AHR-ARNT SIGNALING PATHWAY MEDIATES TRANSCRIPTIONAL ACTIVATION OF HSV-1 IN GLIAL CELLS: A PATHOGENIC FACTOR THAT MIGHT AFFECT AD DEVELOPMENT

Abstract

Despite extensive research on the abnormalities of AD brain, the underlying causes are still unknown. Among others, increasing evidence was presented for neurotropic HSV-1 as a causative element in AD, although no distinct factor reactivating passive HSV-1 was revealed yet. While HSV-1 lytic cycle activation in brain typically linked to stress, immunosuppression or inflammation, another factor was overlooked, namely body burden dioxin (BBD). In this study, in cilico search for DREs in HSV-1 genes was performed by CITECON, a tool recognizing transcriptional factor binding sites. HSV-1 titers in dioxin-treated murine Apoe(-/-) astrocytes, monkey primary astrocytes and human astrocytoma cells U-87MG were determined by a plaque assay, and viral DNA – by hybridization and PCR. Dioxin is the most potent xenobiotic so far known, which bioaccumulates and has estimated half-life up to 10 yr in human body. The concept emerged from a finding of up-regulation of some common vires in human cells at dioxin concentrations lower than current BBD level of ∼3.0 ppt in the general population. Such strong viral susceptibility to BBD is exclusively due to multiple potentially active “dioxin responsive elements” (DRE) in regulatory area of viral genes. Here, within five HSV-1 genes, including critical immediate-early (IE) ones, SITECON detected 7 to 8 potentially active DREs in the regulatory regions. Alongside, we conducted pilot studies demonstrating multi-fold elevated replication of HSV-1 caused by 1.0 ppt dioxin in all infected astrocyte cell lines studied. We chose astrocyte models because amyloid plaques appear early during AD, and their development is intimately linked to activated astrocytes and microglia. Also, the results obtained stick to the recent report that the dioxinspecific AhR, a key member of the transcriptional complex activating HSV-1 replication, is found in brain tissue, and may be associated with glial cells rather than neurons. Here we present data on newly molecular mechanism of how host cell dioxin receptor (AhR-Arnt) complex trans-activate neurotropic HSV-1 linked to AD.