Language

English

Publication Date

4-22-2025

Journal

Cell Reports

DOI

10.1016/j.celrep.2025.115464

PMID

40156834

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

Animals, Female, Zika Virus, Zika Virus Infection, Infectious Disease Transmission, Vertical, Pregnancy, Humans, Hepatitis A Virus Cellular Receptor 1, Mice, Placenta, Virus Internalization, Trophoblasts, Endocytosis, AP2S1, CP: Microbiology, GATA3, HAVCR1, IgV domain, ZIKV receptor, clathrin-mediated endocytosis, genome-wide CRISPR screens, placental trophoblast, susceptibility, vertical transmission

Published Open-Access

yes

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