Human Cytomegalovirus-IE2 Affects Embryonic Liver Development and Survival in Transgenic Mouse

BACKGROUND & AIMS: Congenital human cytomegalovirus (HCMV) infection is a common cause of liver injury. The major immediate-early protein 2 (IE2) of HCMV is critical for the progression of HCMV infection. As a result of species isolation, there are no animal models suitable for HCMV infection, which aimed to study the long-term effects of IE2 on embryonic liver development in vivo. Hence, this study aimed to investigate the role of IE2 in liver development using a transgenosis mouse model. METHODS: Rosa26-Loxp-STOP-Loxp (LAS)-IE2(+/−), cre mice that could specifically and stably express IE2 in the liver, were constructed. Phenotypic analysis, immunolocalization studies, messenger RNA analyses, transcriptome sequencing, and flow cytometry analysis were performed on Rosa26-LSL-IE2(+/−), cre mice during hepatogenesis. RESULTS: Rosa26-LSL-IE2(+/−), cre mice could consistently express IE2 at different embryonic stages in vivo. With the development of Rosa26-LSL-IE2(+/−), cre embryos from embryonic day 17.5 to postnatal day 1, progressive liver hypoplasia and embryonic deaths were observed. Furthermore, molecular evidence that IE2 expression inhibited hepatocyte proliferation, increased cell apoptosis, and impaired hepatocyte maturation was provided. CONCLUSIONS: Rosa26-LSL-IE2(+/−), cre mice could stably express IE2 in the liver. IE2 expression resulted in embryonic liver hypoplasia by disrupting hepatic morphogenesis and hepatocyte maturation, which may be responsible for embryonic deaths. This study is helpful in understanding the mechanism of liver injuries induced by HCMV infection.