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

Herpes simplex virus type 1 (HSV-1) is the leading cause of sporadic viral encephalitis, where uncontrolled viral replication and neuroinflammation drive fatal brain injury. Inherited RIPK3 deficiency predisposes humans to severe disease, but the protective mechanism remains unclear. Using single-cell transcriptomics, genetic knockout models, and analysis of viral replication, interferon production, and cell death across neurons, astrocytes, microglia, and myeloid cells, we show that RIPK3 acts as a cell-type-specific molecular switch.

RIPK3 scaffolding promotes interferon response and viral control in multiple central nervous system cell types, while RIPK3-dependent apoptosis limits myeloid accumulation. In contrast, RIPK3 kinase activity in astrocytes triggers necroptosis, leading to neuronal loss and lethal neuroinflammation. Genetic or pharmacological inhibition of RIPK3 kinase suppresses astrocyte necroptosis, enhances IFN responses, preserves brain integrity, and improves survival.

These findings suggest that selective modulation of RIPK3 signaling may balance antiviral defense with limitation of neuropathology in HSV-1 encephalitis. We acknowledge the INLET Core facility of LSU Health Shreveport for assistance with Incucyte Zoom live cell imaging (RRID: SCR_024990), the Microscopy Imaging-Research Core Facility (RRID: SCR_024775) for confocal imaging, the CAIPP Bioinformatics and Modeling Core for single-cell sequencing and analysis (RRID: SCR_024779), and the CAIPP Immunophenotyping Core for flow cytometry (RRID: SCR_024781). We acknowledge BioRender for the creation of illustrations for Figs. 5d and Fig. 7a, u.

This work is supported by NIH grants R21AI175590, R21CA303392, R01AI189875, R01EY034120, and COBRE P20GM134974 (to H.G.). Department of Microbiology and Immunology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, 71130, USA Shuqi Wang, Jian Wang, Madison Hicks, Sushma Bharrhan, Matthew Woolard & Hongyan Guo Center for Applied Immunology and Pathological Processes, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, 71130, USA Jian Wang, Sushma Bharrhan & Matthew Woolard The authors declare no competing interests. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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