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To evaluate whether uterine injury caused by hepatitis E virus (HEV) infection is responsible for adverse pregnancy outcomes. HEV-infected female BALB/c mice were coupled with healthy male BALB/c mice at 0, 7, 14, 21, and 91 dpi to explore the uterine injury caused by HEV infection. Mice were euthanized after 10 days of copulation, and uteruses were collected for HEV RNA and antigen detection and histopathological analysis. Inflammatory responses; apoptosis; and estrogen receptor ɑ (ER-ɑ), endomethal antibody (ERAb), cytokeratin-7 (CK7), vimentin (VIM), and vascular endothelial growth factor (VEGF) expression levels were evaluated. After 10 days of copulation, miscarriage and nonpregnancy, as well as enlarged uteruses filled with inflammatory cytokines, were found in HEV-infected mice. HEV RNA and antigens were detected in the sera and uteruses of HEV-infected mice. Significant endometrial thickness (EMT) thinning, severe inflammatory responses, and aggravated apoptosis in the uteruses of HEV-infected mice that experienced miscarriage might contribute to adverse pregnancy outcomes. Furthermore, significantly suppressed ER-ɑ expression and increased ERAb, CK7, VIM, and VEGF expression levels were found in the uteruses of HEV-infected mice that had miscarried. However, uterine damage recovered after complete HEV clearance, and impaired fertility was improved. EMT injury, severe inflammatory responses, and aggravated apoptosis in the uterus caused by HEV infection are responsible for poor pregnancy outcomes.

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Hepatitis E virus (HEV) infection is the most common cause of acute viral hepatitis worldwide. However, host-HEV interactions have yet to be fully understood. Zincfinger antiviral protein (ZAP) is a novel interferon (IFN)-stimulated gene product that inhibits a variety of viruses in synergy with IFNβ. To evaluate the role of ZAP in HEV infection, its expressions in HEV-infected patients and in cell cultures were measured.We report a significant inhibition of ZAP expression in patients with HEV genotype four acute infection. The expression of ZAP in the HEV life cycle was monitored in cultures of HEV-infected cells. Results indicated that the ZAP level decreased significantly after HEV infection. ZAP over-expression inhibited HEV replication, whereas its knockdown by RNA interference significantly increased HEV RNA. These suggest that ZAP serves as an antiviral in HEV infection. Moreover, silencing ZAP decreased IFN regulatory factor 3 (IRF3) phosphorylation in HEV-infected cells treated with poly(I:C), indicating that ZAP synergizes with IFNβ. In conclusion, ZAP is an important anti-HEV host factor and in synergy with IFNβ, inhibits HEV replication.

Background Hepatitis E virus (HEV) infection is a common cause of acute hepatitis worldwide and causes approximately 30% case fatality rate among pregnant women. Pregnancy serum (PS), which contains a high concentration of estradiol, facilitates HEV replication in vitro through the suppression of the PI3K–AKT–mTOR and cAMPK–PKA–CREB signaling pathways. However, the proteomics of the complex host responses to HEV infection, especially how PS facilitates viral replication, remains unclear. Methods In this study, the differences in the proteomics of HEV-infected HepG2 cells supplemented with fetal bovine serum (FBS) from those of HEV-infected HepG2 cells supplemented with serum from women in their third trimester of pregnancy were quantified by using isobaric tags for relative and absolute quantification technology. Results A total of 1511 proteins were identified, among which 548 were defined as differentially expressed proteins (DEPs). HEV-infected cells supplemented with PS exhibited the most significant changes at the protein level. A total of 328 DEPs, including 66 up-regulated and 262 down-regulated proteins, were identified in HEV-infected cells supplemented with FBS, whereas 264 DEPs, including 201 up-regulated and 63 down-regulated proteins, were found in HEV-infected cells supplemented with PS. Subsequently, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed that in HEV-infected cells, PS supplementation adjusted more host genes and signaling pathways than FBS supplementation. The DEPs involved in virus–host interaction participated in complex interactions, especially a large number of immune-related protein emerged in HEV-infected cells supplemented with PS. Three significant or interesting proteins, including filamin-A, thioredoxin, and cytochrome c, in HEV-infected cells were functionally verified. Conclusions The results of this study provide new and comprehensive insight for exploring virus–host interactions and will benefit future studies on the pathogenesis of HEV in pregnant women.