The HAVCR1-centric host factor network drives Zika virus vertical transmission.

IF 6.9 1区生物学 Q1 CELL BIOLOGY Cell reports Pub Date : 2025-04-22 Epub Date: 2025-03-28 DOI:10.1016/j.celrep.2025.115464

Wenzhe Yu, Jun Tao, Hongmin Cao, Wanshan Zheng, Beiang Zhang, Yue Zhang, Peiqun Xu, Yiwei Zhang, Xuan Liu, Yinan Wang, Han Cai, Gang Liu, Fan Liu, Haibin Wang, Haiyan Zhao, Indira U Mysorekar, Xiaoqian Hu, Bin Cao

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Abstract

Zika virus (ZIKV) vertical transmission results in devastating congenital malformations and pregnancy complications; however, the specific receptor and host factors facilitating ZIKV maternal-fetal transmission remain elusive. Here, we employ a genome-wide CRISPR screening and identify multiple placenta-intrinsic factors modulating ZIKV infection. Our study unveils that hepatitis A virus cellular receptor 1 (HAVCR1) serves as a primary receptor governing ZIKV entry in placental trophoblasts. The GATA3-HAVCR1 axis regulates heterogeneous cell tropism in the placenta. Notably, placenta-specific Havcr1 deletion in mice significantly impairs ZIKV transplacental transmission and associated adverse pregnancy outcomes. Mechanistically, the immunoglobulin variable-like domain of HAVCR1 binds to ZIKV via domain III of envelope protein and virion-associated phosphatidylserine. Proteomic profiling and function analyses reveal that AP2S1 cooperates with HAVCR1 for ZIKV internalization through clathrin-mediated endocytosis. Overall, our work underscores the pivotal role of HAVCR1 in mediating ZIKV vertical transmission and highlights a therapeutic target for alleviating congenital Zika syndrome.

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以havcr1为中心的宿主因子网络驱动寨卡病毒垂直传播。

寨卡病毒（ZIKV）垂直传播导致毁灭性的先天性畸形和妊娠并发症；然而，促进寨卡病毒母胎传播的特定受体和宿主因子仍然难以捉摸。在这里，我们采用全基因组CRISPR筛选并鉴定了调节寨卡病毒感染的多个胎盘内在因子。我们的研究揭示了甲型肝炎病毒细胞受体1 （HAVCR1）是控制ZIKV进入胎盘滋养细胞的主要受体。在胎盘中，GATA3-HAVCR1轴调控异质细胞的趋向性。值得注意的是，小鼠胎盘特异性Havcr1缺失显著损害了寨卡病毒经胎盘传播和相关的不良妊娠结局。从机制上讲，HAVCR1的免疫球蛋白样结构域通过包膜蛋白和病毒粒子相关磷脂酰丝氨酸的结构域III与ZIKV结合。蛋白质组学分析和功能分析表明，AP2S1通过网格蛋白介导的内吞作用与HAVCR1合作，使寨卡病毒内化。总之，我们的工作强调了HAVCR1在介导寨卡病毒垂直传播中的关键作用，并强调了缓解先天性寨卡综合征的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.