Long Non-Coding RNA NEAT1 Inhibits Enterovirus 71 Replication by Enhancing IFN-β Transcription Through DDX60 Signaling: Pathological Insights and Clinical Implications

Enterovirus 71 (EV71) is the principal pathogen linked to severe hand, foot, and mouth disease (HFMD), with its pathogenesis remaining poorly understood. Here, we found that EV71 infection dramatically increases the expression of NEAT1, resulting in the formation of paraspeckles. Notably, NEAT1 specifically enhances IFN-β transcription via the DDX60-IRF7 pathway, thereby promoting host resistance to EV71. Further experiments indicated that NEAT1 serves as a positive feedback for DDX60 signaling. In detail, NEAT1 facilitates the relocation of the paraspeckle protein SFPQ to the paraspeckle. This action alleviates SFPQ's transcriptional repression on DDX60 and MDA5, which collaborate to promote IFN-β transcription. Subsequently, we noted a comparable regulation of NEAT1 in vivo. Importantly, our case-control study found that lower NEAT1-2 expression in peripheral blood leukocytes during early HFMD stages correlates with disease severity. Our findings suggest that NEAT1 serves as an intrinsic anti-EV71 molecule, with reduced levels potentially indicating a poor prognosis.