Immature Brain Cortical Neurons Have Low Transcriptional Competence to Activate Antiviral Defences and Control RNA Virus Infections

Divya Narayanan; Nagaraj Moily; Hayley A McQuilten; Katherine Kedzierska; Jason M Mackenzie; Lukasz Kedzierski; John K Fazakerley

doi:10.1159/000525291

Immature Brain Cortical Neurons Have Low Transcriptional Competence to Activate Antiviral Defences and Control RNA Virus Infections

J Innate Immun. 2023;15(1):50-66. doi: 10.1159/000525291. Epub 2022 Jun 23.

Authors

Divya Narayanan¹, Nagaraj Moily², Hayley A McQuilten¹, Katherine Kedzierska¹, Jason M Mackenzie¹, Lukasz Kedzierski^{1

3}, John K Fazakerley^{1

3}

Affiliations

¹ Department of Microbiology and Immunology at the Peter Doherty Institute of Infection and Immunity, The University of Melbourne, Melbourne, Victoria, Australia.
² Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, Victoria, Australia.
³ Faculty of Veterinary and Agricultural Sciences at the Peter Doherty Institute of Infection and Immunity, The University of Melbourne, Melbourne, Victoria, Australia.

Abstract

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.

Keywords: Alphavirus; Innate immunity; Interferon; Neuron.

MeSH terms

Animals
Antiviral Agents
Brain
Humans
Immunity, Innate
Interferon Type I*
Mice
Neurons
RNA Virus Infections*
Virus Diseases*

Substances

Interferon Type I
Antiviral Agents

Grants and funding

The work was funded by a University of Melbourne grant to J.K.F. D.N. was a recipient of Melbourne International Fee Remission Scholarship and Melbourne International Research Scholarship. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.