Neutral sphingomyelinase 2 knockdown attenuates disease severity and modulates immune responses in enterovirus A71-infected mice

Severe hand, foot, and mouth disease (HFMD) is a febrile illness that is caused by enterovirus A71 (EV-A71). We previously identified neutral sphingomyelinase 2 (NSM2) as a critical host factor that supports EV-A71 replication in vitro. To define its role in vivo, we employed a suckling mouse model of EV-A71 infection. Using a small interfering RNA (siRNA) targeting NSM2 (si-NSM2), we achieved efficient knockdown. Treatment with si-NSM2 significantly reduced EV-A71 viral protein levels and genomic RNA loads in the brain, lung, heart, and intestine of infected ICR suckling mice. We further evaluated the biological consequences of NSM2 knockdown during EV-A71 infection. Body weight of EV-A71-infected mice recovered and clinical symptoms were alleviated. Notably, NSM2 knockdown also altered serum levels of inflammatory cytokines in infected mice. Our findings demonstrate that NSM2 is essential for EV-A71 pathogenesis in vivo and represents a promising host-directed target for the development of novel antiviral strategies against EV-A71 infection.