Mechanisms of Viral Pathogenesis in the Central Nervous System

National Institute Of Allergy And Infectious Diseases

Investigators

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Abstract

The innate immune response to virus infection has a strong influence on virus infection in the brain and the clinical outcome of disease. Our studies have focused on two animal models of virus-mediated neuropathogenesis to determine the host response proteins that regulate disease induction for virus replication and viral pathogenesis. In FY2014, we primarily focused on examining the mechanisms responsible for age-related susceptibility to LACV-induced neurological disease. In both humans and mice, LACV-induced neurological disease is age-dependent with adults being resistant to virus infection. We used a mouse model where young mice are highly susceptible to neurological disease and adult mice are resistance. We identified a strong correlation between early type I interferon (IFN) production in response to LACV with protection and demonstrated that adults deficient in the generation of this response were as susceptible as young animals to LACV-induced disease (Taylor, et.al. J. Virol. 2014). We determined that young mice were deficient in their ability to generate a protective response due to their low levels of myeloid dendritic cells (mDCs) as compared to adult animals. We further demonstrated that treatment with IFN or stimulation of mDCs in young mice was sufficient for protection against LACV-induced neurological disease when administered within the first few days of infection.