LAUSR

Summary 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. Graphical Abstract Figure. No Caption available. HighlightsComponents of the necroptotic cell death pathway limit neuronal Zika virus infectionViral control is due to cell‐intrinsic limitation of viral growth, not cell deathUpregulation of the metabolic enzyme IRG1 in neurons underlies viral restrictionItaconate, the product of IRG1, induces an antiviral metabolic state in neurons &NA; Daniels et al. find that molecules traditionally associated with necroptotic cell death engage a death‐independent transcriptional program in neurons during Zika virus infection. This transcriptional program includes the enzyme IRG1, whose product, itaconate, reprograms neuronal metabolism in a manner that restricts Zika virus replication.