Date Published: March 14, 2019
Publisher: Public Library of Science
Author(s): Giovanna De Chiara, Roberto Piacentini, Marco Fabiani, Alessia Mastrodonato, Maria Elena Marcocci, Dolores Limongi, Giorgia Napoletani, Virginia Protto, Paolo Coluccio, Ignacio Celestino, Domenica Donatella Li Puma, Claudio Grassi, Anna Teresa Palamara, Robert F. Kalejta.
Herpes simplex virus type 1 (HSV-1) is a DNA neurotropic virus, usually establishing latent infections in the trigeminal ganglia followed by periodic reactivations. Although numerous findings suggested potential links between HSV-1 and Alzheimer’s disease (AD), a causal relation has not been demonstrated yet. Hence, we set up a model of recurrent HSV-1 infection in mice undergoing repeated cycles of viral reactivation. By virological and molecular analyses we found: i) HSV-1 spreading and replication in different brain regions after thermal stress-induced virus reactivations; ii) accumulation of AD hallmarks including amyloid-β protein, tau hyperphosphorylation, and neuroinflammation markers (astrogliosis, IL-1β and IL-6). Remarkably, the progressive accumulation of AD molecular biomarkers in neocortex and hippocampus of HSV-1 infected mice, triggered by repeated virus reactivations, correlated with increasing cognitive deficits becoming irreversible after seven cycles of reactivation. Collectively, our findings provide evidence that mild and recurrent HSV-1 infections in the central nervous system produce an AD-like phenotype and suggest that they are a risk factor for AD.
Herpes simplex virus type 1 (HSV-1) is a neurotropic virus that establishes a latent infection in sensory, typically the trigeminal, ganglia and periodically reactivates giving rise to the well-known cold sores and blisters on orolabial mucosa . Following reactivation, HSV-1 may also reach the central nervous system (CNS) [2–5] resulting in either a severe, but rare, form of herpetic encephalitis (HSE) or establishing latency [6, 7]. Increasing evidence suggests a possible link between HSV-1 infection and Alzheimer’s disease (AD), the most common neurodegenerative disease associated with dementia in the elderly [8–10]. Previous studies demonstrated the presence of HSV-1 genome in the brain of AD patients, particularly those carrying the ε4 allele of apolipoprotein E that is a risk factor for AD [11–13]. More recently, population-based studies correlated the level and avidity index of anti-HSV-1 IgG and IgM (markers of HSV-1 infection and reactivation, respectively) to the risk of developing AD [14–18]. Many in vitro studies including ours supported the hypothesis that HSV-1 is involved in AD pathogenesis. Specifically, we demonstrated that HSV-1 infection in cultured neurons induces the amyloidogenic processing of amyloid precursor protein (APP) and intra- and extra-neuronal accumulation of amyloid-β protein (Aβ) and other neurotoxic APP fragments [19, 20]. We also demonstrated that HSV-1 activates intracellular processes leading to neurodegeneration through different mechanisms, most of them driven by APP fragments [21–23]. Others groups pointed out the effects of HSV-1 infection on the microtubule-associated protein tau, showing that the virus triggers its hyperphosphorylation and aggregation, likely leading to its deposition in neurofibrillary tangles (NFTs), another hallmark of AD [24, 25]. Altogether these data strongly support the hypothesis that accumulation of AD biomarkers triggered by recurrent infection, if not properly cleared, may drive neurodegeneration. This view was supported by the results of in vivo studies showing inflammatory and neurodegenerative markers in a mouse model of HSE induced by intranasal HSV-1 inoculation . However, a clear cause-effect relationship among multiple HSV-1 reactivations, active viral replication in the brain, accumulation of AD molecular markers and cognitive deficits has yet to be demonstrated. This issue is very relevant for personalized medicine approaches when considering the role of microbial agents in neurodegenerative diseases. Hence, we established a mouse model of HSV-1 infection and reactivation to verify whether multiple viral reactivations throughout life result in an AD-like phenotype. Following virus reactivations, we found that: i) HSV-1 actively replicated in the brain; ii) AD biomarkers progressively accumulated in neocortex and hippocampus of infected mice; iii) AD biomarker accumulation was associated with cognitive impairment. These biochemical and functional alterations increased with the number of virus reactivations.
Here, we provide novel evidence in mice that, after HSV-1 infection followed by numerous cycles of viral reactivations, the virus reaches and replicates in the brain where it triggers the progressive accumulation of AD molecular hallmarks leading to cognitive decline.