Investigating the interactions between viral infection, Tau pathology, and neuroinflammation

University Of North Carolina Charlotte, Charlotte NC

Investigators

Abstract

Project Summary Increasing evidence points to the neuroimmune system as a primary contributor to Alzheimer’s disease (AD). Environmental factors that increase neuroinflammation, including viral infections, correlate with risk of AD; however, the mechanisms by which microbial infections promote AD are not well understood. AD is defined by the presence of two hallmark pathologies—extracellular senile plaques composed of aggregated amyloid beta peptide (Aβ) and intracellular neurofibrillary tangles composed of the hyperphosphorylated microtubule associated protein tau. Recent studies have suggested that Aβ may act as an antimicrobial peptide, in which its aggregation can restrict microbial infection by trapping it in the extracellular space. We hypothesize that as an intracellular protein, Tau may act as an antimicrobial peptide against viruses, which are obligate intracellular pathogens. Our preliminary data shows that following intracranial inoculation with an attenuated strain of West Nile virus, Kunjin virus (KUNV), Tau becomes hyperphosphorylated and aggregates. Furthermore, transgenic mice expressing elevated levels of aggregation-prone Tau show reduced viral burden in their brains. Here we propose to study the interactions between viral infection, Tau pathology, and neuroinflammation using a murine model of encephalitic KUNV infection. Aim 1 will determine whether viral infection increases Tau pathology by measuring aggregation, phosphorylation, and truncation. Aim 2 will assess the impact of Tau aggregation on viral replication and whether Tau interacts directly with viral components. Aim 3 will examine the effect of Tau pathology on the neuroinflammatory response to viral infection. Together, these experiments will determine whether viral infection impacts the development of Tau pathology and the role of Tau pathology in modulating the neuroimmune response to viral infection. Successful completion of this project will establish a mechanistic link between AD and viral pathogens.