Characterization of Coxsackievirus Infection in Neural Stem and Progenitor Cells Derived from a Transgenic Mouse Model for Alzheimer's Disease

Coxsackievirus B3 (CVB3) is an enterovirus that may leave serious, long-lasting effects in the central nervous system (CNS) of the surviving host. Our laboratory has characterized the ability of CVB3 to infect neural progenitor and stem cells (NPSCs) and persist in the CNS in our pediatric model of infection. We wish to characterize the effects of a persistent CVB3 infection in hAPP751 transgenic mice, a model for Alzheimer’s disease (AD). AD is largely characterized by the formation of amyloid-β plaques. hAPP751 mice express the amyloid-β_1-42 protein under the murine Thy1 promoter and reproduce aspects of AD pathology. hAPP751 transgenic mice infected with CVB3 shortly after birth showed increased mortality, as compared to infected non-transgenic littermates and mock-infected hAPP751 transgenic mice over a 7 month period. Ongoing analysis of CNS histopathology will determine if an increase in amyloid plaque formation occurred in infected hAPP751 mice. We hypothesize that fundamental molecular changes in neurons derived from persistently-infected NPSCs, including alterations in autophagy, may accelerate AD in hAPP751 mice. Therefore, we will isolate NPSCs from three-day-old hAPP751 mice, culture them to form neurosphere aggregates, and infect them with a recombinant CVB3 expressing the enhanced green fluorescence protein (eGFP-CVB3). Infected hAPP751 neurospheres will be observed over time and allowed to differentiate. We will determine whether persistent eGFP-CVB3 infection alters neuronal production, and autophagy flux will be monitored in these neurons utilizing fluorescence microscopy. Our preliminary results suggest that a previous neurotropic infection which persists in the host may accelerate a subsequent neurological disease.