Echoviruses are among the most common worldwide causes of
aseptic meningitis, which can cause long-term sequelae and death, particularly in neonates. However, the mechanisms by which these viruses induce meningeal
inflammation are 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 show that expression of the human homologue of the primary echovirus receptor, the
neonatal Fc receptor (FcRn), is not sufficient for
infection of the brains of neonatal mice. However, ablation of type I, but not III,
interferon (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. Using this model, we defined the immunological response of the brain to
echovirus infection and identified key
cytokines, such as
granulocyte colony-stimulating factor (
G-CSF) and
interleukin 6 (IL-6), that were induced by this
infection. Lastly, we showed that echoviruses specifically 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 that delineates the differential roles of type I and
type III IFNs in echovirus-associated neuronal disease and defines the specificity of echoviral
infections within the meninges. IMPORTANCE Echoviruses are among the most common worldwide causes of
aseptic meningitis, 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 FcRn, the primary receptor for echoviruses, and ablation of type I 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.