Recurrent herpes simplex virus-1 infection induces hallmarks of neurodegeneration and cognitive deficits in mice

• Published in: PLoS pathogens 2019-03, Vol.15 (3), p.e1007617-e1007617
• Main Authors: De Chiara, Giovanna, Piacentini, Roberto, Fabiani, Marco, Mastrodonato, Alessia, Marcocci, Maria Elena, Limongi, Dolores, Napoletani, Giorgia, Protto, Virginia, Coluccio, Paolo, Celestino, Ignacio, Li Puma, Domenica Donatella, Grassi, Claudio, Palamara, Anna Teresa
• Format: Article
• Language: English
• Subjects: Accumulation; Activation; Advertising executives; Alzheimer Disease - metabolism; Alzheimer's disease; Alzheimers disease; Amyloid; Amyloid beta-Peptides; Animals; Biological markers; Biology and Life Sciences; Biomarkers; Brain; Brain - virology; Brain research; Central nervous system; Cognition - physiology; Cognition Disorders - etiology; Cognition Disorders - metabolism; Cognition Disorders - virology; Cognitive ability; Cognitive Dysfunction - etiology; Cognitive Dysfunction - metabolism; Cognitive Dysfunction - virology; Deoxyribonucleic acid; Disease Models, Animal; DNA; Encephalitis; Female; Ganglia; Genetic aspects; Gliosis; Health aspects; Herpes simplex; Herpes simplex virus; Herpes viruses; Herpesvirus 1, Human - metabolism; Herpesvirus 1, Human - pathogenicity; Herpesvirus infections; Hypotheses; IL-1β; Infection; Infections; Infectious diseases; Inflammation; Interleukin 6; Laboratories; Laboratory rats; Medicine and Health Sciences; Memory; Mice; Mice, Inbred BALB C; Neocortex; Nervous system; Neurodegeneration; Neurodegenerative Diseases - etiology; Neurodegenerative Diseases - virology; Phenotypes; Phosphorylation; Physiology; Proteins; Public health; Recurrence (Disease); Recurrent infection; Research and Analysis Methods; Risk analysis; Risk factors; Supervision; Tau protein; Thermal stress; Trigeminal ganglion; Trigeminal Ganglion - virology; Virus Activation - physiology; Virus Replication - physiology; Viruses
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1007617

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.