SCI-induced deficits in antiviral immunity: The role of sTNF.

SCI 引起的抗病毒免疫缺陷：sTNF 的作用。

• 批准号: 10441446
• 负责人: John Roland Bethea
• 金额: $ 49.2万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10441446
• 关键词: Affect; Antibodies; Antigen Presentation; Antiviral Response; Apoptosis; Attenuated; Biological; CD8-Positive T-Lymphocytes; Cause of Death; Cells; Chest; Chronic; Complex; Data; Dendritic Cells; Environmental Risk Factor; Equilibrium; Glutamates; Goals; Hyperactivity; Immune; Immune System Diseases; Immune response; Immune system; Immunity; Impairment; Individual; Infection; Inflammation; Inflammatory; Influenza A virus; Injury; Interneurons; Lead; Life; Longevity; Lung; Mediating; Mediator of activation protein; Modeling; Mus; NF-kappa B; Neuronal Plasticity; Neurons; Outcome; Pathologic; Patients; Peripheral; Persons; Pharmacology; Play; Pneumonia; Population; Reflex action; Regulation; Risk; Role; Signal Transduction; Spinal; Spinal Cord; Spinal cord injury; Spinal cord injury patients; Splenocyte; T cell response; TNF gene; TNFRSF1A gene; Testing; Thoracic spinal cord structure; Viral Load result; Virus Diseases; antiviral immunity; base; cell type; experimental study; genetic approach; healthspan; hospital readmission; hypothalamic-pituitary-adrenal axis; immune depression; improved; influenzavirus; insight; lymphoid organ; macrophage; mortality; nervous system disorder; neuroinflammation; neuronal excitability; neutrophil; patch clamp; pathogen; prevent; receptor; recruit; therapy development

Abstract Individuals suffering from chronic neurological disorders, such as spinal cord injury (SCI), are at greater risk of serious life-threatening complications from infections, including Influenza A virus (IAV) and pneumonia. Infections are the leading cause of re-hospitalization and mortality in patients living with chronic SCI. Therefore, reducing complications from infections is critical for improving the health and life span of SCI patients. Several groups, including ours, have endeavored to uncover the mechanisms underlying SCI-induced immune depression. For example, high-thoracic (T3) SCI disrupts sympathetic regulation of lymphoid organs and leads to impaired antibody synthesis and increased splenocyte apoptosis. Elegant studies by Ueno and colleagues demonstrated that high-thoracic SCI-induced immune dysfunction is due, in large part, to massive reorganization of the spinal sympathetic reflex circuit, e.g. the recruitment of glutamatergic interneurons, that results in increased sensitivity of this circuit. Silencing these glutamatergic interneurons restored immune balance, in the absence of pathogen challenge, demonstrating that immune balance can be affected by neurogenic mechanisms. However, the mediator(s) of pathological plasticity and glutamatergic interneuron activation post-SCI have not been established. We have exciting preliminary data suggesting that inhibiting soluble Tumor Necrosis Factor (sTNF) in the spinal cord following SCI: attenuates neuroinflammation and aberrant neuronal plasticity and activation, reduces immune dysfunction, and improves antiviral immunity (reduced viral load, increased specific CD8 T cells). Collectively, these data provide for a strong scientific premise to explore the role of sTNF in SCI- induced immune dysfunction. We hypothesize that heightened levels of sTNF in the spinal cord after injury play a crucial role in triggering robust neuroinflammation (e.g., NF-kB activation) and aberrant plasticity that, in turn, lead to hyperactivity of sympathetic circuitry after SCI and peripheral immune dysfunction. These important findings highlight the role of local sTNF signaling in influencing peripheral immunity. Based upon these data, in the following specific aims, we will: Aim 1: Determine the extent that sTNF/TNFR1 signaling in neurons contributes to immune depression following SCI. Aim 2: Investigate the contribution of sTNF to extrinsic (peripheral) factors of impaired antiviral immune responses in chronic SCI mice.

摘要 患有慢性神经系统疾病的个体，如脊髓损伤（SCI）， 感染（包括甲型流感病毒（IAV）和肺炎）导致严重危及生命的并发症的风险。 感染是慢性SCI患者再次住院和死亡的主要原因。 因此，减少感染并发症对改善SCI患者的健康和寿命至关重要 患者 包括我们在内的几个研究小组都致力于揭示SCI诱导的细胞凋亡的潜在机制。 免疫抑制例如，高位胸（T3）SCI破坏了淋巴器官的交感神经调节 并导致抗体合成受损和脾细胞凋亡增加。上野的优雅研究， 他的同事证明，高胸SCI诱导的免疫功能障碍在很大程度上是由于大量的 脊髓交感神经反射回路的重组，例如脊髓交感神经能中间神经元的募集， 导致该电路的灵敏度增加。沉默这些神经元能恢复免疫 平衡，在没有病原体挑战的情况下，表明免疫平衡可能受到以下因素的影响： 神经机制然而，病理性可塑性介质和神经递质能中间神经元 SCI后激活尚未建立。我们有令人兴奋的初步数据表明， SCI后脊髓中的可溶性肿瘤坏死因子（sTNF）：减轻神经炎症， 异常的神经元可塑性和激活，减少免疫功能障碍，提高抗病毒免疫力 （病毒载量减少，特异性CD 8 T细胞增加）。 总的来说，这些数据为探索sTNF在SCI中的作用提供了强有力的科学前提。 诱发免疫功能紊乱。我们推测，脊髓中sTNF水平的升高可能与脊髓损伤有关。 损伤在触发强烈的神经炎症中起关键作用（例如，NF-kB激活）和异常 可塑性，这反过来又导致SCI后交感神经回路的过度活跃和外周免疫 功能障碍 这些重要的发现强调了局部sTNF信号在影响外周免疫中的作用。 根据这些数据，我们将在以下具体目标中： 目的1：确定神经元中sTNF/TNFR 1信号通路对免疫应答的贡献程度。 SCI后抑郁症 目的2：探讨sTNF在抗病毒免疫受损的外在（外周）因素中的作用 慢性SCI小鼠的反应。