Increased oestradiol in hepatitis E virus‐infected pregnant women promotes viral replication

Abstract

Hepatitis E virus (HEV) infection causes subclinical diseases, leading to high mortality (>25%) in pregnant women. HEV replication is aggressively escalated in pregnant women, especially in the third trimester of pregnancy. Oestrogen plays an important role in pregnancy. However, the pathogenesis of HEV in pregnant women or immunosuppressive pregnant women (such as HIV-infected or organ-transplanted pregnant women) remains unclear. We investigated the role of oestradiol in HEV infection in a cell culture system. HEV-infected pregnant women had significantly higher oestradiol levels compared with uninfected individuals. HEV infection was significantly increased in cells treated with analogues of oestradiol, diethylstilbestrol (DES) or 17β-oestradiol in a dose-dependent way. However, tamoxifen, an antagonist oestrogen, inhibited HEV replication. HEV infection inhibits oestrogen receptor (ER-α) expression. Immunofluorescence and co-immunoprecipitation assays indicated that ER-α interacted with the helicase of HEV ORF1 indirectly. More importantly, HEV infection was exacerbated in immunosuppressive cells treated with an inhibitor of PI3K-AKT-mTOR signal pathway (LY296004) and supplemented with pregnant women serum with high oestradiol simultaneously. These results strongly suggest that pregnant women with high oestradiol and/or immunosuppression will be vulnerable to HEV infection.

Vertical transmission of hepatitis E virus in pregnant rhesus macaques

“…The successful establishment provided a valuable chance to explore the underlying mechanism of HEV infection. In this study, higher viral titers were detected in the fecal and blood samples of pregnant rhesus macaques than in non-pregnant rhesus macaque; this result was consistent with the classical clinical symptoms of HEV infection in pregnant women 45 . In our previous study, we confirmed estrogen-promoting HEV replication in cells when estrogen analogs are supplied (17β-estradiol or diethylstilbestrol) 45 .…”

Hepatitis E virus infection during pregnancy

“…The levels of the three hormonal factors were found to be higher in HEV-positive pregnant FHF patients than in HEV-negative patients or controls [104]. Increased estradiol in the serum of HEV-infected pregnant women promoted viral replication [114,115], which may be associated with poor outcomes [86]. In addition, a high level of estrogen was found to be related to preterm delivery, low birth weight infants and fetal mortality through placental dysfunction in pregnant women with HEV infection [116].…”

Reproductive Health and Liver Disease: Practice Guidance by the American Association for the Study of Liver Diseases

“…(288) Proposed factors contributing to risk in pregnancy include HEV genotype 1 (with varying replication efficiency at the maternal-fetal placenta interface), (289,290) folate or other nutritional deficiencies, (291) and immunologic changes in pregnancy. (292) Acute HEV is responsible for an estimated 3,000 stillbirths worldwide annually, (293) with fetal and neonatal mortality rates likely influenced by the severity of maternal illness. A systematic review reported the median fetal and neonatal case fatality rate of 33% (interquartile range [IQR], 19%-37%) and 8% (IQR, 3%-20%), respectively.…”