RNaseT2 deficient mice reveal the interferon-driven brain phenotype of congenital CMV infection and type I interferonopathies

Infantile-onset RNaseT2 deficient leukoencephalopathy is characterised by cystic brain lesions, multifocal white matter alterations, cerebral atrophy, and severe psychomotor impairment. The phenotype is indistinguishable from congenital cytomegalovirus brain infection and overlaps with typeI interferonopathies like Aicardi-Goutieres syndrome, strongly suggesting a role for innate immunity in its pathophysiology. To date, pathophysiological studies have been hindered by the lack of mouse models recapitulating the neuroinflammatory encephalopathy found in patients. In this study, we generated Rnaset2-/- mice using CRISPR/Cas9-mediated genome editing. Strikingly, Rnaset2-/- mice revealed strong upregulation of interferon-stimulated genes and concurrent neuroinflammation, with infiltration of CD8+ effector memory T cells and inflammatory monocytes into the grey and white matter. Homeostatic dysfunctions in glia cells and neurons revealed by single nuclei RNA sequencing provides initial insights into the mechanism of hippocampal-accentuated brain atrophy and cognitive impairment. Thus, Rnaset2 -/- mice provide an important model, to develop therapies for inborn RNaseT2 deficiency, congenital viral brain infection and further type I interferonopathies. Single Cell Sequencing from hippocampus and putamen of RNaseT2 knockout mice and controls婴儿起病型RNaseT2缺陷性脑白质病（Infantile-onset RNaseT2 deficient leukoencephalopathy）以囊性脑损伤、多灶性白质改变、脑萎缩及严重精神运动障碍为特征。该疾病的表型与先天性巨细胞病毒脑感染难以区分，且与艾卡迪-古特雷斯综合征（Aicardi-Goutieres syndrome）等I型干扰素病存在表型重叠，强烈提示先天免疫在其病理生理过程中发挥关键作用。迄今为止，由于缺乏能够重现患者体内神经炎性脑病的小鼠模型，相关病理生理学研究进展受阻。本研究通过CRISPR/Cas9介导的基因组编辑技术构建了Rnaset2-/-小鼠。令人意外的是，Rnaset2-/-小鼠表现出干扰素刺激基因的显著上调及伴随的神经炎症，CD8+效应记忆T细胞与炎性单核细胞浸润至灰质与白质区域。通过单细胞核RNA测序（single nuclei RNA sequencing）揭示的神经胶质细胞与神经元稳态功能异常，为理解海马区加重型脑萎缩及认知障碍的发病机制提供了初步见解。因此，Rnaset2-/-小鼠可为先天性RNaseT2缺陷症、先天性病毒性脑感染及其他I型干扰素病的治疗研发提供重要的动物模型。本数据集涵盖RNaseT2基因敲除小鼠与对照小鼠的海马及壳核的单细胞测序数据。