The impact of systemic viral infections on the innate immune response in the brain in chronic neurodegeneration

被称为巨噬细胞的细胞是我们抵御伤害和感染的第一道防线。众所周知，它们可能以多种不同的功能状态存在：它们不仅检测和杀死入侵的生物体，而且参与组织修复。在大脑中，有一群被称为小胶质细胞的常驻组织巨噬细胞，通常受到大脑微环境的严格控制。然而，在脑损伤和疾病期间，它们会被激活。随着英国和发展中国家的人口寿命延长，慢性神经退行性疾病的患病率也在增加，带来了深远的社会和经济后果。最常见的慢性神经退行性疾病是阿尔茨迈尔-S病，与大脑中错误折叠的蛋白积聚、广泛的神经元变性和小胶质细胞激活有关。目前尚不清楚观察到的小胶质细胞激活增加是否通过防止错误折叠的蛋白质积累起到有益的作用，或者它们的活动是否有助于疾病的病理。最近的数据表明，在阿尔茨海默病患者中，细菌或病毒感染引起的全身炎症与认知能力减退和行为问题的恶化有关。众所周知，向大脑发出全身性炎症信号涉及小胶质细胞。在这项建议中，我们将使用我们定义良好的慢性进行性神经变性的实验室模型，即小鼠的Pron病，来研究全身性病毒感染如何影响疾病大脑中激活的小胶质细胞，以及这是否影响神经退化的进展。我们将使用行为分析和神经病理学来研究病毒感染是如何改变疾病进展的。我们将使用分子、细胞和生化技术来研究病毒感染如何改变大脑中小胶质细胞的激活状态。我们将使用最先进的生物信息技术来比较我们关于小胶质细胞激活状态的数据与关于使个人容易患阿尔茨海默氏病的基因的数据。通过了解小胶质细胞的作用，我们可以帮助建立导致脑损伤的机制，从而促进未来治疗包括错误折叠蛋白积聚的慢性神经退行性疾病的方法的发展。如果全身性感染推动了疾病的发展，那么可以对其进行治疗，以延缓疾病的发展，提高神经退行性疾病患者的生活质量。

Cells known as macrophages are our first line of defence against injury and infection. It is well recognised that they may exist in many different functional states: they not only detect and kill invading organisms but are involved in tissue repair. In the brain there is a population of resident tissue macrophages known as the microglia, which is normally kept under tight control by the brain microenvironment. However, during brain injury and disease they become activated. As the population of the UK and developing world lives longer so the prevalence of chronic neurodegenerative diseases is increasing with profound social and economic consequences. The most common form of chronic neurodegenerative disease, Alzhemier?s disease, is associated with accumulation of misfolded protein in the brain, widespread neuronal degeneration and activation of microglia. It is not clear whether the observed increase in microglia activation has beneficial effects by preventing misfolded protein accumulation or whether their activity contributes to the pathology of the disease. Recent data suggests that systemic inflammation caused by bacterial or viral infections in individuals with Alzheimer?s disease is associated with accelerated cognitive decline and exacerbation of behavioural problems. It is known that signalling of systemic inflammation to the brain involves microglia. In this proposal we will use our well-defined laboratory model of chronic progressive neurodegeneration, prion disease in mice, to investigate how a systemic viral infection impacts on the activated microglia in the diseased brain and whether this affects the progression of neurodegeneration. We will use behavioural assays and neuropathology to investigate how the viral infection alters disease progression. We will use molecular, cellular and biochemical techniques to study how the viral infection alters the state of activation of the microglia in the brain. We will use state of the art bio-information techniques to compare our data on microglia activation states with data about genes that make individuals susceptible to Alzheimer?s disease. In understanding the role of microglia we can help to establish the mechanisms causing brain damage thus facilitating development of future therapeutic approaches for chronic neurodegenerative disease involving the accumulation of misfolded protein disease. If systemic infections are driving disease progression they can be treated to delay disease progression and improve the quality of life of patients with neurodegenerative disease.