miR-451a Regulates Neuronal Apoptosis by Modulating 14-3-3ζ-JNK Axis upon Flaviviral Infection

Japanese Encephalitis Virus (JEV)/West Nile Virus (WNV)-induced encephalitis, although observed in selective cases, is associated with fatal consequences ranging from decline in cognitive abilities among recovered patients to coma/death. Loss of neuronal cells following viral infection-induced neuronal death imposes significant challenge to the central nervous system (CNS) homeostasis eventually resulting in loss of CNS tissue integrity and poor disease outcome in patients. In our present study, we aim to evaluate the role played by miRNA in modulating neuronal death upon neurotropic flaviviral infections. Infection of neuronal cell line resulted in upregulation of miR-451a abundance. Upon its upregulation, miR-451a has been demonstrated to target 3'-UTR of 14-3-3ζ transcript culminating into downregulation of 14-3-3ζ at the protein level. In response to 14-3-3ζ protein depletion in the cytosol upon flavivirus infection, increased phosphorylation of JNK protein has been shown to take place thus paving way for the cell to undergo apoptosis. Reversal of virus-induced miR-451a-upregulation helped abrogate neuronal apoptosis which is accompanied by a restoration of 14-3-3ζ protein and phosphorylated-JNK abundance to its normal level. Our findings hence provide a possible therapeutic target for preventing JEV/WNV-induced neuronal apoptosis thus improving disease outcome in flaviviral infection-associated encephalitis. IMPORTANCE Neuronal infection by JEV/WNV culminates into neuronal cell death thus contributing to signs and symptoms exhibited by patients that suffer from and that have recovered from JEV/WNV-induced encephalitis. In the present study we have evaluated the role of miRNA in promoting flavivirus-induced neuronal apoptosis. miR-451a has been demonstrated to promote neuronal cell death by targeting 14-3-3ζ protein function. The function of miR-451a in modulating neuronal physiology toward self-destruction has been shown to be independent of its effect upon the virus infection life cycle. The 14-3-3ζ transcript upon being targeted by miR-451a promotes JNK phosphorylation hence culminating into neuronal death by activation of apoptotic machinery. Inhibition of miR-451a upon neuronal infection by JEV/WNV helped reduce apoptotic machinery activation hence providing us with possible future therapeutic strategy in ameliorating flavivirus-induced neurological manifestations and overall disease burden in terms of morbidity.