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Peer-reviewedCC BY-NC-NDNature communications

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

  • Shuqi Wang1
  • Jian Wang1,2
  • Madison Hicks1
  • Sushma Bharrhan1,2
  • Matthew Woolard1,2
  • Hongyan Guo3
  1. 1Department of Microbiology and Immunology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, 71130, USA.
  2. 2Center for Applied Immunology and Pathological Processes, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, 71130, USA.
  3. 3Department of Microbiology and Immunology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, 71130, USA. [email protected].
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{wang2026ripk3,
  title = {{RIPK3 acts as a molecular switch between neuroprotection and neuropathology during herpes simplex encephalitis.}},
  author = {Shuqi Wang and Jian Wang and Madison Hicks and Sushma Bharrhan and Matthew Woolard and Hongyan Guo},
  journal = {Nature communications},
  year = {2026},
  month = sep,
  doi = {10.1038/s41467-026-77881-7},
  url = {https://europepmc.org/article/MED/42907439},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - RIPK3 acts as a molecular switch between neuroprotection and neuropathology during herpes simplex encephalitis.
AU  - Shuqi Wang
AU  - Jian Wang
AU  - Madison Hicks
AU  - Sushma Bharrhan
AU  - Matthew Woolard
AU  - Hongyan Guo
PY  - 2026
DA  - 2026/09/21
JO  - Nature communications
DO  - 10.1038/s41467-026-77881-7
UR  - https://europepmc.org/article/MED/42907439
AB  - 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.
SN  - 2041-1723
ER  -