Hepatitis E virus (HEV) causes adverse clinical outcomes in pregnant women, including preterm delivery, miscarriage, stillbirth, fulminant hepatic failure (FHF), and mortality. The underlying mechanisms of these clinical manifestations remain poorly understood. Unfortunately, attempts to develop an animal model using pregnant rhesus macaques or pregnant sows that could reproduce the severe diseases observed in infected pregnant women were unsuccessful. However, pregnant rabbits have evolved as a potential model for HEV-induced adverse clinical outcomes observed in a high percentage of HEV-infected pregnant women.
A recent study led by Dr. Hassan Mahsoub and Prof. Xiang-Jin Meng from the Virginia Polytechnic Institute and State University, USA, utilized a genotype 3 HEV from rabbit (HEV-3ra) and its cognate host (rabbits) to delineate the mechanisms of pregnancy-associated adverse effects during HEV infection. They systematically investigated the clinical consequences, viral replication dynamics, and host immune and hormonal responses of HEV infection during pregnancy.
First, they found a significant fetal loss of 23% in HEV-infected pregnant rabbits, indicating an early-stage miscarriage. Next, they showed that HEV infection in pregnant rabbits was characterized by generally higher viral loads in feces, intestinal contents, liver, and spleen tissues, as well as a longer and earlier onset of viremia than that in infected nonpregnant rabbits. Furthermore, they demonstrated that HEV infection altered the gene expression levels of several cytokine genes in the liver of pregnant rabbits and caused a transient increase of serum IFN-γ shortly after a notable increase in viral replication, which might have contributed to early fetal loss. They further showed that histological lesions in the spleen were more pronounced in infected pregnant rabbits, although moderate liver lesions were seen in both infected pregnant and nonpregnant rabbits. Total bilirubin was elevated in infected pregnant rabbits. Moreover, they examined the role of the pregnancy hormone estradiol (E2) in HEV infection, and found that the serum levels of E2 in HEV-infected pregnant rabbits were significantly higher than those in mock-infected pregnant rabbits at 14 days postinoculation and correlated positively with higher viral loads in feces, liver, and spleen tissues at 28 dpi, suggesting that it may play a role in extrahepatic virus dissemination.
These findings have important implications for understanding the underlying mechanisms of severe diseases associated with HEV infection during pregnancy.
This study was published in mBio. 2023; e0041823. Read the full research article https://journals.asm.org/doi/10.1128/mbio.00418-23.
