞中观察到大量病毒核蛋白沉积。接种 IAV 的内皮细胞系显示病毒蛋白沉积并引起细胞死亡，而 IAV 几乎不扩增。抑制病毒转录和翻译可抑制内皮细胞死亡和小鼠模型的致死率。这些数据表明脑病的发作应该是由IAV脑内皮感染引起的。因此，IAV 进入内皮细胞以及病毒 RNA 的转录和/或翻译，而不是病毒增殖，应该是 IAE 的关键发病机制。