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

Enterovirus 71 (EV71) is a viral pathogen responsible for causing hand, foot, and mouth disease, which can lead to severe neurological complications. This study aims to elucidate the pyroptosis mechanism underlying brain injury induced by EV71 infection. EV71-infected BALB/c suckling mice exhibited characteristic symptoms, including weight loss, lethargy, and limb weakness. Notably, elevated levels of the inflammatory proteins IL-1β and IL-18 were detected in the brain tissue of the infected mice. Research findings indicate that EV71 infection activates the NLRP3 inflammasome, resulting in an increased release of IL-1β and IL-18. Furthermore, upregulation of the expression of Caspase-1, Caspase-11, and the pyroptosis-related protein GSDMD was observed in the context of EV71 infection. Importantly, the administration of inhibitors targeting Caspase-1 and Caspase-11 led to the downregulation of these protein expression levels and simultaneously reduced the severity of the inflammatory response in the brain tissue. These results highlight the critical regulatory role and cross-talk between Caspase-1 and Caspase-11 in EV71-induced brain injury, which involves inflammatory responses and pyroptosis. The significance of these findings enhances our understanding of the pathogenic mechanisms associated with EV71 infection and offers valuable insights for the development of new therapeutic strategies. IMPORTANCE: 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.