Tingling J D, Krauklis S A, Haak P L, Carr R, Louie A Y, Johnson R W, Steelman A J
Department of Animal Sciences, University of Illinois at Urbana-Champaign, 1201 W. Gregory Dr., Urbana, IL, 61801, USA.
Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, 1201 W. Gregory Dr., Urbana, IL, 61801, USA.
Brain Behav Immun Health. 2024 Oct 9;42:100891. doi: 10.1016/j.bbih.2024.100891. eCollection 2024 Dec.
Respiratory infection by influenza A virus (IAV) is known to cause systemic inflammation, neuroinflammation, and cognitive impairment. We previously found that experimental infection with IAV affected oligodendrocyte homeostasis, which was associated with altered expression of genes involved in myelin maintenance as well as the lipidome. In this study, we sought to determine if clemastine, an antihistamine with myelin promoting properties, could reverse the effects of IAV on oligodendrocyte (OL) specific genes, as well as mitigate infection-induced cognitive impairment. Male and female C57BL/6J mice were randomized into experimental groups based on clemastine treatment, infection, and sex. Treatment with vehicle or clemastine (10 mg/kg/d) commenced seven days prior to inoculation with either saline or IAV and continued throughout the experiment. Body weight was measured throughout the infection. Spatial learning and memory were assessed by Morris water maze. Sickness behavior was assessed by measuring burrowing response. Immune cell responses were determined by flow cytometry, RT-qPCR, antigen recall assays and ELISA, and viral load assessed by RT-qPCR. Hippocampal levels of neuroinflammatory () and myelin (, , ) genes were determined by RT-qPCR. Mice infected with IAV developed weight loss, impaired cognitive flexibility, reduced burrowing behavior, altered lung immune cell infiltration, increased circulating anti-viral IgM and IgG levels and increased T cell responses to IAV epitopes. Infection increased hippocampal levels of genes associated with neuroinflammation and decreased levels of genes involved in myelination. Clemastine treatment resulted in earlier recovery of weight loss in males and increased IgM levels for both sexes, but neither affected expression levels of or , nor rescued changes to oligodendrocyte genes. However, treatment mitigated infection-induced neurocognitive impairment.
已知甲型流感病毒（IAV）引起的呼吸道感染会导致全身炎症、神经炎症和认知障碍。我们之前发现，IAV实验性感染会影响少突胶质细胞的稳态，这与参与髓鞘维持的基因表达改变以及脂质组有关。在本研究中，我们试图确定具有促进髓鞘形成特性的抗组胺药氯马斯汀是否可以逆转IAV对少突胶质细胞（OL）特异性基因的影响，并减轻感染引起的认知障碍。根据氯马斯汀治疗、感染情况和性别，将雄性和雌性C57BL/6J小鼠随机分为实验组。在接种生理盐水或IAV前7天开始用赋形剂或氯马斯汀（10 mg/kg/d）进行治疗，并在整个实验过程中持续给药。在整个感染过程中测量体重。通过莫里斯水迷宫评估空间学习和记忆。通过测量掘洞反应评估疾病行为。通过流式细胞术、RT-qPCR、抗原回忆试验和ELISA确定免疫细胞反应，并通过RT-qPCR评估病毒载量。通过RT-qPCR确定海马中神经炎症（）和髓鞘（，，）基因的水平。感染IAV的小鼠出现体重减轻、认知灵活性受损、掘洞行为减少、肺部免疫细胞浸润改变、循环抗病毒IgM和IgG水平升高以及T细胞对IAV表位的反应增加。感染增加了海马中与神经炎症相关的基因水平，并降低了参与髓鞘形成的基因水平。氯马斯汀治疗使雄性小鼠体重减轻恢复得更早，并且使两性的IgM水平升高，但既不影响或的表达水平，也不能挽救少突胶质细胞基因的变化。然而，治疗减轻了感染引起的神经认知障碍。
