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

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.

The defining features of several common neurodegenerative diseases include the accumulation of misfolded protein within the CNS, degeneration of synapses and neurons and the activation of astrocytes and microglia. Microglia, in common with other tissue macrophage populations, can adopt a number of different phenotypes that contribute to the outcome of tissue injury and disease. There is evidence that systemic inflammation, induced by bacterial and viral mimetics, can modulate the microglia phenotype in both the healthy and diseased brain. We aim in this study to test the following hypothesis: Systemic viral infection during chronic neurodegeneration switches the innate immune response of microglia from a relatively neuroprotective phenotype to a tissue damaging phenotype which will exacerbate disease progression. One of the best characterised laboratory models of chronic neurodegenerative disease in which accumulation of misfolded protein leads to activation of microglia and widespread neurodegeneration is prion disease. The locus and timing of the initiation of neurodegeneration is under precise experimental control and rodent models of these diseases display all the features of a chronic inexorable neurodegenerative process with early behavioural changes, loss of cognitive function and loss of motor function. The behavioural changes are associated with synaptic dysfunction and subsequent widespread death of neurones. We will carry out a study of viral infection before and during the course of a prion infection in our well established murine models. A comprehensive panel of readouts will comprise behavioural studies, pathological, biochemical and microarray analysis. We will establish whether viral infections modify the microglia phenotype in the diseased brain and if so how long this switching of phenotype persists and whether this may alter the course of disease. The findings from this study will have an important impact on our understanding as to how systemic viral infections may contribute to cognitive decline and disease progression in patients with chronic neurodegenerative disease. In understanding the exact role of brain macrophage populations we can establish the molecular pathways leading to neuronal damage thus facilitating development of future therapeutic approaches for protein misfolding neurodegenerative diseases.