p38 Inhibitor SB203580 Inhibits HEV Infection and Prevents HEV ‐Related Adverse Pregnancy Outcomes in a Pregnant Rabbit Model

BACKGROUND AND AIMS: Hepatitis E virus (HEV) infection during pregnancy can lead to severe adverse pregnancy outcomes including stillbirth, preterm birth, abortion, maternal death, and vertical transmission. Off-label use of ribavirin or pegylated interferon-α is proved effective for treating HEV infection, but they are both contraindicated for pregnant women. A safe and effective treatment against HEV infection during pregnancy is urgently needed. METHODS: We used JEG-3 choriocarcinoma cells to investigate the p38-MAPK signalling pathway in HEV replication. The cells were treated with varying concentrations of SB203580, a selective p38-MAPK inhibitor. For in vivo validation, HEV-infected pregnant rabbits were treated with SB203580. HEV replication, cytokine secretion, apoptosis, and pathological changes were measured. The effects on pregnancy outcomes, including vertical transmission, were also monitored. RESULTS: In this study, with a HEV-infected choriocarcinoma cell line, the JEG-3 cell model, we found that HEV infection significantly altered the expression patterns of the p38-MAPK signalling pathway. SB203580 can inhibit HEV replication and reduce the secretion of proinflammatory cytokines and apoptosis in vitro. Further in vivo validation with the HEV-infected pregnant rabbit model also revealed that SB203580 treatment during pregnancy significantly reduced the viral load in faeces and serum, the secretion of proinflammatory cytokines, and apoptosis in placental tissues. Most importantly, SB203580 is not only safe but can also effectively prevent HEV-related adverse pregnancy outcomes in pregnant rabbits and vertical transmission of HEV to pups. CONCLUSIONS: These results demonstrate that the p38 inhibitor SB203580 is an effective compound with potential as a therapeutic candidate against HEV infection during pregnancy.