Premium
P2‐063: HSV‐1 Transcriptionally Activated Via AHR‐ARNT Signaling Pathway in Glial Cells May Be a Pathogenic Factor That Affects Alzheimer's Disease Development
Author(s) -
Tsyrlov Ilya B.,
Wu Jerome S.,
Shur Iri.
Publication year - 2016
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2016.06.1268
Subject(s) - lytic cycle , microglia , biology , immunology , population , astrocyte , virology , inflammation , virus , medicine , neuroscience , central nervous system , environmental health
Background:Despite extensive research on the abnormalities of AD brain, the underlying causes are still unknown. Among others, increasing evidencewas 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). Methods: In this study, in cilico search for DREs in HSV1 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-87MGwere determined by a plaque assay, and viral DNA – by hybridization and PCR. Results:Dioxin is the most potent xenobiotic so far known, which bio-accumulates 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 w3.0 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 dioxin-specific 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. Conclusions: Here we present data on newly molecular mechanism of how host cell dioxin receptor (AhR-Arnt) complex trans-activates neurotropic HSV-1 linked to AD.