Valproic Acid Downregulates Cytokine Expression in Human Macrophages Infected with Dengue Virus

Abstract

Natural infection with dengue virus (DENV) induces an increase in the production of cytokines that play an important role in disease pathogenesis. Despite numerous scientific studies, there are still no commercially available disease-specific therapeutics. Previous evidence shows that inhibiting histone deacetylase enzymes (HDACs) regulates the immune response in several inflammatory disease models. The aim of the current study was to evaluate the effect of HDAC inhibition in the production of inflammatory cytokines in human monocyte-derived macrophages infected with DENV serotype 2 (DENV-2). To this end, human monocyte-derived macrophages (MDMs) were treated with valproic acid (VPA) before or after infection and the inflammatory cytokine concentration was quantified by flow cytometry. We found that infected MDMs secreted IL-8, IL-1b, IL-6, TNF-alpha, and IL-10, but not IL-12. Strikingly, treatment of infected cells with VPA had a differential and concentration-dependent effect on the production of specific cytokines without eliciting significant changes in cell viability. Using the highest concentration of VPA, a significant reduction in the production of all cytokines was observed. These results suggest that HDAC inhibition during DENV-2 infection could exert an important regulatory effect in the production of inflammatory cytokines, representing a significant advance in the design of novel therapeutic dengue treatments.

Virtual Screening and Molecular Dynamics Simulation Suggest Valproic Acid Co-A could Bind to SARS-CoV2 RNA Depended RNA Polymerase

“…3) by acetyl Co-A synthetase 19 , which have moderate distribution on most of the human body organs. Despite of a GABA transaminase 20 blocker of neural receptor, valproic acid has extensive study history in antiviral treatment 21 including dengue infection 22 .…”

Targeting histone epigenetics to control viral infections

“…On the other hand, the HDAC inhibitor valproic acid significantly reduced the secretion of inflammatory cytokines, namely, IL-8, IL-1b, IL-6, and TNF-alpha, and also of the TH2 cytokine IL-10 in human monocyte-derived macrophages (MDMs) infected with DENV-2 serotype. 20 In this context, it is important to take into account the association of histone function with DENV infection, where it has been shown that DENV-capsid protein (C) can bind to the nuclear histone proteins H2A, H2B, H3, and H4 and act as a histone mimic, which could disrupt nucleosome formation and normal host cell homeostasis in favor of viral replication. 197 This has also been shown in the context of yellow fever virus, where the core viral protein displays an impressive homology to the histone H4 as well as other histone proteins, in addition to its ability to undergo acetylation and bind to nuclear proteins, which could point to shared properties between arboviruses.…”

Treating post‐dengue mania: Is role of valproate and quetiapine related to histone deacetylase inhibition?

“…This comes in the background of increasing reports of significant neurological sequelae with acute encephalitis, Guillian‐Barre Syndrome (GBS), myelitis, and stroke syndromes 2 . While the exact pathogenesis of neuropsychiatric sequelae is not well understood, it is known that increase in the production of cytokines plays an important role in the pathogenesis of dengue 3 . Histone Deacetylase (HDAC) enzyme plays a pivotal role in the biochemical and epigenetic pathways of the "cytokine storm" that follows the activation of toll‐like receptors by pathogens.…”

“…HDAC enzyme inhibition regulates the immune response in several inflammatory disease models and HDAC inhibitors like valproate are found to decrease the severity of the acute phase of dengue through reduction of this cytokine response 3 . Recently, quetiapine has demonstrated HDAC inhibitory activity in the hippocampus and the nucleus accumbens 4 .…”