A Tick-Borne Encephalitis Model in Infant Rats Infected With Langat Virus
A Tick-Borne Encephalitis Model in Infant Rats Infected With Langat Virus
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DOI：
10.1097/nen.0000000000000131
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发表时间：
2014-12-01
影响因子：
3.2
通讯作者：
Leib, Stephen L.
中科院分区：
文献类型：
--
作者：
Maffioli, Carola;Grandgirard, Denis;Leib, Stephen L.
蜱传脑炎病毒（TBEV）是人类TBE的病原体，这是一种可引起长期神经系统后遗症的严重感染。与TBEV密切相关的Langat病毒（LGTV）对人类宿主的毒力较低，已被用作对付TBEV的活疫苗。人类自然感染LGTV引起的蜱传脑炎尚未见报道，但18,500名LGTV疫苗接种者中有一人患脑炎。TBEV的发病机制尚不清楚，目前尚无有效的治疗方法。我们建立了以LGTV为感染因子的TBE幼鼠模型。在感染后第2、4、7和9天，对幼龄Wistar大鼠腹腔内接种106个病灶形成单位的LGTV，并评估其临床疾病和神经病理表现。LGTV感染导致步态障碍、运动障碍和体重增加或减少。感染动物脑脊液RANTES、干扰素- f、干扰素- a、白细胞介素-6和单核细胞趋化蛋白-1浓度升高。LGTV脑炎动物的大脑表现出特征性的血管周围炎性袖口和胶质结节；免疫组织化学证实LGTV存在于丘脑、海马、中脑、额极和小脑。因此，幼鼠的LGTV脑膜脑炎模仿了人类TBE的重要临床和组织病理学特征。这一新模型为研究致脑性黄病毒的发病机制和评估新的治疗策略提供了工具。
Tick-borne encephalitis virus (TBEV) is the causative agent of human TBE, a severe infection that can cause long-lasting neurologic sequelae. Langat virus (LGTV), which is closely related to TBEV, has a low virulence for human hosts and has been used as a live vaccine against TBEV. Tick-borne encephalitis by natural infection of LGTV in humans has not been described, but one of 18,500 LGTV vaccinees developed encephalitis. The pathogenetic mechanisms of TBEV are poorly understood and, currently, no effective therapy is available. We developed an infant rat model of TBE using LGTV as infective agent. Infant Wistar rats were inoculated intracisternally with 10 6 focus-forming units of LGTV and assessed for clinical disease and neuropathologic findings at Days 2, 4, 7, and 9 after infection. Infection with LGTV led to gait disturbance, hypokinesia, and reduced weight gain or weight loss. Cerebrospinal fluid concentrations of RANTES, interferon-F, interferon-A, interleukin-6, and monocyte chemotactic protein-1 were increased in infected animals. The brains of animals with LGTV encephalitis exhibited characteristic perivascular inflammatory cuffs and glial nodules; immunohistochemistry documented the presence of LGTV in the thalamus, hippocampus, midbrain, frontal pole, and cerebellum. Thus, LGTV meningoencephalitis in infant rats mimics important clinical and histopathologic features of human TBE. This new model provides a tool to investigate disease mechanisms and to evaluate new therapeutic strategies against encephalitogenic flaviviruses.