The neonatal Fc receptor is a pan-echovirus receptor

Abstract

AbstractEchoviruses are the main causative agents of aseptic meningitis worldwide and are particularly devastating in the neonatal population, where they are associated with severe hepatitis, neurological disease including meningitis and encephalitis, and even death. Here, we identify the neonatal Fc receptor (FcRn) as a pan-echovirus receptor. We show that loss of expression of FcRn or its binding partner beta 2 microglubulin (β2M) renders human brain microvascular cells resistant to infection by a panel of echoviruses at the stage of virus attachment and that a blocking antibody to β2M inhibit echovirus infection in cell lines and in primary human fetal intestinal epithelial cells. We also show that expression of human, but not mouse, FcRn renders non-permissive human and mouse cells sensitive to echovirus infection and that the extracellular domain of human FcRn directly binds echoviral particles and neutralizes infection. Lastly, we show that primary cells isolated from mice that express human FcRn are highly susceptible to echovirus infection. Our findings thus identify FcRn as a pan-echovirus receptor, which may explain the enhanced susceptibility of neonates to echovirus infections.SignificanceEchoviruses are associated with aseptic meningitis and induce severe disease, and even death, in neonates and young infants. Here, we identify the neonatal Fc receptor (FcRn) as a pan-echovirus receptor. FcRn is expressed on the surface of the human placenta, and throughout life in intestinal enterocytes, liver hepatocytes, and in the microvascular endothelial cells that line the blood-brain barrier. This pattern of expression is consistent with the organ sites targeted by echoviruses in humans, with the primary entry site of infection in the intestinal tract and subsequent infection of secondary tissues including the liver and brain. These findings provide important insights into echovirus pathogenesis and may explain the enhanced susceptibility of infants and neonates to echovirus-induced disease.