Desingu, P.A. and Mishra, S. and Dindi, L. and Srinivasan, S. and Rajmani, R.S. and Ravi, V. and Tamta, A.K. and Raghu, S. and Murugasamy, K. and Pandit, A.S. and Sundaresan, N.R. (2023) PARP1 inhibition protects mice against Japanese encephalitis virus infection. In: Cell Reports, 42 (9).
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Abstract
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. © 2023 The Author(s)
| Item Type: | Journal Article |
|---|---|
| Publication: | Cell Reports |
| Publisher: | Elsevier B.V. |
| Additional Information: | The Copyright for this article belongs to the Authors. |
| Department/Centre: | Division of Biological Sciences > Microbiology & Cell Biology Division of Biological Sciences > Centre for Infectious Disease Research |
| Date Deposited: | 09 Nov 2023 11:12 |
| Last Modified: | 09 Nov 2023 11:12 |
| URI: | https://eprints.iisc.ac.in/id/eprint/83313 |
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