Severe enterovirus A71 pathogenesis and immune responses in human nucleolin transgenic mice.

Abstract

Enterovirus A71 (EV-A71) infection is known to cause hand-foot-mouth disease, which may develop severe symptoms such as encephalitis, herpangina, and paralysis, leading to pulmonary edema and even death in children under five years old. Existing animal models for EV-A71 pathogenesis have limitations, necessitating novel models to study human-relevant disease mechanisms. Using glycoproteomic profiling to identify EV-A71-interacting proteins, we previously discovered human nucleolin (hNCL) as an attachment molecule that enhances viral binding and infection in vitro. Here, we developed human nucleolin transgenic (hNCL-Tg) mice to investigate EV-A71 pathogenesis in vivo. Compared to wild-type (WT) mice, EV-A71-infected hNCL-Tg mice exhibited higher clinical scores, progressive limb paralysis, and increased mortality. Six days post-infection, hNCL-Tg mice showed elevated viral loads in the spinal cord and skeletal muscle, with pronounced EV-A71 VP1 expression in these tissues and the brainstem. Histopathology revealed severe skeletal muscle damage and significant pulmonary edema, characterized by lung congestion, hemorrhage, and erythrocyte infiltration into alveoli. Infected hNCL-Tg mice also displayed elevated levels of encephalitis- and pulmonary edema-associated proinflammatory cytokines (IL-1β, IL-6, IL-13). These findings establish the hNCL-Tg mouse as a robust model for studying EV-A71 pathogenesis and evaluating preclinical therapeutics.