Title : The Herpesviruses’ protein dUTPase induces neuroinflammatory mediators: Implications for Neurological Diseases associated with infections by these viruses
Abstract:
Abstract:
We have previously reported that the dUTPase protein from human herpesvirus 6A (HHV-6A) and Epstein-Barr virus (EBV) increased the expression and secretion of pro-inflammatory cytokines from hDCs in a TLR2-dependent manner. Because IL-1β and IL-6 can disrupt the blood brain barrier (BBB) and neurocognitive functions and are elevated in patients with Alzheimer disease, we conducted time-course studies to examine whether the HHV-6A dUTPase protein could modulate the expression of genes important in maintaining BBB integrity and/or synaptic plasticity in immortalized human cerebral microvascular endothelial cells, astrocytes, and microglia cells by qRT-PCR. Treatment of human cerebral microvascular endothelial cells with HHV-6A dUTPase protein resulted in a rapid increase in IL-1β (6-fold), IL-6 (11-fold) and TNFα (215-fold) mRNA expression, beginning at 1 h after treatment and reaching maximum induction levels at 4 h (361-fold and 35-fold) for IL-1β and IL-6, respectively, and at 2 h (817.5-fold) for TNFα compared to the control. The increase in IL-1β, IL-6 and TNFα mRNA expression was accompanied by a parallel increase in TLR2 (6-fold) and NFκB (11.76-fold) gene expression in these cells. Interestingly, HHV-6A dUTPase induced upregulation of VEGFA (2.4-fold), cyclooxygenase 2 (COX-2)/PTGS2 (12.46-fold) mRNA expression and downregulated the expression of genes important in maintaining BBB integrity (cingulin/CGN and β-catenin/CTNNB1) in human cerebral microvascular endothelial cells. In astrocytes, HHV-6A dUTPase treatment significantly increased IL6 (73-fold), IL-1β (3-fold), TLR2 (6.91-fold), NFκB (3.56-fold) and COX2 (3-fold) mRNA expression. In microglial cells the dUTPase proteins from HHV-6A, HSV-1/2 and VZV downregulated (2.5 to 7-fold) the expression of early growth response 1 (Egr-1) gene, a key regulator of synaptic plasticity. In Summary, these studies provide exciting new data suggesting a novel mechanism by which the human herpesvirus dUTPase proteins, including HHV-6, EBV, Human simplex virus (HSV) and Varicella-Zoster virus (VZV) may modulate immune activation and alter BBB integrity as well as the structure/function of neurological synapses resulting in loss of neurocognitive functions and promoting neuronal cell death.
What will audience learn from your presentation?
• The etiologies and drivers of AD are poorly understood, and there currently no biomarkers of disease progression. Thus, there is a critical need to identify triggers and drivers of the disease. This presentation will provide exciting new data highlighting previously unexplored mechanisms by which the human herpesvirus dUTPase proteins, including HHV-6, EBV, HSV and VZV may modulate immune activation and alter BBB integrity as well as the structure/function of neurological synapses resulting in loss of neurocognitive functions and promoting neuronal cell death.
• It will raise awareness toward how select herpesvirus dUTPases could be used as a novel target for the development of alternative therapeutic approaches
• It will also provide a platform for exploring these viral proteins as potential biomarkers and/or aid direct treatment in a subset of AD patients
