Hepatitis E virus 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. However, the underlying mechanisms remain unclear because of the lack of a HEV-1-specific pregnancy animal model or a suitable in vitro model to mimic HEV infection at the maternal-fetal interface. In clinical case reports of human hepatitis E, HEV RNA was detected in newborns or placental tissues suggesting that the virus may cross the placental barrier, but in experimental animal HEV transmission studies, HEV-1 cannot be transmitted from pregnant monkeys to offsprings and an avian strain of HEV could not complete the vertical transmission cycle in chickens either. Therefore, whether HEV can be vertically transmitted from infected pregnant women to their newborns by crossing the placental barrier as a mechanism of pregnancy-associated adverse outcomes remains a debatable topic.
A recent study led by Dr. Debin Tian in the laboratory of Prof. X.J. Meng, and in collaboration with neurobiologist Dr. Wen Li, from the Virginia Polytechnic Institute and State University, USA, demonstrated that antiviral resistance and barrier integrity at maternal-fetal interface restrict HEV from crossing the placental barrier. They showed that HEV-1 robustly infects pregnant gerbils and causes pregnancy-associated adverse outcomes. However, they could not demonstrate vertical transmission of HEV-1 from mother gerbils to newborns, as there is no detectable HEV-1 RNA in uterus tissues or in newborn pups. Subsequently, they established an in vitro blood-placental barrier by co-culturing human placental trophoblast cells (BeWo) and umbilical vein endothelial cells (HUVEC) in Transwell inserts. By using this in vitro placental barrier co-culture system, they showed that quasi-enveloped or non-enveloped HEV-1, HEV-3 or HEV-4 virions do not readily cross the placental barrier prior to 4 days post-inoculation when the placental barrier has high barrier integrity. They also revealed that the in vitro placental barrier induces anti-HEV effectors of type Ⅲ interferons (IFN-λ1, λ2/3) and the chemokine CXCL10 to restrict HEV replication. Importantly, they showed that the anti-HEV resistance from the placental barrier can be transferred to nonplacental HepG2 liver cells. Their findings help understand the mechanisms of HEV-1-associated adverse outcomes during pregnancy.
This study was published in Proc. Natl. Acad. Sci. USA; 2025 May 6;122(18):e2501128122: www.pnas.org/doi/10.1073/pnas.2501128122.
