Graphical Abstract Highlights d A multidisciplinary approach to study effects of environmental factors on astrocytes d Linuron boosts IRE1a-XBP1 signaling in astrocytes via Sigmar1 d Astrocytic IRE1a-XBP1 signaling promotes CNS inflammation in EAE d IRE1a-XBP1 signaling is activated in astrocytes in multiple sclerosis
Zika virus (ZIKV) is a flavivirus linked to multiple birth defects including microcephaly, known as congenital ZIKV syndrome. The identification of host factors involved in ZIKV replication may guide efficacious therapeutic interventions. In genome-wide transcriptional studies, we found that ZIKV infection triggers aryl hydrocarbon receptor (AHR) activation. Specifically, ZIKV infection induces kynurenine production, which activates AHR limiting the production of type I interferons involved in anti-viral immunity. Moreover, ZIKV-triggered AHR activation suppresses intrinsic immunity driven by the promyelocytic leukemia protein (PML), which limits ZIKV replication. AHR inhibition suppressed the replication of multiple ZIKV strains in vitro, and also of the related flavivirus dengue. Finally, AHR inhibition with a nanoparticle-delivered AHR antagonist or an inhibitor developed for human use limited ZIKV replication and ameliorated newborn microcephaly in a murine model. In summary, we identified AHR as a host factor for ZIKV replication, and PML as a driver of anti-ZIKV intrinsic immunity.
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