Localization of Viral Antigens Improves Understanding of Congenital Rubella Syndrome Pathophysiology

Abstract

Rubella virus (RV) is responsible for benign postnatal and deadly antenatal infections. Its involvement in developmental defects in children following congenital transmission was first made by Sir Norman McAlister Gregg in 1941. Indeed, the maternal primary infection results in an RV viremia and placental transfer. If it occurs before 12 weeks of gestation, during organogenesis, it can result in severe fetal damage causing miscarriage or malformations primarily affecting the cardiovascular system, eyes, ears and the central nervous system; it is fatal in nearly one third of cases during the first year of life (Tondury and Smith, 1966). This severe RV infection acquired in utero early in pregnancy is named as Congenital Rubella Syndrome or CRS. In 2014, 141 CRS cases were reported from 114 countries mostly from South-East Asia (n = 86/141), although reporting is probably inconsistent according to the authors themselves (Grant et al., 2015). This number had been estimated as closer to 100,000 cases each year in developing countries alone (Cutts and Vynnycky, 1999). To better understand the pathogenesis of CRS in the absence of an animal model, the first histopathological explorations were conducted in some of the 20,000 fetuses infected during the 1964–1965 epidemics in the US when about 12.5 M Rubella cases were reported (National Communicable Disease Center, 1969). Although these studies identified histological lesions in the heart, blood vessels, crystalline lens, ears, brain, teeth and liver consistent with clinical features and sequelae of CRS, they did not solved the mechanisms of virus teratogenicity (Tondury and Smith, 1966, Esterly and Oppenheimer, 1969). In particular, until recently, the exact nature of the cell types infected with RV remained unknown.