Gabele Lea, Bochow Isabell, Rieke Nele, Sieben Christian, Michaelsen-Preusse Kristin, Hosseini Shirin, Korte Martin
Department of Cellular Neurobiology, Zoological Institute, Technische Universität Braunschweig, Braunschweig, Germany.
Helmholtz Centre for Infection Research, Research Group Neuroinflammation and Neurodegeneration, Braunschweig, Germany.
Front Cell Neurosci. 2024 Aug 7;18:1444876. doi: 10.3389/fncel.2024.1444876. eCollection 2024.
Influenza A virus (IAV) infection can increase the risk of neuroinflammation, and subsequent neurodegenerative diseases. Certain IAV strains, such as avian H7N7 subtype, possess neurotropic properties, enabling them to directly invade the brain parenchyma and infect neurons and glia cells. Host sex significantly influences the severity of IAV infections. Studies indicate that females of the reproductive age exhibit stronger innate and adaptive immune responses to IAVs compared to males. This heightened immune response correlates with increased morbidity and mortality, and potential neuronal damage in females. Understanding the sex-specific neurotropism of IAV and associated mechanisms leading to adverse neurological outcomes is essential. Our study reveals that primary hippocampal cultures from female mice show heightened interferon-β and pro-inflammatory chemokine secretion following neurotropic IAV infection. We observed sex-specific differences in microglia activation: both sexes showed a transition into a hyper-ramified state, but only male-derived microglia exhibited an increase in amoeboid-shaped cells. These disparities extended to alterations in neuronal morphology. Neurons derived from female mice displayed increased spine density within 24 h post-infection, while no significant change was observed in male cultures. This aligns with sex-specific differences in microglial synaptic pruning. Data suggest that amoeboid-shaped microglia preferentially target postsynaptic terminals, potentially reducing neuronal hyperexcitability. Conversely, hyper-ramified microglia may focus on presynaptic terminals, potentially limiting viral spread. In conclusion, our findings underscore the utility of primary hippocampal cultures, incorporating microglia, as an effective model to study sex-specific, virus-induced effects on brain-resident cells.
甲型流感病毒（IAV）感染会增加神经炎症以及后续神经退行性疾病的风险。某些IAV毒株，如禽H7N7亚型，具有嗜神经性，能够直接侵入脑实质并感染神经元和神经胶质细胞。宿主性别会显著影响IAV感染的严重程度。研究表明，与男性相比，育龄女性对IAV表现出更强的先天性和适应性免疫反应。这种增强的免疫反应与女性发病率和死亡率的增加以及潜在的神经元损伤相关。了解IAV的性别特异性嗜神经性以及导致不良神经学结果的相关机制至关重要。我们的研究表明，来自雌性小鼠的原代海马培养物在嗜神经性IAV感染后显示出更高的干扰素-β和促炎趋化因子分泌。我们观察到小胶质细胞激活存在性别特异性差异：两性均表现出向高度分支状态的转变，但只有雄性来源的小胶质细胞显示出阿米巴样细胞的增加。这些差异延伸到神经元形态的改变。来自雌性小鼠的神经元在感染后24小时内显示出棘突密度增加，而在雄性培养物中未观察到显著变化。这与小胶质细胞突触修剪的性别特异性差异一致。数据表明，阿米巴样小胶质细胞优先靶向突触后终末，可能降低神经元的过度兴奋性。相反，高度分支的小胶质细胞可能集中在突触前终末，可能限制病毒传播。总之，我们的研究结果强调了包含小胶质细胞的原代海马培养物作为研究性别特异性、病毒诱导的对脑驻留细胞影响的有效模型的实用性。
