Pathogenic mechanisms of Echovirus 18-induced encephalitis in a novel hFcRn transgenic mouse model

ABSTRACT Echovirus 18 (E18) poses an escalating neurological threat in children, with its complex pathogenesis impeded by the absence of robust animal models for comprehensive mechanistic investigation. This study establishes an E18-induced viral encephalitis (VE) model in 7-day-old human neonatal Fc receptor (hFcRn) transgenic mice. After intracranial inoculation with 4.0 × 10 6 PFU of E18, mice developed marked signs of infection, characterized by progressive weight loss, motor impairment, elevated viral loads in the brain, and histopathological evidence of VE, ultimately resulting in approximately 75% mortality. The E18-infected mouse brains were accompanied by lymphocytic and granulocytic infiltration, neuronal shrinkage, and focal hemorrhage, with magnetic resonance imaging revealing prominent signal abnormalities in the subarachnoid space and periventricular regions. Interestingly, although all cell types of the brain can serve as carriers of the virus at the single-cell level, E18 exhibits distinct cellular tropism by preferentially targeting astrocytes and microglia rather than neurons and neurofilaments. Additionally, E18 infection orchestrates a complex and adaptive immune response, with dynamic changes among astrocytic subtypes reflecting the evolution of this immune response. Overall, this study successfully establishes a disease model that enhances our understanding of E18-induced encephalitis and provides a valuable platform for evaluating therapeutic interventions and developing vaccines. IMPORTANCE E18 represents an important pathogen in infectious diseases, with potential neurological complications that warrant further investigation. However, due to ethical and technical limitations, its neuropathological mechanisms have long remained unexplored. This study presents a novel encephalitis model using 7-day-old hFcRn Tg mice. The integration of MRI, histopathology, and multi-omics analysis elucidated the molecular mechanisms of viral neural invasion, offering critical insights into pediatric viral encephalitis and potential therapeutic strategies. This animal model provides a valuable platform for understanding E18-induced encephalitis mechanisms and evaluating potential therapeutics and vaccines.