Astrocytic RIPK3 confers protection against deleterious neuroinflammation during Zika virus infection

Abstract This study aims to identify the function(s) of RIPK3 signaling in astrocytes following Zika virus infection. Previous work found that RIPK3 signaling in Zika virus-infected neurons activates inflammatory transcription factors such as NFκB and IRF1, leading to the upregulation of inflammation-associated transcripts. We were thus interested in determining the role of RIPK3 signaling in astrocytes, which are critical regulators of neuroinflammation. Using mice with an astrocyte-specific conditional Ripk3 deletion, we found that intracranial Zika virus infection was significantly more lethal in mice deficient in astrocytic Ripk3 than in littermate controls. To identify mechanisms underlying this difference, we isolated and infected primary fore- and hind-brain astrocytes with Zika virus to determine the transcriptional consequences of genetic Ripk3 ablation. Surprisingly, we found increased expression of several chemokines, cytokines and ISGs in Ripk3−/− hindbrain astrocytes, in contrast to our previous findings in neurons. Subsequent leukocyte profiling from the brains of Zika virus-infected mice revealed increased numbers of CD4+ and CD8+ T cells, natural killer cells, and monocytes in mice deficient in astrocytic Ripk3 compared to those found in littermate controls. As previous work has demonstrated that astrocytic type I interferon signaling in the hindbrain is responsible for downregulating proinflammatory molecules to prevent lethal neuroinflammation, our data suggest that synergistic signaling between type I IFN and RIPK3 in hindbrain astrocytes suppresses deleterious neuroinflammation and promotes host survival in the setting of Zika virus encephalitis. Supported by a grant from NIH (R01 NS120895).