PARP1 inhibition protects mice against Japanese encephalitis virus infection

Autor: Perumal Arumugam Desingu, Sneha Mishra, Lavanya Dindi, Shalini Srinivasan, Raju S. Rajmani, Venkatraman Ravi, Ankit Kumar Tamta, Sukanya Raghu, Krishnega Murugasamy, Anwit Shriniwas Pandit, Nagalingam R. Sundaresan
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: Cell Reports, Vol 42, Iss 9, Pp 113103- (2023)
Druh dokumentu: article
ISSN: 2211-1247
DOI: 10.1016/j.celrep.2023.113103
Popis: Summary: 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.
Databáze: Directory of Open Access Journals