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 (Kyn) production, which activates AHR, limiting the production of type I interferons (IFN-I) involved in antiviral immunity. Moreover, ZIKV-triggered AHR activation suppresses intrinsic immunity driven by the promyelocytic leukemia (PML) protein, which limits ZIKV replication. AHR inhibition suppressed the replication of multiple ZIKV strains in vitro and also suppressed replication 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 protein as a driver of anti-ZIKV intrinsic immunity.

寨卡病毒 (ZIKV) 是一种黄病毒，与多种出生缺陷有关，包括小头畸形，称为先天性 ZIKV 综合征。鉴定参与 ZIKV 复制的宿主因素可以指导有效的治疗干预。在全基因组转录研究中，我们发现 ZIKV 感染会触发芳烃受体 (AHR) 激活。具体来说，ZIKV 感染会诱导犬尿氨酸 (Kyn) 的产生，从而激活 AHR，从而限制参与抗病毒免疫的 I 型干扰素 (IFN-I) 的产生。此外，ZIKV 触发的 AHR 激活抑制了由早幼粒细胞白血病 (PML) 蛋白驱动的内在免疫，从而限制了 ZIKV 复制。AHR 抑制在体外抑制了多种 ZIKV 毒株的复制，也抑制了相关黄病毒登革热的复制。最后，使用纳米颗粒递送的 AHR 拮抗剂或为人类使用而开发的抑制剂的 AHR 抑制限制了 ZIKV 复制并改善了小鼠模型中的新生儿小头畸形。总之，我们将 AHR 确定为 ZIKV 复制的宿主因子，并将 PML 蛋白确定为抗 ZIKV 内在免疫的驱动因素。