Interactions Between Diverse Brain Cell Types Drive Aicardi-Goutieres Neuropathology

ABSTRACT Aicardi Goutières (AGS) is a severe autoinflammatory disease that predominantly affects the brain, leading to severe cognitive and physical disabilities. Although this disease is genetically heterogeneous, all genotypes lead to multi-system excessive type 1 interferon (IFN) activity. How the systemic inflammatory response in AGS leads to predominant central nervous system (CNS) injury is not entirely understood, which limits development of effective and targeted therapies for this destructive disease. In this study proposal, we aim to uncover the “driver” cell in either the peripheral or CNS immune system or at brain vascular interfaces that converts genetic mutations into progressive, IFN-mediated neuronal and oligodendrocyte injury. Using the first rodent models with AGS patient mutations that confer neuropathology, paired with new viral targeting approaches and immune chimeric models, we will test which cell(s) promote(s) neuropathology. We will use these approaches to further interrogate which compartment requires rescue for AGS treatment. This proposal leverages the unique expertise of three separate laboratories at the University of Pittsburgh (Wang) and Children’s Hospital of Philadelphia (Bennett and Vanderver) to dissect, for the first time, the distinct populations of cells driving AGS neuropathology and treatment.