PARP1 inhibition protects mice against Japanese encephalitis virus infection.

Autor:	Desingu PA; Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru 560012, India. Electronic address: padesingu@gmail.com., Mishra S; Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru 560012, India., Dindi L; Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru 560012, India., Srinivasan S; Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru 560012, India., Rajmani RS; Centre for Infectious Disease Research, Indian Institute of Science, Bengaluru 560012, India., Ravi V; Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru 560012, India., Tamta AK; Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru 560012, India., Raghu S; Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru 560012, India., Murugasamy K; Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru 560012, India., Pandit AS; Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru 560012, India., Sundaresan NR; Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru 560012, India. Electronic address: rsundaresan@iisc.ac.in.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2023 Sep 26; Vol. 42 (9), pp. 113103. Date of Electronic Publication: 2023 Sep 06.
DOI:	10.1016/j.celrep.2023.113103
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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