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Description
Group B coxsackieviruses are pathogenic viruses known to cause acute and chronic inflammatory diseases of the brain, heart, and pancreas in humans. Central nervous system (CNS) infections that are left untreated may contribute to long-term sequelae such as neurological diseases. The molecular mechanisms determining the tropism of coxsackieviruses and their ability to persist in the host CNS remain unclear. Previous data in our laboratory have suggested neural progenitor and stem cells (NPSCs) are primary targets for coxsackievirus B3 (CVB3) infection. We investigated the effects of a persistent infection upon neural stem cell function in the adult host. Three-day-old C57BL/6 pups were mock-infected, or alternatively, infected with a sublethal dose of a recombinant CVB3 expressing the enhanced green fluorescence protein (eGFP-CVB3). After 90 days post-infection (PI) NPSCs were isolated and analyzed for alterations in neurogenesis and their ability to differentiate into neurons, astrocytes, and oligodendrocytes. We observed a reduction in proliferation potential and impaired lineage commitment in neurons and astrocytes, but not oligodendrocytes. Separately, the susceptibility of NPSCs derived from adult mice was compared to neonatally-derived NPSCs. Following infection, neonatal NPSCs exhibited more robust eGFP expression along with higher viral titers. We also observed that NPSC proliferative capacity may be able to predict the level of susceptibility to infection. In addition, we investigated the consequences of a carrier-state infection in NPSCs derived from hAPP751 transgenic mice, a model of Alzheimer's disease. Following persistent infection, transgenic NPSCs showed higher LC3-II to LC3-I ratios following treatment with rapamycin and chloroquine as compared to mock-infected transgenic NPSCs, suggesting impaired autophagic flux. These results indicate that persistent CVB3 infection following exposure early in life may have long-term consequences on neurodevelopment. Also, neural stem cells in the adult CNS may remain potential target cells for CVB3. In addition, persistent CVB3 infection can alter the neuronal housekeeping processes such as autophagy which may accelerate progression to neurodegenerative disease.
