SIRT2 protects against Japanese encephalitis virus infection in mice

Japanese encephalitis virus (JEV) is a mosquito-borne zoonotic RNA virus that causes Japanese encephalitis (JE) and poses a major threat to public health in Southeast Asia and the Western Pacific. Current strategies rely on prophylactic methods to prevent disease, as no effective antiviral therapy exists. Here, we report that SIRT2, an NAD+-dependent deacetylase enzyme, mediates antiviral activity against JEV infection in mice. Interestingly, our study reveals that SIRT2 is downregulated in JEV infection, SIRT2 genetic deficiency/small molecule inhibition increases viral yield in neuronal cells and mice brains thereby reducing the survival rate in the infected mice, whereas SIRT2 gene therapy to the JEV-infected mice by Adeno-associated virus vector reduced the JEV load in mice brains and improved the survival rate. SIRT2 deficiency activates inflammatory cytokines and chemokines response in the JEV-infected mice brains through activating NF-κB transcription factor. Mechanistically, SIRT2 deacetylates NF-κB to reduce the transcriptional factor activity of NF-κB that down-regulates the Beclin-1-mediated autophagy, which is needed for the JEV replication. Overall, the present findings establish SIRT2 as a potential regulator of JEV infection.