Innate Immunity and Infection, Helmholtz Centre for Infection Research, 38124, Braunschweig, Germany.
Present Address: Institute of Virology, Hannover Medical School, 30625, Hannover, Germany.
J Neuroinflammation. 2020 Sep 20;17(1):278. doi: 10.1186/s12974-020-01951-w.
Tick-borne encephalitis virus (TBEV) is an important human pathogen that can cause the serious illness tick-borne encephalitis (TBE). Patients with clinical symptoms can suffer from severe meningoencephalitis with sequelae that include cognitive disorders and paralysis. While less than 30% of patients with clinical symptoms develop meningoencephalitis, the number of seropositive individuals in some regions indicates a much higher prevalence of TBEV infections, either with no or subclinical symptoms. The functional relevance of these subclinical TBEV infections and their influence on brain functions, such as learning and memory, has not been investigated so far.
To compare the effect of low and high viral replication in the brain, wildtype and Irf-7 mice were infected with Langat virus (LGTV), which belongs to the TBEV-serogroup. The viral burden was analyzed in the olfactory bulb and the hippocampus. Open field, elevated plus maze, and Morris water maze experiments were performed to determine the impact on anxiety-like behavior, learning, and memory formation. Spine density of hippocampal neurons and activation of microglia and astrocytes were analyzed.
In contrast to susceptible Irf-7 mice, wildtype mice showed no disease signs upon LGTV infection. Detection of viral RNA in the olfactory bulb revealed CNS infections in wildtype and Irf-7 mice. Very low levels of viral replication were detectable in the hippocampus of wildtype mice. Although wildtype mice develop no disease signs, they showed reduced anxiety-like behavior and impaired memory formation, whereas Irf-7 mice were not affected. This impairment was associated with a significant decrease in spine density of neurons in the hippocampal CA1 region of wildtype mice. Microglia activation and astrogliosis were detected in the hippocampus.
In this study, we demonstrate that subclinical infections by viruses from the TBEV-serogroup affected anxiety-like behavior. Virus replication in the olfactory bulb induced far-reaching effects on hippocampal neuron morphology and impaired hippocampus-dependent learning and memory formation.
蜱传脑炎病毒（TBEV）是一种重要的人类病原体，可引起严重的蜱传脑炎（TBE）疾病。有临床症状的患者可罹患严重的脑膜脑炎，并伴有认知障碍和瘫痪等后遗症。虽然不到 30%有临床症状的患者发生脑膜脑炎，但在一些地区，血清阳性个体的数量表明 TBEV 感染的流行率更高，且这些感染可能没有临床症状或呈亚临床症状。迄今为止，尚未研究这些亚临床 TBEV 感染的功能相关性及其对学习和记忆等脑功能的影响。
为了比较低水平和高水平病毒在大脑中的复制的影响，野生型和 Irf-7 小鼠分别用属于 TBEV 血清群的兰格特病毒（LGTV）感染。分析嗅球和海马中的病毒载量。通过旷场实验、高架十字迷宫实验和 Morris 水迷宫实验，确定其对焦虑样行为、学习和记忆形成的影响。分析海马神经元的棘突密度和小胶质细胞及星形胶质细胞的激活情况。
与易感 Irf-7 小鼠不同，野生型小鼠在 LGTV 感染后没有出现疾病迹象。嗅球中病毒 RNA 的检测表明野生型和 Irf-7 小鼠的中枢神经系统感染。在野生型小鼠的海马中可检测到非常低水平的病毒复制。尽管野生型小鼠没有出现疾病迹象，但它们表现出焦虑样行为减少和记忆形成受损，而 Irf-7 小鼠则未受影响。这种损伤与野生型小鼠海马 CA1 区神经元棘突密度的显著减少有关。在海马中检测到小胶质细胞激活和星形胶质细胞增生。
在这项研究中，我们证明了 TBEV 血清群病毒的亚临床感染会影响焦虑样行为。嗅球中的病毒复制对海马神经元形态产生了深远的影响，并损害了海马依赖的学习和记忆形成。
