Dengue Virus Replication Is Associated with Catecholamine Biosynthesis and Metabolism in Hepatocytes.

George Mpekoulis,Georgios Panos,Vassilina Tsopela,Katerina I Kalliampakou,Diamantis C Sideris,Dido Vassilacopoulou,Efseveia Frakolaki,Anna Chalari,Raphaela S Milona,Niki Vassilaki

doi:10.3390/v14030564

George Mpekoulis, Georgios Panos + Show 8 more

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https://doi.org/10.3390/v14030564

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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.

Highlights

Dengue virus (DV) poses a considerable public health problem in over 100 countries, with a high possibility of further transmission [1]
We examined how the suppression of Dopa decarboxylase (DDC) expression affects the replication of DV genome
We outline that DV replication is restricted by the production, uptake and metabolism of catecholamines in liver cells, and, in turn, DV has developed ways to counteract the effect of catecholamines by reducing their cytoplasmic levels

Summary

Introduction

Dengue virus (DV) poses a considerable public health problem in over 100 countries, with a high possibility of further transmission [1]. High viremia levels in DV infection have been associated with the involvement of different organs, such as the liver and brain, in the severe form of the disease [3]. The liver is the most commonly involved organ in dengue. DV is an enveloped virus possessing a positive sense, single-stranded m7G-capped RNA genome, which encodes a single polyprotein [6,7]. This is proteolytically cleaved into structural proteins (C, prM, and E), that are involved in receptor binding, virus fusion, and virion assembly, and non-structural (NS) proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5), that are responsible for the replication of the viral genome and critical for the evasion from host cell immune responses. Viral replication can occur in cells of a broad range of tissues, including hepatocytes [8–10]

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