Sensing of HSV-1 by the cGAS-STING pathway in microglia orchestrates antiviral defence in the CNS

Nat Commun. 2016 Nov 10;7:13348. doi: 10.1038/ncomms13348.

Abstract

Herpes simplex encephalitis (HSE) is the most common form of acute viral encephalitis in industrialized countries. Type I interferon (IFN) is important for control of herpes simplex virus (HSV-1) in the central nervous system (CNS). Here we show that microglia are the main source of HSV-induced type I IFN expression in CNS cells and these cytokines are induced in a cGAS-STING-dependent manner. Consistently, mice defective in cGAS or STING are highly susceptible to acute HSE. Although STING is redundant for cell-autonomous antiviral resistance in astrocytes and neurons, viral replication is strongly increased in neurons in STING-deficient mice. Interestingly, HSV-infected microglia confer STING-dependent antiviral activities in neurons and prime type I IFN production in astrocytes through the TLR3 pathway. Thus, sensing of HSV-1 infection in the CNS by microglia through the cGAS-STING pathway orchestrates an antiviral program that includes type I IFNs and immune-priming of other cell types.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / therapeutic use
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Astrocytes / virology
  • Cells, Cultured
  • Encephalitis, Herpes Simplex / drug therapy
  • Encephalitis, Herpes Simplex / genetics
  • Encephalitis, Herpes Simplex / virology*
  • Herpesvirus 1, Human / drug effects
  • Herpesvirus 1, Human / physiology*
  • Host-Pathogen Interactions / drug effects
  • Humans
  • Interferon Type I / metabolism
  • Membrane Proteins / deficiency*
  • Membrane Proteins / genetics
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microglia / drug effects
  • Microglia / metabolism
  • Microglia / virology*
  • Nucleotidyltransferases / deficiency*
  • Nucleotidyltransferases / genetics
  • Signal Transduction / drug effects
  • Signal Transduction / genetics

Substances

  • Antiviral Agents
  • Interferon Type I
  • Membrane Proteins
  • Sting1 protein, mouse
  • Nucleotidyltransferases
  • cGAS protein, mouse