Influenza A Virus (H1N1) Infection Induces Microglial Activation and Temporal Dysbalance in Glutamatergic Synaptic Transmission.
Influenza A Virus (H1N1) Infection Induces Microglial Activation and Temporal Dysbalance in Glutamatergic Synaptic Transmission.
复制标题
DOI：
10.1128/mbio.01776-21
复制
发表时间：
2021-10-26
期刊：
影响因子：
6.4
通讯作者：
Dunay IR
中科院分区：
文献类型：
--
作者：
Düsedau HP;Steffen J;Figueiredo CA;Boehme JD;Schultz K;Erck C;Korte M;Faber-Zuschratter H;Smalla KH;Dieterich D;Kröger A;Bruder D;Dunay IR
甲型流感病毒(IAV)引起呼吸道疾病，是影响所有年龄段的季节性和重复性流行病的原因。除了发烧和疲劳等典型的疾病症状外，IAV感染还与行为改变有关，推测这可能会导致严重抑郁症的发展。以前使用IAV/H1N1感染模型的实验已经显示出海马神经元形态和认知能力受损，但潜在的途径还没有完全描述。在这项研究中，我们证明了感染低剂量的非神经营养性H1N1 IAV毒株会引起充足的外周免疫反应，随后会出现暂时性的血脑屏障障碍。虽然组织学检查没有显示感染IAV的小鼠大脑中明显的病理过程，但免疫细胞的详细多维流式细胞术特征揭示了小胶质细胞激活状态的细微变化。更具体地说，我们检测到主要组织相容性复合体I和II类、CD80和F4/80的表达模式发生了变化，并伴随着CD36、CD68、C1QA和C3的mRNA水平升高，这表明突触修剪是进化的。为了更好地评估这些深刻的变化是如何影响突触平衡的，我们建立了一种基于高度灵敏的多重流式细胞术的方法，称为流式突触测定法。这项新技术的引入使我们能够同时量化不同大脑区域突触前和突触后的丰富程度。我们的数据显示，大脑皮质和海马区兴奋性突触前终末的VGLUT1显著减少，这表明H1N1感染后小鼠的谷氨酸能突触传递存在微小的失衡。总而言之，我们的结果强调了全身性IAV引发的炎症对中枢神经系统的后果以及神经元变化的诱导和进展。
Influenza A virus (IAV) causes respiratory tract disease and is responsible for seasonal and reoccurring epidemics affecting all age groups. Next to typical disease symptoms, such as fever and fatigue, IAV infection has been associated with behavioral alterations presumably contributing to the development of major depression. Previous experiments using IAV/H1N1 infection models have shown impaired hippocampal neuronal morphology and cognitive abilities, but the underlying pathways have not been fully described. In this study, we demonstrate that infection with a low-dose non-neurotrophic H1N1 strain of IAV causes ample peripheral immune response followed by a temporary blood-brain barrier disturbance. Although histological examination did not reveal obvious pathological processes in the brains of IAV-infected mice, detailed multidimensional flow cytometric characterization of immune cells uncovered subtle alterations in the activation status of microglial cells. More specifically, we detected an altered expression pattern of major histocompatibility complex classes I and II, CD80, and F4/80 accompanied by elevated mRNA levels of CD36, CD68, C1QA, and C3, suggesting evolved synaptic pruning. To closer evaluate how these profound changes affect synaptic balance, we established a highly sensitive multiplex flow cytometry-based approach called flow synaptometry. The introduction of this novel technique enabled us to simultaneously quantify the abundance of pre- and postsynapses from distinct brain regions. Our data reveal a significant reduction of VGLUT1 in excitatory presynaptic terminals in the cortex and hippocampus, identifying a subtle dysbalance in glutamatergic synapse transmission upon H1N1 infection in mice. In conclusion, our results highlight the consequences of systemic IAV-triggered inflammation on the central nervous system and the induction and progression of neuronal alterations.