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Published on: July 6, 2013
Human Cytomegalovirus-IE2 Affects Embryonic Liver Development and Survival in Transgenic Mouse
Xianjuan Zhang1, Shasha Jiang1, Xiaoqiong Zhou1
1Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, China.
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.
Insights
Human cytomegalovirus (HCMV) major immediate-early protein 2 (IE2) causes embryonic liver hypoplasia and death in mice. IE2 disrupts liver development by inhibiting hepatocyte proliferation and maturation.
Area of Science:
- Hepatology
- Virology
- Developmental Biology
Background:
- Congenital human cytomegalovirus (HCMV) infection is a significant cause of liver injury.
- The HCMV major immediate-early protein 2 (IE2) is crucial for viral replication and pathogenesis.
- Lack of suitable animal models hinders the study of HCMV's long-term effects on embryonic development.
Purpose of the Study:
- To investigate the in vivo role of HCMV IE2 in embryonic liver development.
- To establish a mouse model for studying IE2's impact on hepatogenesis.
- To elucidate the molecular mechanisms underlying IE2-induced liver abnormalities.
Main Methods:
- Construction of Rosa26-Loxp-STOP-Loxp (LAS)-IE2+/-, cre transgenic mice for liver-specific IE2 expression.
- Phenotypic, immunolocalization, and molecular analyses (mRNA, transcriptome sequencing, flow cytometry) during hepatogenesis.
- Assessment of embryos from embryonic day 17.5 to postnatal day 1.
Main Results:
- Consistent IE2 expression in the liver of transgenic mice throughout embryonic development.
- Progressive liver hypoplasia and increased embryonic lethality observed in IE2-expressing embryos.
- IE2 inhibited hepatocyte proliferation, induced apoptosis, and impaired hepatocyte maturation.
Conclusions:
- Stable IE2 expression in the liver disrupts hepatic morphogenesis and hepatocyte maturation, leading to embryonic liver hypoplasia and death.
- The findings provide insights into the mechanisms of liver injury caused by HCMV infection.
- This study establishes a valuable model for understanding HCMV-related developmental disorders.
