Upon Intranasal Vesicular Stomatitis Virus Infection, Astrocytes in the Olfactory Bulb Are Important Interferon Beta Producers That Protect from Lethal Encephalitis
Open accessAbstract
Previously we found that following intranasal (i.n.) infection with neurotropic vesicular stomatitis virus (VSV) type I interferon receptor (IFNAR) triggering of neuroectodermal cells was critically required to constrain intracerebral virus spread. To address whether locally active IFN-β was induced proximally, we studied spatiotemporal conditions of VSV-mediated IFN-β induction. To this end, we performed infection studies with IFN-β reporter mice. One day after intravenous (i.v.) VSV infection, luciferase induction was detected in lymph nodes. Upon i.n. infection, luciferase induction was discovered at similar sites with delayed kinetics, whereas on days 3 and 4 postinfection enhanced luciferase expression additionally was detected in the foreheads of reporter mice. A detailed analysis of cell type-specific IFN-β reporter mice revealed that within the olfactory bulb IFN-β was expressed by neuroectodermal cells, primarily by astrocytes and to a lesser extent by neurons. Importantly, locally induced type I IFN triggered distal parts of the brain as indicated by the analysis of ISRE-eGFP mice which after i.n. VSV infection showed enhanced green fluorescent protein (eGFP) expression throughout the brain. Compared to wild-type mice, IFN-β−/−mice showed increased mortality to i.n. VSV infection, whereas upon i.v. infection no such differences were detected highlighting the biological significance of intracerebrally expressed IFN-β. In conclusion, upon i.n. VSV instillation, IFN-β responses mounted by astrocytes within the olfactory bulb critically contribute to the antiviral defense by stimulating distal IFN-β-negative brain areas and thus arresting virus spread. IMPORTANCE The central nervous system has long been considered an immune privileged site. More recently, it became evident that specialized immune mechanisms are active within the brain to control pathogens. Previously, we showed that virus, which entered the brain via the olfactory route, was arrested within the olfactory bulb by a type I IFN-dependent mechanism. Since peripheral type I IFN would not readily cross the blood-brain barrier and within the brain thus far no abundant type I IFN responses have been detected, here we addressed from where locally active IFN originated from. We found that upon intranasal VSV instillation, primarily astrocytes, and to a lesser extent neurons, were stimulated within the olfactory bulb to mount IFN-β responses that also activated and protected distal brain areas. Our results are surprising because in other infection models astrocytes have not yet been identified as major type I IFN producers.
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The cytokine storm theory proposes that the SARS-CoV-2 inflammatory response in the CNS is mediated by massive glial cell cytokine release, such as IL1b, IL-6, and IFN I-III.
“Finally, the cytokine storm theory proposes that SARS-CoV-2 inflammatory response in the CNS is mediated by the massive glial cell cytokine release, such as IL1b, IL-6, and IFN I-III [168, 169].”
From Cognitive decline following acute viral infections: literature review and projections for post-COVID-19 (2022) · cites this paper as [168]
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Infectious immunity in the central nervous system and brain function
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- Authors
- Detje, C. N., Lienenklaus, S., Chhatbar, C., Spanier, J., Prajeeth, C. K., Soldner, C., Tovey, M. G., Schlüter, D., Weiss, S., Stangel, M., & Kalinke, U.
- Affiliations
- Medizinische Hochschule Hannover (DE)
- Helmholtz Centre for Infection Research (DE)
- Laboratory of Biotechnology Applied Pharmacology, École Normale Supérieure de Cachan, Cachan Cedex, France
- ORCID
- Venue
- Journal of Virology
- Publisher
- American Society for Microbiology
- Published
- 2015-03
- Volume
- 89
- Issue
- 5
- Pages
- 2731-2738
- ISSN
- 0022-538X (ISSN-L)
- 1098-5514
- PMC
- PMC4325722
- OpenAlex
- W2009904875
- Cited by
- 76
- References
- 34
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 4 · 2023: 5 · 2022: 8 · 2021: 13 · 2020: 6 · 2019: 8 · 2018: 5 · 2017: 9 · 2016: 7 · 2015: 3
- FWCI
- 2.89
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Virology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HZI (Helmholtz Centre for Infection Research) (submittedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Health Sciences › Medicine › Epidemiology › Virology and Viral Diseases
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Viral Infections and Immunology Research
- Keywords
- intranasal infection, interferon-beta, astrocytes, olfactory bulb, type I interferon, neuroectodermal cells, encephalitis, antiviral defense, IFNAR, neuroinflammation
- MeSH terms
- Animals, Astrocytes, Disease Models, Animal, Luciferases, Mice, Inbred C57BL, Neurons, Olfactory Bulb, Survival Analysis, Interferon-beta, Genes, Reporter, Vesiculovirus, Mice, Knockout, Rhabdoviridae Infections, Encephalitis, Viral, Gene Expression Profiling, Green Fluorescent Proteins
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