PARP1 inhibition protects mice against Japanese encephalitis virus infection

Japanese encephalitis (JE) is a vector-borne viral disease that causes acute encephalitis in children. Although vaccines have been developed against the JE virus (JEV), no effective antiviral therapy exists. Our study shows that inhibition of poly(ADP-ribose) polymerase 1 (PARP1), an NAD+-dependent (poly-ADP) ribosyl transferase, protects against JEV infection. Interestingly, PARP1 is critical for JEV pathogenesis in Neuro-2a cells and mice. Small molecular inhibitors of PARP1, olaparib, and 3-aminobenzamide (3-AB) significantly reduce clinical signs and viral load in the serum and brains of mice and improve survival. PARP1 inhibition confers protection against JEV infection by inhibiting autophagy. Mechanistically, upon JEV infection, PARP1 PARylates AKT and negatively affects its phosphorylation. In addition, PARP1 transcriptionally upregulates PTEN, the PIP3 phosphatase, negatively regulating AKT. PARP1-mediated AKT inactivation promotes autophagy and JEV pathogenesis by increasing the FoxO activity. Thus, our findings demonstrate PARP1 as a potential mediator of JEV pathogenesis that can be effectively targeted for treating JE. [Display omitted] •JEV infection increases PARP1 activity in Neuro2a cells•PARP1 inhibition reduces clinical signs and improves survival in JEV-infected mice•PARP1 regulates JEV pathogenesis through autophagy•PARP1 inhibition promotes AKT signaling and protects against viral replication Desingu et al. describe the role of PARP1 in the pathogenesis of the Japanese encephalitis virus (JEV). PARP1 inhibits AKT signaling to activate the transcription factor FoxO and promotes autophagy to favor viral replication. Notably, PARP1 inhibition reduces clinical signs and improves the survival of JEV-infected mice.