Antiviral resistance and barrier integrity at the maternal- fetal interface restrict hepatitis E virus from crossing the placental barrier

• 成果类型: Article
• 署名作者: Tian, Debin; Li, Wen; Heffron, C. Lynn; Mahsoub, Hassan M.; Wang, Bo; LeRoith, Tanya; Meng, Xiang-Jin
• 署名单位: Virginia Polytechnic Institute & State University; Virginia Polytechnic Institute & State University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12233
• DOI: 10.1073/pnas.2501128122
• 发表日期: 2025-05-06
• 关键词: vertical transmission; viral-hepatitis; pregnant-women; zika virus; infection; exosomes; brain; hev; delivery; FAILURE

摘要

Hepatitis E virus (HEV) genotype 1 (HEV-1) infection in pregnant women is associated with adverse outcomes of pregnancy including fulminant hepatic failure, fetal loss, premature birth, and neonatal mortality, although the underlying mechanisms remain largely unclear. In this study, we first demonstrated that HEV-1 robustly infects pregnant gerbils and causes pregnancy-associated adverse outcomes, which were recorded in 4/6 HEV-1-infected but only 1/5 in PBS-inoculated pregnant gerbils. However, vertical transmission of HEV-1 from mothers to newborns is not evident, as HEV-1 RNA was not detected in uterus tissues or in newborn pups. To further determine whether HEV-1 can cross the placental barrier, we established an in vitro blood-placental barrier by coculturing human placental trophoblast cells (BeWo) and umbilical vein endothelial cells (HUVEC) in Transwell inserts. By using the placental barrier under the conditions in this study, we showed that quasi-enveloped or nonenveloped HEV-1, HEV-3, or HEV-4 virions do not readily cross the barrier prior to 4 d postinoculation when it has high barrier integrity. Importantly, we demonstrated that the placental barrier induces local antiviral resistance at the maternal-fetal interface, that interactions between maternal-and fetal-derived cocultured cells are important for induction of antiviral resistance, and that anti-HEV resistance can be transferred to nonplacental HepG2 liver cells. We also revealed that the main effectors of antiviral resistance at the placental barrier are type III interferons (IFN-lambda 1, lambda 2/3) and the chemokine CXCL10. The findings have important implications in understanding the mechanisms leading to HEV-1-associated maternal and fetal adverse outcomes in pregnant women.