美国麻省理工学院和哈佛大学Francisco J. Quintana、阿根廷CONICET-昆米卡生物技术研究所Cybele C. Garcia以及巴西圣保罗大学Jean Pierre Schatzmann Peron研究组合作取得新进展。他们揭示AHR是寨卡病毒（ZIKV）宿主因子，也是抗病毒治疗的候选靶标。2020年7月20日出版的《自然-神经科学》发表了这一成果。

在全基因组转录研究中，他们发现ZIKV感染会触发芳烃受体（AHR）激活。具体而言，ZIKV感染会诱导犬尿氨酸（Kyn）产生，激活AHR，从而限制了参与抗病毒免疫的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）蛋白驱动的固有免疫力，这限制了ZIKV复制。

AHR抑制抑制了体外多个ZIKV病毒株的复制，也抑制了相关黄病毒登革热的复制。最后，用纳米颗粒递送的AHR拮抗剂或开发用于人类的抑制剂，对AHR的抑制作用限制了ZIKV复制，并改善了小鼠模型中的新生儿小头畸形。总之，他们确定AHR是ZIKV复制的宿主因子，而PML蛋白则是抗ZIKV固有免疫的驱动器。

据悉，ZIKV是一种黄病毒，与包括先天性ZIKV综合征在内的多种小头畸形有关。ZIKV复制中涉及的宿主因子的识别可能指导有效的治疗干预措施。

附：英文原文

Title: AHR is a Zika virus host factor and a candidate target for antiviral therapy

Author: Federico Giovannoni, Irene Bosch, Carolina Manganeli Polonio, Mara F. Torti, Michael A. Wheeler, Zhaorong Li, Leonardo Romorini, Mara S. Rodriguez Varela, Veit Rothhammer, Andreia Barroso, Emily C. Tjon, Liliana M. Sanmarco, Maisa C. Takenaka, Seyed Mohamad Sadegh Modaresi, Cristina Gutirrez-Vzquez, Ngela Ghabdan Zanluqui, Nilton Barreto dos Santos, Carolina Demarchi Munhoz, Zhongyan Wang, Elsa B. Damonte, David Sherr, Lee Gehrke, Jean Pierre Schatzmann Peron, Cybele C. Garcia, Francisco J. Quintana

Issue&Volume: 2020-07-20

Abstract: 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. Giovannoni et al. report that the aryl hydrocarbon receptor (AHR) is a novel host factor exploited by Zika virus and dengue virus to evade the immune response. AHR is a candidate target for the treatment of Zika virus congenital syndrome and dengue fever.

DOI: 10.1038/s41593-020-0664-0

Source: https://www.nature.com/articles/s41593-020-0664-0