Brain immune cells undergo cGAS/STING-dependent apoptosis during herpes simplex virus type 1 infection to limit type I IFN production
Open accessAbstract
Protection of the brain from viral infections involves the type I IFN (IFN-I) system, defects in which render humans susceptible to herpes simplex encephalitis (HSE). However, excessive cerebral IFN-I levels lead to pathologies, suggesting the need for tight regulation of responses. Based on data from mouse models, human HSE cases, and primary cell culture systems, we showed that microglia and other immune cells undergo apoptosis in the HSV-1-infected brain through a mechanism dependent on the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway, but independent of IFN-I. HSV-1 infection of microglia induced cGAS-dependent apoptosis at high viral doses, whereas lower viral doses led to IFN-I responses. Importantly, inhibition of caspase activity prevented microglial cell death and augmented IFN-I responses. Accordingly, HSV-1-infected organotypic brain slices or mice treated with a caspase inhibitor exhibited lower viral load and an improved infection outcome. Collectively, we identify an activation-induced apoptosis program in brain immune cells that downmodulates local immune responses.
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Induction of apoptosis occurs in a cGAS-STING-dependent manner upon viral CNS infection.
“This is in line with previous reports showing the induction of apoptosis in a cGAS-STING-dependent manner upon viral CNS infection 67 .”
From AAV vectors trigger DNA damage response-dependent pro-inflammatory signalling in human iPSC-derived CNS models and mouse brain (2025) · cites this paper as [67]
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- Authors
- Reinert, L. S., Rashidi, A. S., Tran, D. N., Katzilieris-Petras, G., Hvidt, A. K., Gohr, M., Fruhwürth, S., Bodda, C., Thomsen, M. K., Vendelbo, M. H., Khan, A. R., Hansen, B., Bergström, P., Agholme, L., Mogensen, T. H., Christensen, M. H., Nyengaard, J. R., Sen, G. C., Zetterberg, H., Verjans, G. M., & Paludan, S. R.
- Affiliations
- Aarhus University (DK)
- Erasmus MC (NL)
- University of Gothenburg (SE)
- University of Bonn (DE)
- Cleveland Clinic (US)
- UK Dementia Research Institute (GB)
- ORCID
- Reinert, Line S.
- Rashidi, Ahmad S.
- Hvidt, Astrid K.
- Fruhwürth, Stefanie
- Bodda, Chiranjeevi
- Thomsen, Martin K.
- Vendelbo, Mikkel H.
- Khan, Ahmad R.
- Hansen, Brian
- Bergström, Petra
- Agholme, Lotta
- Mogensen, Trine H.
- Christensen, Maria H.
- Nyengaard, Jens R.
- Sen, Ganes C.
- Zetterberg, Henrik
- Verjans, Georges MGM
- Paludan, Søren R.
- Venue
- Journal of Clinical Investigation
- Published
- 2021-01-04
- Volume
- 131
- Issue
- 1
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC7773356
- OpenAlex
- W3091305781
- Cited by
- 118
- References
- 65
- Citations by year
- 2026: 17 · 2025: 20 · 2024: 24 · 2023: 21 · 2022: 22 · 2021: 14
- FWCI
- 4.99
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (acceptedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Funders
- European Research Council (ERC-AdG ENVISION, 786602)
- The Novo Nordisk Foundation (NNF18OC0030274)
- Lundbeck Foundation (R198-2015-171, R268-2016-3927)
- Swedish Research Council (2018-02463)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Health Sciences › Medicine › Epidemiology › Herpesvirus Infections and Treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- herpes simplex virus type 1, herpes simplex encephalitis, cGAS-STING pathway, microglia, apoptosis, type I interferon, caspase inhibition, brain immune response, viral load, innate immunity regulation
- MeSH terms
- STING Protein, Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase, Animals, Brain, Herpes Simplex, Humans, Interferon Type I, Male, Membrane Proteins, Nucleotidyltransferases, Apoptosis, Microglia, Herpesvirus 1, Human, Mice, Knockout, Mice
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