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Pawan Kumar Singh, Shailendra Giri, Ashok Kumar; AMP-activated Kinase (AMPK) Promotes Innate immunity and Antiviral Defense against Zika Virus Induced Ocular Infection.. Invest. Ophthalmol. Vis. Sci. 2018;59(9):4935.
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© ARVO (1962-2015); The Authors (2016-present)
We recently reported that Zika Virus infected multiple retinal cell types and caused chorioretinal atrophy in mouse eyes. In this study, we investigated the potential role of AMPK, a master regulator of cellular metabolism, in pathogenesis of ocular ZIKV infection.
Primary human RPE cells were infected with ZIKV strain PRVABC59 for various time points and AMPK phosphorylation (T172) was measured by Western blotting. AMPK activity was modulated by its pharmacological activators (AICAR and Metformin) and inhibitor (Compound C). Zika virus replication was assessed by immunofluorescence staining for 4G2 and western blot detection of ZIKV NS3 protein. For in vivo studies C57BL/6 mice eye were challenged with ZIKV with or without AICAR treatment and disease progression were measured by fundus imaging. Activation of innate immune and antiviral response genes was assessed by quantitative PCR.
ZIKV challenge upregulated the AMPK phosphorylation in Pr. RPE cells in a time dependent fashion. Our results indicate that AMPK deficient mouse embryonic fibroblast (MEF) cells were more permissive to ZIKV replication as compared to WT MEFs. AMPK activation using AICAR and Metformin restricted ZIKV replication in Pr. RPE cells and presence of Compound C reversed the effect of AICAR/Metformin. In vivo AICAR treatment ameliorated ZIKV-induced chorioretinal atrophy in mice with increased antiviral responses. ZIKV infection leads to activation of MEK pathways and an MEK pathways inhibitor, U0126, attenuated ZIKV replication.
Collectively, these findings indicate that the AMPK activation evokes antiviral innate responses and restricts ZIKV replication. Hence, targeting AMPK signaling can be explored to develop anti-viral therapy against ZIKV infection.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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