Wu Wenxin, Alexander Jeremy S, Booth J Leland, Miller Craig A, Metcalf Jordan P, Drevets Douglas A
Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Room 425, RP1 800 N. Research Pkwy, Oklahoma City, OK, 73104, USA.
Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State University, Oklahoma State University, Stillwater, OK, USA.
Immun Ageing. 2024 Jun 21;21(1):39. doi: 10.1186/s12979-024-00447-y.
Age > 65 years is a key risk factor for poor outcomes after human influenza infection. Specifically, in addition to respiratory disease, non-neurotropic influenza A virus (IAV) causes neuro-cognitive complications, e.g. new onset depression and increases the risk of dementia after hospitalization. This study aimed to identify potential mechanisms of these effects by determining differences between young and old mice in brain gene expression in a mouse model of non-neurotropic IAV infection.
Young (12 weeks) and old (70 weeks) C57Bl/6J mice were inoculated intranasally with 200 PFU H1N1 A/PR/34/8 (PR8) or sterile PBS (mock). Gene expression in lung and brain was measured by qRT-PCR and normalized to β-actin. Findings were confirmed using the nCounter Mouse Neuroinflammation Array (NanoString) and analyzed with nSolver 4.0 and Ingenuity Pathway Analysis (IPA, Qiagen).
IAV PR8 did not invade the central nervous system. Young and old mice differed significantly in brain gene expression at baseline and during non-neurotropic IAV infection. Expression of brain Ifnl, Irf7, and Tnf mRNAs was upregulated over baseline control at 3 days post-infection (p.i.) only in young mice, but old mice expressed more Ifnl than young mice 7 days p.i. Gene arrays showed down-regulation of the Epigenetic Regulation, Insulin Signaling, and Neurons and Neurotransmission pathways in old mice 3 days p.i. while young mice demonstrated no change or induction of these pathways at the same time point. IPA revealed marked baseline differences between old and young mice. Gene expression related to Cognitive Impairment, Memory Deficits and Learning worsened in old mice relative to young mice during IAV infection. Aged mice demonstrate more severe changes in gene expression related to memory loss and cognitive dysfunction by IPA.
These data suggest the genes and pathways related to learning and cognitive performance that were worse at baseline in old mice were further worsened by IAV infection, similar to old patients. Early events in the brain triggered by IAV infection portend downstream neurocognitive pathology in old adults.
年龄大于65岁是人类感染流感后预后不良的关键风险因素。具体而言，除了呼吸系统疾病外，非嗜神经性甲型流感病毒（IAV）还会引发神经认知并发症，例如新发抑郁症，并增加住院后患痴呆症的风险。本研究旨在通过确定非嗜神经性IAV感染小鼠模型中年轻和老年小鼠脑基因表达的差异，来识别这些影响的潜在机制。
将12周龄的年轻和70周龄的老年C57Bl/6J小鼠经鼻接种200 PFU H1N1 A/PR/34/8（PR8）或无菌PBS（假手术）。通过qRT-PCR测量肺和脑中的基因表达，并将其标准化为β-肌动蛋白。使用nCounter小鼠神经炎症阵列（NanoString）对结果进行确认，并使用nSolver 4.0和 Ingenuity通路分析（IPA，Qiagen）进行分析。
IAV PR8未侵入中枢神经系统。年轻和老年小鼠在基线以及非嗜神经性IAV感染期间脑基因表达存在显著差异。仅在年轻小鼠中，感染后3天（p.i.）脑Ifnl、Irf7和Tnf mRNA的表达相对于基线对照上调，但老年小鼠在感染后7天表达的Ifnl比年轻小鼠更多。基因阵列显示，感染后3天老年小鼠的表观遗传调控、胰岛素信号传导以及神经元和神经传递通路下调，而年轻小鼠在同一时间点这些通路无变化或被诱导。IPA揭示了老年和年轻小鼠之间明显的基线差异。在IAV感染期间，与年轻小鼠相比，老年小鼠中与认知障碍、记忆缺陷和学习相关的基因表达恶化。通过IPA分析，老年小鼠在与记忆丧失和认知功能障碍相关的基因表达方面表现出更严重的变化。
这些数据表明，与学习和认知表现相关的基因和通路在老年小鼠基线时较差，并且IAV感染使其进一步恶化，这与老年患者相似。IAV感染引发的脑早期事件预示着老年人下游的神经认知病理学。
