Introduction
Rubella virus infection during pregnancy can result in abortion, stillbirth and severe defects in embryogenesis resulting in congenital rubella syndrome (CRS). Low vaccination coverage in developing regions results in estimated 100,000 CRS cases in infants per year with a mortality rate over 30%. The molecular pathomechanisms and potential treatments remain largely unexplored. Endothelial cells of the placenta are infected by rubella virus (RuV). Fetal histopathology in CRS demonstrates damage to the endothelium of the heart and other blood vessels, as well as focal and obliterate lesions in large blood vessels and cellular damage in the myocardium. The elicited vascular abnormalities can lead to a number of clinical manifestations, including patent ductus arteriosus, pulmonary artery stenosis, and septal and valvular defects. The clinical manifestations of CRS, such as general growth retardation, deafness, and neurodegenerative damage, indicate vascular insufficiency. The effective rubella vaccine has been available since 1969. The availability of an effective vaccine may have reduced efforts to study the molecular and cellular human pathology that remains largely undetermined. In addition, mechanistic research of RuV infection during pregnancy is hampered by the lack of an animal model.

Objective and Methods
We hypothesized that RuV infection might have direct effects on angiogenic function of EC. To determine the effects of RuV on human EC, we used deep RNA sequencing and 2D and 3D angiogenesis models after RuV infection

Results
Infection with rubella virus reduced angiogenic (-33% network formation assay and -65% sprouting in spheroid assay vs control, respectively) and migratory capacity primary human endothelial cells whereas cell cycle and apoptosis rate were not affected. Next generation sequencing analysis revealed an induction of antiviral type I and III interferons (IFN) (+37,738- and 17,128-fold vs control, respectively, P<0.05) that induced of angiogenesis-inhibiting cytokines such as CXCL10 on RNA (+447,901-fold vs control, P<0.05) and protein level. The transcriptional profile induced by RuV resembled the effects of IFN-β (type I IFN) treatment, leading to an increase of CXCL10 (16,130-fold, P<0.05). Indeed, serum from RuV IgM-positive patients showed an increase in CXCL10 and inhibited angiogenesis (-31% sprouting, P>0.05). RuV-mediated inhibition of angiogenesis was rescued by treatment with neutralizing antibodies targeting CXCL10 and IFN-β receptor. The data identify an important role for anti-viral IFN-mediated induction of CXCL10 in controlling endothelial cell function during rubella infection.