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

• Published in: Cell reports (Cambridge) Vol. 44; no. 4; p. 115464
• Main Authors: Yu, Wenzhe, Tao, Jun, Cao, Hongmin, Zheng, Wanshan, Zhang, Beiang, Zhang, Yue, Xu, Peiqun, Zhang, Yiwei, Liu, Xuan, Wang, Yinan, Cai, Han, Liu, Gang, Liu, Fan, Wang, Haibin, Zhao, Haiyan, Mysorekar, Indira U., Hu, Xiaoqian, Cao, Bin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.04.2025; Elsevier
• Subjects: Animals; AP2S1; clathrin-mediated endocytosis; CP: Microbiology; Endocytosis; Female; GATA3; genome-wide CRISPR screens; HAVCR1; Hepatitis A Virus Cellular Receptor 1 - genetics; Hepatitis A Virus Cellular Receptor 1 - metabolism; Humans; IgV domain; Infectious Disease Transmission, Vertical; Mice; Placenta - metabolism; Placenta - virology; placental trophoblast; Pregnancy; susceptibility; Trophoblasts - metabolism; Trophoblasts - virology; vertical transmission; Virus Internalization; Zika Virus - pathogenicity; Zika Virus - physiology; Zika Virus Infection - metabolism; Zika Virus Infection - transmission; Zika Virus Infection - virology; ZIKV receptor; ZIKV receptor; susceptibility; placental trophoblast; IgV domain; genome-wide CRISPR screens; CP: Microbiology; vertical transmission; AP2S1; GATA3; HAVCR1; clathrin-mediated endocytosis
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2025.115464

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. [Display omitted] •CRISPR knockout library screens placental-specific factors driving ZIKV infection•The GATA3-HAVCR1 axis dictates trophoblast lineage-specific ZIKV susceptibility•The ZIKV-E-HAVCR1-AP2S1 network regulates ZIKV entry in trophoblasts•ZIKV exploits murine Havcr1 to traverse the maternal-fetal interface Yu et al. identify host factors governing placental ZIKV infection using an unbiased CRISPR gene-knockout screen. They unravel that GATA3-hepatitis A virus cellular receptor 1 (HAVCR1)-adaptor protein 2 small σ2 (AP2S1) serves as a placenta-intrinsic regulatory axis indispensable for ZIKV entry and maternal-fetal transmission during pregnancy.