DEC-205+ Dendritic Cells are Effective at Stimulating a Protective T Cell Response Against WNV Encephalitis

DEC-205 树突状细胞可有效刺激针对 WNV 脑炎的保护性 T 细胞反应

• 批准号: 10327693
• 负责人: Douglas Matthew Durrant
• 金额: $ 11.03万
• 依托单位: CALIFORNIA STATE POLY U POMONA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-10 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10327693
• 关键词: Activated Lymphocyte; Address; Adoptive Cell Transfers; Antigen Presentation; Antigens; Binding; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain region; Cells; Central Nervous System Viral Diseases; DEC-205 receptor; Dendritic Cells; Development; Disease; Ensure; Equilibrium; Flavivirus; Genes; Immune; Immune response; Immune system; Immunity; Inflammation; Inflammation Mediators; Inflammatory; Injury; Invaded; Knockout Mice; Learning; Life Cycle Stages; Lymphocyte; Maintenance; Mediating; Modeling; Mus; Nervous System control; Neuraxis; Neuronal Injury; Neurons; Neuropathogenesis; Population; Positioning Attribute; Prevention; Process; Production; Research; Role; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Tissues; Viral; Viral Antigens; Viral Pathogenesis; Viral Physiology; Virus; Virus Diseases; Virus Replication; West Nile Encephalitis; West Nile viral infection; West Nile virus; antigen-specific T cells; brain cell; chemokine; cytokine; experimental group; experimental study; immunopathology; knockout gene; medical specialties; mouse model; nervous system disorder; neuron loss; neuronal survival; neuropathology; neurotropic; prevent; receptor; uptake

PROJECT SUMMARY West Nile virus (WNV) is a significant cause of neuronal injury and inflammation that results in severe disease that can potentially be lethal. In order to reduce or eliminate invading viruses from the central nervous system (CNS) and protect the brain, it is vital that T cells enter the virally-infected CNS and perform their anti-viral functions. However, due to the sensitivity of neurons, the presence activated T cells within the CNS may also contribute to neuropathology if not rigorously regulated. Previous research showed that dendritic cells (DCs) are critical for establishing virologic control within the CNS during WNV neuro-invasive disease. Yet, little is known as to how these cells accomplish protection without causing neuronal damage. We hypothesize that a specific subset of DCs (DEC-205-expressing DCs) promote virologic control and protection against WNV neuro-invasive disease through the appropriate activation of the T cells migrating into the virally-infected CNS. To address this hypothesis, we will use a well-established mouse model of WNV encephalitis, where one experimental group will be genetically deficient for the DEC-205 gene, effectively eliminating this subset of DCs from the brain and elsewhere. Using this model, we will be able to determine the role of these cells in limiting viral infection, replication, and neuronal injury within the WNV-infected CNS. We will also perform an adoptive transfer of these cells into the genetically deficient mice at a critical stage during WNV neuro-invasive disease. Through this study, we will determine the mechanisms by which this specific subset of DCs provide protection against WNV neuro- invasive disease. Together, these studies will illuminate and enhance our understanding of our immune responses to viral infections in the brain and the balance between an effective immune response and immunopathology with injury to neurons. It also has clear implications for the control and prevention of WNV neuro-invasive disease.

项目总结 西尼罗河病毒(WNV)是导致严重疾病的神经细胞损伤和炎症的重要原因 这可能是致命的。为了减少或消除来自中枢神经系统的入侵病毒 对于中枢神经系统(CNS)和保护大脑来说，T细胞进入病毒感染的中枢神经系统并发挥抗病毒作用至关重要 功能。然而，由于神经元的敏感性，中枢神经系统内存在激活的T细胞也可能 如果没有严格的监管，就会导致神经病理。先前的研究表明，树突状细胞(DC)是 对于在西尼罗河病毒神经侵袭性疾病期间建立中枢神经系统内的病毒学控制至关重要。然而，人们对此知之甚少 这些细胞如何在不造成神经元损伤的情况下完成保护。我们假设一个特定的 树突状细胞亚群(DEC-205表达的树突状细胞)促进对西尼罗河病毒神经侵袭的病毒学控制和保护 通过适当激活迁移到病毒感染的中枢神经系统的T细胞而致病。要解决这个问题 假设，我们将使用一种成熟的WNV脑炎小鼠模型，其中一个实验组 将是DEC-205基因的遗传缺陷，有效地从大脑中消除这一DC亚群，并 其他地方。使用这个模型，我们将能够确定这些细胞在限制病毒感染方面的作用， 西尼罗河病毒感染的中枢神经系统内的复制和神经元损伤。我们还将对这些人进行收养转让 在西尼罗河病毒神经侵袭性疾病的关键阶段，将细胞注入基因缺陷小鼠。通过这项研究， 我们将确定这一特定的DC亚群提供保护西尼罗河病毒神经- 侵袭性疾病。综上所述，这些研究将阐明并加强我们对免疫系统的了解 对大脑中病毒感染的反应以及有效的免疫反应和 神经元损伤的免疫病理学。这对西尼罗河病毒的控制和预防也有明确的影响。 神经侵袭性疾病。