The Nucleotide Sensor ZBP1 and Kinase RIPK3 Induce the Enzyme IRG1 to Promote an Antiviral Metabolic State in Neurons

Immunity. 2019 Jan 15;50(1):64-76.e4. doi: 10.1016/j.immuni.2018.11.017. Epub 2019 Jan 8.


As long-lived post-mitotic cells, neurons employ unique strategies to resist pathogen infection while preserving cellular function. Here, using a murine model of Zika virus (ZIKV) infection, we identified an innate immune pathway that restricts ZIKV replication in neurons and is required for survival upon ZIKV infection of the central nervous system (CNS). We found that neuronal ZIKV infection activated the nucleotide sensor ZBP1 and the kinases RIPK1 and RIPK3, core components of virus-induced necroptotic cell death signaling. However, activation of this pathway in ZIKV-infected neurons did not induce cell death. Rather, RIPK signaling restricted viral replication by altering cellular metabolism via upregulation of the enzyme IRG1 and production of the metabolite itaconate. Itaconate inhibited the activity of succinate dehydrogenase, generating a metabolic state in neurons that suppresses replication of viral genomes. These findings demonstrate an immunometabolic mechanism of viral restriction during neuroinvasive infection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Death
  • Cells, Cultured
  • Disease Models, Animal
  • Glycoproteins / genetics
  • Glycoproteins / metabolism*
  • Humans
  • Hydro-Lyases / genetics
  • Hydro-Lyases / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurons / physiology*
  • Neuroprotection
  • RNA, Viral / immunology
  • RNA-Binding Proteins
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
  • Receptors, Pattern Recognition / metabolism*
  • Succinate Dehydrogenase / metabolism
  • Succinates / metabolism
  • Virus Replication
  • Zika Virus / physiology*
  • Zika Virus Infection / immunology*


  • Glycoproteins
  • RNA, Viral
  • RNA-Binding Proteins
  • Receptors, Pattern Recognition
  • Succinates
  • Zbp1 protein, mouse
  • Succinate Dehydrogenase
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk3 protein, mouse
  • Hydro-Lyases
  • Irg1 protein, mouse
  • itaconic acid