The mechanism behind rubella virus (RV) teratogenicity is still unknown. Its elucidation requires suitable cell culture models. We are investigating human induced pluripotent stem cells (iPSCs) as a representative cell culture model. As a pluripotent stem cell type they are similar to human embryonic stem cells (ESCs), wich are derived from the inner cell mass of human blastocysts. Both cell types can be differentiated into derivatives of the three embryonic germ layers, ectoderm, mesoderm, and endoderm. As such they can be regarded as a cell culture platform for blastocyst- and gastrulation-like stages and thus for early human development (Figure 1). We were able to show that RV can establish a sucessful infection in iPSCs and can be maintained in culture for several passages (Hübner et al., 2017).
Figure 1. Overview of induced pluripotent stem cells and iPSC-derived ectodermal, mesodermal, and endodermal cells as a cell culture model for early human development.
In contrast to recombinant coxsackievirus B3 expressing green fluorescent protein (EGFP) and measles virus (edmonston strain) RV does not display any notable cytopathogenicty on iPSCs and as such enables their differentiation into derivatives of the three embryonic germ layers (Figure 2). Metabolic alterations were noted during infection with all three viruses and could be a general property on virus infections of iPSCs.
Figure 2. The pattern of infection of rubella virus (RV) on iPSCs as compared to recombinant coxsackievirus B3 expressing green fluorescent protein (CVB3-EGFP) and measles virus (MV, Edmonston strain). Infection by CVB3-EGFP, MV, and RV is shown through expression of EGFP and the viral proteins E1 envelope glycoprotein and phosphoprotein (P), respectively. The course of infection was assessed with regard to alterations of cellular metabolism, induction of cytopathogenic effects and the effect of differentiation capacity.
We are currently working on further characterization of the impact of RV infection on developmental pathways by the use of iPSCs and iPSC-derived ectodermal, mesodermal, and endodermal cells.
Hübner D, Jahn K, Pinkert S, Böhnke J, Jung M, Fechner H, Rujescu D, Liebert UG, Claus C. Infection of iPSC Lines with Miscarriage-Associated Coxsackievirus and Measles Virus and Teratogenic Rubella Virus as a Model for Viral Impairment of Early Human Embryogenesis. ACS Infect Dis. 2017 Dec 8;3(12):886-897. doi: 10.1021/acsinfecdis.7b00103. Epub 2017 Oct 26.