Enterovirus 71 infection induces pyroptotic brain injury via synergistic activation of classical inflammasome and viral gasdermin D cleavage

Abstract

This study elucidated the molecular mechanism underlying pyroptosis-mediated brain injury during EV71 infection in hand, foot, and mouth disease (HFMD), addressing a critical knowledge gap in neuroinflammatory pathogenesis. Using a BALB/c suckling mouse model, we demonstrated that EV71 infection induced a significant upregulation of the pro-inflammatory cytokines IL-1β and IL-18 in brain tissues. Mechanistically, the activation of the caspase-1/11-GSDMD axis was confirmed via Western blot analysis, which revealed an increase in cleaved GSDMD levels in the presence of EV71, indicating a definitive link between the virus and pyroptotic cell death, as supported by studies on GSDME’s role in EV71-induced cell pyroptosis. Specific inhibitors targeting caspase-1/11 have been shown to effectively suppress protein expression, reduce neuroinflammatory markers, and improve survival rates, as demonstrated in studies involving acute pancreatitis, EAE, and non-canonical cell death. These findings not only advance the understanding of EV71 neuropathogenesis but also identify caspase-1/11 as promising therapeutic targets for mitigating HFMD-associated brain injury.