Replication of hepatitis E virus in the ovary and promotion of oocyte apoptosis in rabbits infected with HEV-4

Hepatitis E virus (HEV) infection can induce infertility and miscarriage in pregnant women and infect neonates through vertical transmission. However, the mechanism of infertility and vertical transmission remains unclear. In the present study, we evaluated the replication of HEV in the ovary and structural and molecular changes induced by HEV after intraperitoneal injection of HEV in rabbits. Positive- and negative-strand HEV RNA was detected in the ovaries at 28 and 49 days post-infection. Positive HEV open reading frames 2 and 3 signals were observed in the ovaries by immunohistochemistry staining. Histopathological changes of ovarian tissues were observed, including scattered cell necrosis and lymphocyte infiltration. The ratio of normal follicles decreased, whereas the ratio of atresia follicles increased in the HEV RNA-positive ovaries compared to the control group by counting the number of follicles at all levels. In addition, TUNEL results showed that apoptosis in follicle cells and oocytes was promoted by HEV infection. These results suggest that the ovary is one of the replication sites of HEV and that the expression of HEV RNA and antigen in ovarian tissue caused structural and molecular changes that promoted germ cell apoptosis. HEV can infect and replicate in the ovum at different stages, which is a novel mechanism for HEV vertical transmission.