Microglia and type I interferon: protective and pathogenic mechanisms (360G-Wellcome-211153_Z_18_Z)

Viral encephalitis is a severe and largely untreatable manifestation of viral infection, with substantial rates of lifelong disability in survivors. The discovery, by myself and others, of rare monogenic diseases that predispose to viral encephalitis indicates that interferon-alpha/beta is an essential mediator of antiviral protection. Determining the underlying mechanism is a critical step towards developing therapeutic agonists of this pathway. Conversely, I and others have also discovered that exaggerated interferon-alpha/beta activity is linked to monogenic neuroinflammatory disease. Establishing causality is a clinical necessity, as therapeutic options are available to block interferon signalling. My proposal will definitively address the following questions: Does interferon protect brain cells against viral infection? Is prolonged interferon signalling damaging to brain cells? What is the specific role of brain-resident macrophages (microglia) in these processes? To address these questions, I exploit new models of human microglia from gene-edited and patient-derived pluripotent stem cells, together with a new knock-in mouse model. Key goals are to create fundamental knowledge about the action and regulation of interferon-alpha/beta in brain cells, and deliver a versatile and genetically-tractable human model in which to interrogate host determinants of viral neuropathogenesis. The skills I develop will underpin my future research programme in viral encephalitis.