Dengue Virus Replication Is Associated with Catecholamine Biosynthesis and Metabolism in Hepatocytes
George MpekoulisVassilina TsopelaAnna ChalariKaterina I. KalliampakouG. PanosEfseveia FrakolakiRaphaela S. MilonaDiamantis C. SiderisDido VassilacopoulouNiki Vassilaki
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Abstract:
Previously, the association between the catecholamine biosynthetic enzyme L-Dopa decarboxylase (DDC) and Dengue virus (DV) replication was demonstrated in liver cells and was found to be mediated at least by the interaction between DDC and phosphoinositide 3-kinase (PI3K). Here, we show that biogenic amines production and uptake impede DV replication in hepatocytes and monocytes, while the virus reduces catecholamine biosynthesis, metabolism, and transport. To examine how catecholamine biosynthesis/metabolism influences DV, first, we verified the role of DDC by altering DDC expression. DDC silencing enhanced virus replication, but not translation, attenuated the negative effect of DDC substrates on the virus and reduced the infection related cell death. Then, the role of the downstream steps of the catecholamine biosynthesis/metabolism was analyzed by chemical inhibition of the respective enzymes, application of their substrates and/or their products; moreover, reserpine, the inhibitor of the vesicular monoamine transporter 2 (VMAT2), was used to examine the role of uptake/storage of catecholamines on DV. Apart from the role of each enzyme/transporter, these studies revealed that the dopamine uptake, and not the dopamine-signaling, is responsible for the negative effect on DV. Accordingly, all treatments expected to enhance the accumulation of catecholamines in the cell cytosol suppressed DV replication. This was verified by the use of chemical inducers of catecholamine biosynthesis. Last, the cellular redox alterations due to catecholamine oxidation were not related with the inhibition of DV replication. In turn, DV apart from its negative impact on DDC, inhibits tyrosine hydroxylase, dopamine beta-hydroxylase, monoamine oxidase, and VMAT2 expression.In rats and mice in different dopaminergic brain structures the immunoreactive axons with agouti-related protein (AGRP) were identified. The double immunofluorescence method shows the presence of AGRP-immunoreactive processes around the bodies of dopaminergic neurons. In experiments in vitro after incubation of brain tissue from ventral tegmental area or hypothalamus with AGRP (83-132) the significant decrease of tyrosine hydroxylase optical density was indicated. The data indicate possible direct inhibitory action of AGRP on tyrosine hydroxylase level in dopaminergic brain neurons and its role as a modulator of the functional activity of dopaminergic neurons.
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