Abstract
In addition to manipulating cellular homeostasis and survivability, autophagy also plays a crucial role in numerous viral infections. In this study, we discover that Japanese encephalitis virus (JEV) infection results in the accumulation of microtubule-associated protein 1 light chain 3-II (LC3-II) protein and GFP-LC3 puncta in vitro and an increase in autophagosomes/autolysosomes in vivo. The fusion between autophagosomes and lysosomes is essential for virus replication. Knockdown of autophagy-related genes reduced JEV replication in vitro, as indicated by viral RNA and protein levels. We also note that JEV infection in autophagy-impaired cells displayed active caspases cleavage and cell death. Moreover, we find that JEV induces higher type I interferon (IFN) activation in cells deficient in autophagy-related genes as the cells exhibited increased phosphorylation and dimerization of interferon regulatory factor 3 (IRF3) and mitochondrial antiviral signaling protein (MAVS) aggregation. Finally, we find that autophagy is indispensable for efficient JEV replication even in an IFN-defective background. Overall, our studies provide the first description of the mechanism of the autophagic innate immune signaling pathway during JEV infection.
Highlights
Acute infection caused by Japanese encephalitis virus (JEV) evokes several distinct innate immune responses, which function partially by a molecular mechanism involving the RIG-I/IRF-3 and PI3K/NF-kB signaling pathways
We found that the suppression of autophagy in JEVinfected cells correlated with an enhanced innate immune response
JEV Infection Induces Autophagy Neuro2a mouse neuroblastoma cells (N2a) were employed because this cell line is permissive to JEV infection [10]
Summary
Acute infection caused by Japanese encephalitis virus (JEV) evokes several distinct innate immune responses, which function partially by a molecular mechanism involving the RIG-I/IRF-3 and PI3K/NF-kB signaling pathways. Activation of the signaling network results in significant changes in the expression of multiple inflammatory cytokines, chemokines and IFN-inducible proteins [1,2,3], which perform their anti-viral functions and contribute to JEV pathogenesis, resulting in encephalitis. The major function of autophagy is to deliver damaged organelles and long-lived proteins to the lysosomal machinery, thereby balancing synthesis, degradation, and subsequent recycling. The first step involves vesicle regulation and nucleation of an isolation membrane. The isolation membrane goes through elongation and fusion processes to form the autophagosome, which is a double-membrane vesicle that sequesters the cytoplasmic materials and organelles. The last major step is docking and fusion of the completed autophagosomes with lysosomes to form autolysosomes, where the captured materials are degraded [5]
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