Undifferentiated and differentiating human pluripotent stem cells as in vitro model for viral alterations in early embryogenesis

• Applicant: Dr. Claudia Claus
• Subject Area: Virology
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 261009079

In utero infection of an embryo can have devastating effects. While there are a number of known and suspected viral teratogens the underlying mechanism of their teratogenicity is largely unknown. There is an ongoing need for a suitable in vitro cell culture model of viral infections in early human embryonic development and subsequently of the safety of live, attenuated virus vaccines in early pregnancy. A promising model for this approach is represented by human induced pluripotent stem cells (hiPSCs) as the in vitro counterpart of the early embryo. This proposal aims at cellular alterations in hiPSCs that are caused by the exceptionally efficient teratogen rubella virus (RV). The evaluation of the effect of RV on undifferentiated and differentiating hiPSCs will be focussed on the expression of pluripotency and subsequently differentiation markers as well as cellular proliferation rate. Maintenance of the pluripotent state requires low mitochondrial activity and in consequence mitochondrial restructuring and enhancement of mitochondrial respiratory chain activity accompany the differentiation process. RV holds the potential to alter pluripotency and/or differentiation through interference with this fine metabolic interplay. This hypothesis is strengthened by results obtained by the applicant. These results highlight RV-induced alterations of mitochondrial respiratory chain activities in differentiated cells. The effect of wild-type RV infection will be compared to an attenuated, non-teratogenic RV vaccine strain and to (control) viruses that lack congenital organ deficiencies of gestational RV infection. The results gained through this proposal will illuminate the initial (primary) events of a teratogenic virus infection and strengthen the interconnectivity between developmental biology and virology.

• DFG Programme: Research Grants