Doctor Institute of Zoology，Chinese Academy of Sciences, China
Abstract: Hepatitis E virus (HEV) infection during pregnancy leads to high maternal mortality and significant adverse fetal outcomes resulting from its cross-placenta transmission. These cases vary across HEV genotypes, especially between genotype 1 (HEV1) and 3 (HEV3). However, since the lack of physical-relevant infection models, the underlying pathologic and virologic mechanisms of different HEV subtypes on placenta remain largely undefined. Here, we developed trophoblast stem cell (hTSC)-based cell and organoid infection models to HEV1 and HEV3, and characterized their infectivity to trophoblast derivatives. We revealed that hTSCs and syncytiotrophoblasts (STB) were permissive for HEV1/3 infection, and the infection was more robust on organoids than on cell models. Based on these models, we found that although HEV3 was more infectious to trophoblast cells than HEV1, post-infection transcriptome analysis indicated more dramatic transcriptional changes upon HEV1 infection. For example, the downregulated KRT3, SLIT3, COL14A1, HOXD8, and PDGFRB suggested disruption of spiral artery remodeling process and upregulated GCM1 suggested a promotion of syncytialization. Trophoblast organoid-based infection models enabled evaluating the antiviral properties of drugs, like sofosbuvir and ribavirin, against HEV infection to placenta. In summary, based on the HEV-infected trophoblast organoid model, we dissect differential placental response to HEV1 and HEV3, and provides a robust platform for developing the antiviral drugs available during pregnancy.
Funding Source: National Natural Science Foundation of Youth Fund (NSFC82301883)
