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

PLoS Pathog. 2019 Mar 14;15(3):e1007617. doi: 10.1371/journal.ppat.1007617. eCollection 2019 Mar.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides
  • Animals
  • Brain / virology
  • Cognition / physiology
  • Cognition Disorders / etiology
  • Cognition Disorders / metabolism*
  • Cognition Disorders / virology*
  • Cognitive Dysfunction / etiology
  • Cognitive Dysfunction / metabolism
  • Cognitive Dysfunction / virology
  • Disease Models, Animal
  • Female
  • Herpesvirus 1, Human / metabolism
  • Herpesvirus 1, Human / pathogenicity*
  • Mice
  • Mice, Inbred BALB C
  • Neurodegenerative Diseases / etiology
  • Neurodegenerative Diseases / virology
  • Trigeminal Ganglion / virology
  • Virus Activation / physiology
  • Virus Replication / physiology

Substances

  • Amyloid beta-Peptides

Grants and funding

This work was supported by grant from the Italian Ministry of Instruction, University and Research (PRIN2015W729WH_001) to ATP and (PRIN2015W729WH_005) to GDC. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.