HHV-6A infection induces amyloid-beta expression and activation of microglial cells
Daria Bortolotti1, Valentina Gentili1, Antonella Rotola1
1Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Via Luigi Borsari, 46, 44121, Ferrara, Italy.
Background:
The control of viral infections in the brain involves the activation of microglial cells, the macrophages of the brain that are constantly surveying the central nervous system, and the production of amyloid-beta (Aβ) as an anti-microbial molecule. Recent findings suggest a possible implication of HHV-6A in AD. We evaluated the effect of HHV-6A infection on microglial cell expression Aβ and the activation status, determined by TREM2, ApoE, cytokines, and tau expression.
Methods:
We have infected microglial cells (HMC3, ATCC®CRL-3304), in monolayer and human peripheral blood monocyte-derived microglia (PBM-microglia) spheroid 3D model, with HHV-6A (strain U1102) cell-free virus inocula with 100 genome equivalents per 1 cell. We collected the cells 1, 3, 7, and 14 days post-infection (d.p.i.) and analyzed them for viral DNA and RNA, ApoE, Aβ (1-40, 1-42), tau, and phospho-tau (Threonine 181) by real-time immunofluorescence and cytokines by immunoenzymatic assay.
Results:
We observed a productive infection by HHV-6A. The expression of Aβ 1-42 increased from 3 d.p.i., while no significant induction was observed for Aβ 1-40. The HHV-6A infection induced the activation (TREM2, IL-1beta, ApoE) and migration of microglial cells. The secretion of tau started from 7 d.p.i., with an increasing percentage of the phosphorylated form.
Conclusions:
In conclusion, microglial cells are permissive to HHV-6A infection that induces the expression of Aβ and an activation status. Meanwhile, we hypothesize a paracrine effect of HHV-6A infection that activates and induces microglia migration to the site of infection.
Insights
Human brain cells (microglia) can be infected by HHV-6A, leading to amyloid-beta production and activation. This HHV-6A infection may contribute to neuroinflammation and Alzheimer's disease pathology.
Area of Science:
- Neuroimmunology
- Virology
- Neurodegenerative Diseases
Background:
- Microglial cells, the brain's immune cells, activate during viral infections and produce amyloid-beta (Aβ) as an antimicrobial defense.
- Recent research suggests a potential role for Human Herpesvirus 6A (HHV-6A) in Alzheimer's disease (AD).
- This study investigates HHV-6A's impact on microglial Aβ expression and activation markers like TREM2, ApoE, cytokines, and tau.
Purpose of the Study:
- To determine if microglial cells are permissive to HHV-6A infection.
- To analyze the effect of HHV-6A infection on microglial expression of Aβ, ApoE, tau, and cytokines.
- To assess HHV-6A's influence on microglial activation and migration.
Main Methods:
- Infection of human microglial cell lines (HMC3) and 3D spheroid models (PBM-microglia) with HHV-6A (strain U1102).
- Analysis of viral DNA/RNA, Aβ (1-40, 1-42), tau, phospho-tau, ApoE, and cytokines at various time points post-infection (1, 3, 7, 14 days).
- Utilized real-time immunofluorescence and immunoenzymatic assays for detection.
Main Results:
- Confirmed productive HHV-6A infection in microglial cells.
- Observed increased Aβ 1-42 expression starting at 3 days post-infection; Aβ 1-40 showed no significant induction.
- HHV-6A infection triggered microglial activation (TREM2, IL-1beta, ApoE), migration, and tau secretion, with increasing phosphorylation over time.
Conclusions:
- Microglial cells are susceptible to HHV-6A infection, which stimulates Aβ production and activates microglial cells.
- Hypothesize that HHV-6A infection may exert a paracrine effect, promoting microglial activation and migration to infection sites.
- Findings suggest a potential link between HHV-6A, microglial activation, and Alzheimer's disease pathogenesis.
