RIPK3 acts as a molecular switch between neuroprotection and neuropathology during herpes simplex encephalitis

ABSTRACT: Herpes simplex virus type 1 (HSV-1) is the leading cause of sporadic viral encephalitis, and uncontrolled viral replication, together with host-driven neuroinflammation, leads to fatal brain injury. Although inherited RIPK3 deficiency predisposes individuals to severe disease, how RIPK3 confers neuroprotection remains unclear. Using single-cell transcriptomics and genetic dissection, we show that RIPK3 acts as a molecular switch that balances antiviral defense with neuropathology in the central nervous system. RIPK3 scaffolding activity drives type I interferon (IFN) production in neurons and coordinates type I and II IFN programs in astrocytes, microglia, and infiltrating myeloid cells, promoting immune differentiation and viral control. RIPK3-dependent apoptosis further limits myeloid accumulation and preserves neuronal homeostasis. In contrast, RIPK3 kinase activation in astrocytes triggers necroptosis, provoking neuronal loss, excessive myeloid infiltration, and lethal neuroinflammation. Genetic or pharmacological inhibition of RIPK3 kinase suppresses astrocyte necroptosis, enhances IFN responses, preserves brain integrity, and improves survival during HSV-1 encephalitis.

ORGANISM(S): Mus musculus

PROVIDER: GSE315221 | GEO | 2026/08/24

REPOSITORIES: GEO