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

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

  • Cell Rep. 2025 Apr 22;44(4):115464. doi: 10.1016/j.celrep.2025.115464.
Wenzhe Yu 1,  Jun Tao 1,  Hongmin Cao 1,  Wanshan Zheng 1,  Beiang Zhang 1,  Yue Zhang 1,  Peiqun Xu 2,  Yiwei Zhang 3,  Xuan Liu 4,  Yinan Wang 1,  Han Cai 1,  Gang Liu 4,  Fan Liu 1,  Haibin Wang 1,  Haiyan Zhao 3,  Indira U Mysorekar 5,  Xiaoqian Hu 6,  Bin Cao 7
Affiliations

Affiliations

  • 1 Fujian Provincial Key Laboratory of Reproductive Health Research, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, Fujian, China.
  • 2 Department of Obstetrics and Gynecology, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen 361102, Fujian, China.
  • 3 State Key Laboratory of Virology and Biosafety, College of Life Sciences, Wuhan University, Wuhan 430072, Hubei, China.
  • 4 State Key Laboratory of Vaccine for Infectious Disease, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, Fujian, China.
  • 5 Department of Medicine, Section of Infectious Diseases, Baylor College of Medicine, Houston, TX 77030, USA.
  • 6 State Key Laboratory of Vaccine for Infectious Disease, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, Fujian, China. Electronic address: xqhu@xmu.edu.cn.
  • 7 Fujian Provincial Key Laboratory of Reproductive Health Research, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, Fujian, China; Department of Obstetrics and Gynecology, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen 361102, Fujian, China. Electronic address: caobin19@xmu.edu.cn.
PMID: 40156834 DOI: 10.1016/j.celrep.2025.115464
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.

Keywords

AP2S1; CP: Microbiology; GATA3; HAVCR1; IgV domain; ZIKV receptor; clathrin-mediated endocytosis; genome-wide CRISPR screens; placental trophoblast; susceptibility; vertical transmission.

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