An in vivo model of echovirus-induced meningitis in neonates

Abstract

AbstractEchoviruses are amongst the most common causes of aseptic meningitis worldwide, which can cause long-term sequelae and death, particularly in neonates. However, the mechanisms by which these viruses induce meningeal inflammation is poorly understood, owing at least in part to the lack of in vivo models that recapitulate this aspect of echovirus pathogenesis. Here, we developed an in vivo neonatal mouse model that recapitulates key aspects of echovirus-induced meningitis. We found that expression of the human homologue of the neonatal Fc receptor (FcRn), the primary echovirus receptor, in neonatal mice was not sufficient for infection of the brain. However, ablation of type I, but not III, IFN signaling in mice expressing human FcRn permitted high levels of echovirus replication in the brain, with corresponding clinical symptoms including delayed motor skills and hind limb weakness. We also defined the immunological response of the brain to echovirus infections and identified key cytokines induced by this infection. Lastly, we found that echoviruses robustly replicate in the leptomeninges, where they induce profound inflammation and cell death. Together, this work establishes an in vivo model of aseptic meningitis associated with echovirus infections and defines the specificity of echoviral infections within the meninges.Significance StatementEchoviruses are amongst the most common causes of aseptic meningitis worldwide, which can cause long-term sequelae or even death. The mechanisms by which echoviruses infect the brain are poorly understood, largely owing to the lack of robust in vivo models that recapitulate this aspect of echovirus pathogenesis. Here, we establish a neonatal mouse model of echovirus-induced aseptic meningitis and show that expression of the human homologue of the neonatal Fc receptor (FcRn), the primary receptor for echoviruses, and ablation of type I interferon (IFN) signaling are required to recapitulate echovirus-induced meningitis and clinical disease. These findings provide key insights into the host factors that control echovirus-induced meningitis and a model that could be used to test anti-echovirus therapeutics.