AHR is a Zika virus host factor and a candidate target for antiviral therapy.
AHR is a Zika virus host factor and a candidate target for antiviral therapy.
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DOI：
10.1038/s41593-020-0664-0
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发表时间：
2020-08
影响因子：
25
通讯作者：
Quintana FJ
中科院分区：
文献类型：
--
作者：
Giovannoni F;Bosch I;Polonio CM;Torti MF;Wheeler MA;Li Z;Romorini L;Rodriguez Varela MS;Rothhammer V;Barroso A;Tjon EC;Sanmarco LM;Takenaka MC;Modaresi SMS;Gutiérrez-Vázquez C;Zanluqui NG;Dos Santos NB;Munhoz CD;Wang Z;Damonte EB;Sherr D;Gehrke L;Peron JPS;Garcia CC;Quintana FJ
寨卡病毒是一种黄病毒，与包括小头畸形在内的多种出生缺陷有关，被称为先天性寨卡病毒综合征。识别参与ZIKV复制的宿主因子可能指导有效的治疗干预。在全基因组转录研究中，我们发现寨卡病毒感染触发芳烃受体（AHR）激活。具体来说，寨卡病毒感染诱导犬尿氨酸产生，从而激活AHR，限制参与抗病毒免疫的I型干扰素的产生。此外，寨卡病毒引发的AHR激活抑制了由早幼粒细胞白血病蛋白（PML）驱动的内在免疫，从而限制了寨卡病毒的复制。AHR的抑制作用抑制了多种寨卡病毒的体外复制，也抑制了相关的登革热黄病毒。最后，在小鼠模型中，纳米颗粒递送的AHR拮抗剂或为人类开发的AHR抑制剂抑制了ZIKV的复制并改善了新生儿小头畸形。总之，我们确定AHR是ZIKV复制的宿主因子，而PML是抗ZIKV内在免疫的驱动因子。
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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影响因子：
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作者：
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通讯作者：
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