Cytosolic DNA sensors activation of human astrocytes inhibits herpes simplex virus through IRF1 induction

Front Cell Infect Microbiol. 2024 May 14:14:1383811. doi: 10.3389/fcimb.2024.1383811. eCollection 2024.

Abstract

Introduction: While astrocytes participate in the CNS innate immunity against herpes simplex virus type 1 (HSV-1) infection, they are the major target for the virus. Therefore, it is of importance to understand the interplay between the astrocyte-mediated immunity and HSV-1 infection.

Methods: Both primary human astrocytes and the astrocyte line (U373) were used in this study. RT-qPCR and Western blot assay were used to measure IFNs, the antiviral IFN-stimulated genes (ISGs), IFN regulatory factors (IRFs) and HSV-1 DNA. IRF1 knockout or knockdown was performed with CRISPR/Cas9 and siRNA transfection techniques.

Results: Poly(dA:dT) could inhibit HSV-1 replication and induce IFN-β/IFN-λs production in human astrocytes. Poly(dA:dT) treatment of astrocytes also induced the expression of the antiviral ISGs (Viperin, ISG56 and MxA). Among IRFs members examined, poly(dA:dT) selectively unregulated IRF1 and IRF9, particularly IRF1 in human astrocytes. The inductive effects of poly(dA:dT) on IFNs and ISGs were diminished in the IRF1 knockout cells. In addition, IRF1 knockout attenuated poly(dA:dT)-mediated HSV-1 inhibition in the cells.

Conclusion: The DNA sensors activation induces astrocyte intracellular innate immunity against HSV-1. Therefore, targeting the DNA sensors has potential for immune activation-based HSV-1 therapy.

Keywords: IFN-stimulated genes (ISGs); astrocytes; dsDNA; interferon regulator factor 1 (IRF1); interferons (IFNs).

MeSH terms

  • Astrocytes* / metabolism
  • Astrocytes* / virology
  • Cell Line
  • Cells, Cultured
  • Cytosol / metabolism
  • DNA, Viral / genetics
  • Gene Knockout Techniques
  • Herpes Simplex / immunology
  • Herpes Simplex / virology
  • Herpesvirus 1, Human* / genetics
  • Herpesvirus 1, Human* / immunology
  • Herpesvirus 1, Human* / physiology
  • Humans
  • Immunity, Innate
  • Interferon Regulatory Factor-1* / genetics
  • Interferon Regulatory Factor-1* / metabolism
  • Poly dA-dT
  • Virus Replication*

Substances

  • Interferon Regulatory Factor-1
  • IRF1 protein, human
  • Poly dA-dT
  • DNA, Viral

Grants and funding

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.