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
  • 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: [email protected].
  • 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: [email protected].
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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