Long-term neuroinflammation induced by influenza A virus infection and the impact on hippocampal neuron morphology and function

Acute influenza infection can be associated with neurological symptoms. Especially after the major pandemics reports about neuropsychiatric complications accumulated. However, the long-term consequences for the CNS of an infection with neurotropic but also non-neurotropic influenza A virus (IAV) variants remain largely elusive. The results presented here show that synapse loss in the hippocampus upon an infection with neurotropic H7N7 (rSC35M) as well as non-neurotropic H3N2 (maHK68) persists well beyond the acute phase of the disease. While hippocampal synapse number was significantly reduced 30 days post infection with both H7N7 and H3N2, full recovery could be observed 120 days post infection. Notably, infection with H1N1 (PR8) which was shown previously to affect spine number and hippocampus-dependent learning during the acute phase had no significant long-term effects. Spine loss was associated with an increase in the number of activated microglia, reduced long-term potentiation and an impairment in spatial memory formation in the water maze indicating long-term inflammation induced functional and structural alterations in the hippocampus. Our data, therefore, provide evidence that while neuroinflammation induced by neurotropic H7N7 showed the strongest effect, also the systemic infection with a non-neurotropic influenza virus can result in long-term impairments in synapse number and function in the hippocampus. While young animals fully recover the outcome might be different in aged or otherwise compromised individuals, thereby directing future treatment strategies to pay attention to IAV induced processes of neuroinflammation. To follow IAV induced gene expression changes in the hippocampus, we performed transcriptome studies. Hippocampi of mice infected with two respective IAVs were prepared at 18 dpi and 30 dpi. RNA was isolated for whole genome microarray analysis.

急性流感感染可伴随神经系统症状。尤其是在历次大流行之后，有关神经精神并发症的报道逐渐增多。然而，嗜神经性与非嗜神经性甲型流感病毒（influenza A virus, IAV）变体感染对中枢神经系统（central nervous system, CNS）的长期影响仍尚不明确。
本研究结果显示，感染嗜神经性H7N7（rSC35M）与非嗜神经性H3N2（maHK68）后，海马体（hippocampus）内的突触丢失现象会持续至急性感染期之后许久。尽管感染上述两种毒株后第30天，海马体突触数量均显著降低，但在感染后第120天可观察到完全恢复。值得注意的是，此前研究表明H1N1（PR8）感染可在急性感染期影响树突棘数量及海马依赖性学习能力，但该毒株并未引发显著的长期效应。
树突棘丢失与活化小胶质细胞数量增加、长时程增强（long-term potentiation, LTP）受损以及莫里斯水迷宫实验中空间记忆形成障碍相关，提示长期炎症可诱导海马体出现结构与功能改变。
因此，本研究数据证实：尽管嗜神经性H7N7诱导的神经炎症影响最为显著，但非嗜神经性流感病毒的全身性感染同样可导致海马体突触数量及功能出现长期损伤。
幼年动物可完全恢复，但老年或其他生理状态受损个体的结局或有不同，这为未来治疗策略指明了方向，即需重视甲型流感病毒诱导的神经炎症过程。
为探究甲型流感病毒感染后海马体中的基因表达变化，我们开展了转录组学研究：在感染后第18天（days post infection, dpi）与第30天，采集感染两种不同甲型流感病毒的小鼠海马体组织，提取RNA以进行全基因组微阵列分析。