Immature Brain Cortical Neurons Have Low Transcriptional Competence to Activate Antiviral Defences and Control RNA Virus Infections
Virus infections of the central nervous system (CNS) cause important diseases of humans and animals. As in other tissues, innate antiviral responses mediated by type I interferons (IFNs) are crucially important in controlling CNS virus infections. The maturity of neuronal populations is an establish...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Karger Publishers
2022-06-01
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| Series: | Journal of Innate Immunity |
| Subjects: | |
| Online Access: | https://www.karger.com/Article/FullText/525291 |
| _version_ | 1818048291062939648 |
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| author | Divya Narayanan Nagaraj Moily Hayley A. McQuilten Katherine Kedzierska Jason M. Mackenzie Lukasz Kedzierski John K. Fazakerley |
| author_facet | Divya Narayanan Nagaraj Moily Hayley A. McQuilten Katherine Kedzierska Jason M. Mackenzie Lukasz Kedzierski John K. Fazakerley |
| author_sort | Divya Narayanan |
| collection | DOAJ |
| description | Virus infections of the central nervous system (CNS) cause important diseases of humans and animals. As in other tissues, innate antiviral responses mediated by type I interferons (IFNs) are crucially important in controlling CNS virus infections. The maturity of neuronal populations is an established critical factor determining the outcome of CNS virus infection. Using primary cultures of mouse cortical neurons, we investigated the relationships between neuronal maturation, type I IFN responses, and the outcome of Semliki Forest virus infection. The virus replicated better, infected more cells, and produced higher titres of infectious viruses in immature neurons. Complete transcriptome analysis demonstrated that resting immature neurons have low transcriptional competence to mount antiviral responses. They had no detectable transcription of the genes Ddx58 and Ifih1, which encode key RNA virus cytoplasmic sensors RIG-I and MDA5, and very low expression of genes encoding key regulators of associated signalling pathways. Upon infection, immature neurons failed to mount an antiviral response as evidenced by their failure to produce chemokines, IFNs, and other cytokines. Treatment of immature neurons with exogenous IFNβ prior to infection resulted in antiviral responses and lower levels of virus replication and infectious virus production. In contrast, resting mature neurons generated a robust antiviral response. This was augmented by pretreatment with IFNβ. Infection of mature neurons derived from IFNAR−/− mice did not make an antiviral response and replicated virus to high levels. |
| first_indexed | 2024-12-10T10:19:21Z |
| format | Article |
| id | doaj.art-88530e0ee6aa4b0a914760a20cedba24 |
| institution | Directory Open Access Journal |
| issn | 1662-811X 1662-8128 |
| language | English |
| last_indexed | 2024-12-10T10:19:21Z |
| publishDate | 2022-06-01 |
| publisher | Karger Publishers |
| record_format | Article |
| series | Journal of Innate Immunity |
| spelling | doaj.art-88530e0ee6aa4b0a914760a20cedba242022-12-22T01:52:55ZengKarger PublishersJournal of Innate Immunity1662-811X1662-81282022-06-0111710.1159/000525291525291Immature Brain Cortical Neurons Have Low Transcriptional Competence to Activate Antiviral Defences and Control RNA Virus InfectionsDivya Narayanan0https://orcid.org/0000-0001-9916-0685Nagaraj Moily1Hayley A. McQuilten2https://orcid.org/0000-0002-7089-5300Katherine Kedzierska3Jason M. Mackenzie4https://orcid.org/0000-0001-6613-8350Lukasz Kedzierski5https://orcid.org/0000-0003-0203-1057John K. Fazakerley6https://orcid.org/0000-0001-7071-105XDepartment of Microbiology and Immunology at the Peter Doherty Institute of Infection and Immunity, The University of Melbourne, Melbourne, VIC, AustraliaDepartment of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC, AustraliaDepartment of Microbiology and Immunology at the Peter Doherty Institute of Infection and Immunity, The University of Melbourne, Melbourne, VIC, AustraliaDepartment of Microbiology and Immunology at the Peter Doherty Institute of Infection and Immunity, The University of Melbourne, Melbourne, VIC, AustraliaDepartment of Microbiology and Immunology at the Peter Doherty Institute of Infection and Immunity, The University of Melbourne, Melbourne, VIC, AustraliaDepartment of Microbiology and Immunology at the Peter Doherty Institute of Infection and Immunity, The University of Melbourne, Melbourne, VIC, AustraliaDepartment of Microbiology and Immunology at the Peter Doherty Institute of Infection and Immunity, The University of Melbourne, Melbourne, VIC, AustraliaVirus infections of the central nervous system (CNS) cause important diseases of humans and animals. As in other tissues, innate antiviral responses mediated by type I interferons (IFNs) are crucially important in controlling CNS virus infections. The maturity of neuronal populations is an established critical factor determining the outcome of CNS virus infection. Using primary cultures of mouse cortical neurons, we investigated the relationships between neuronal maturation, type I IFN responses, and the outcome of Semliki Forest virus infection. The virus replicated better, infected more cells, and produced higher titres of infectious viruses in immature neurons. Complete transcriptome analysis demonstrated that resting immature neurons have low transcriptional competence to mount antiviral responses. They had no detectable transcription of the genes Ddx58 and Ifih1, which encode key RNA virus cytoplasmic sensors RIG-I and MDA5, and very low expression of genes encoding key regulators of associated signalling pathways. Upon infection, immature neurons failed to mount an antiviral response as evidenced by their failure to produce chemokines, IFNs, and other cytokines. Treatment of immature neurons with exogenous IFNβ prior to infection resulted in antiviral responses and lower levels of virus replication and infectious virus production. In contrast, resting mature neurons generated a robust antiviral response. This was augmented by pretreatment with IFNβ. Infection of mature neurons derived from IFNAR−/− mice did not make an antiviral response and replicated virus to high levels.https://www.karger.com/Article/FullText/525291alphavirusinterferonneuroninnate immunity |
| spellingShingle | Divya Narayanan Nagaraj Moily Hayley A. McQuilten Katherine Kedzierska Jason M. Mackenzie Lukasz Kedzierski John K. Fazakerley Immature Brain Cortical Neurons Have Low Transcriptional Competence to Activate Antiviral Defences and Control RNA Virus Infections Journal of Innate Immunity alphavirus interferon neuron innate immunity |
| title | Immature Brain Cortical Neurons Have Low Transcriptional Competence to Activate Antiviral Defences and Control RNA Virus Infections |
| title_full | Immature Brain Cortical Neurons Have Low Transcriptional Competence to Activate Antiviral Defences and Control RNA Virus Infections |
| title_fullStr | Immature Brain Cortical Neurons Have Low Transcriptional Competence to Activate Antiviral Defences and Control RNA Virus Infections |
| title_full_unstemmed | Immature Brain Cortical Neurons Have Low Transcriptional Competence to Activate Antiviral Defences and Control RNA Virus Infections |
| title_short | Immature Brain Cortical Neurons Have Low Transcriptional Competence to Activate Antiviral Defences and Control RNA Virus Infections |
| title_sort | immature brain cortical neurons have low transcriptional competence to activate antiviral defences and control rna virus infections |
| topic | alphavirus interferon neuron innate immunity |
| url | https://www.karger.com/Article/FullText/525291 |
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