in vivo and in vitro study of the neuroinfection and neuropathogeny induced by dengue virus

In some cases, dengue virus (DENV) can induce neurological manifestations due to direct infection or the nervous immune response in brain. To learn more about these events, our group standardized a dengue neuro-infection model in suckling mice, using a neuroadapted dengue virus, which has a neurotropic and neurovirulet behavior. This virus strain (D4MB-6) infect newborn mice and viral antigen was detected in neurons, microglial and endothelial cells suggesting that this virus strain enters the nervous tissue using both retrograde axonal transport or altering the blood-brain barrier (BBB). The latter events were evaluated in an in vitro BBB model containing endothelial and astrocytic cells, confirming that the D4MB-6 virus induced the rearrangement of endothelial cells tight junction proteins, which favored the pass-through of viral particles, and immune cells. We also observed some inflammatory mediators modulation suggesting the establishment of an antiviral immune response and immune evasion strategies by the virus. Moreover, we found that the astrocytes were refractory to the infection, both in vitro and in vivo, although they showed clear signs of activation. Finally, it was found that the infection induced massive neurons loss, a strong immune response and glutamate excitotoxicity, because animals treated with valproic acid (VPA) or NMDA antagonist MK-801 did not develop lethal encephalitis. The standardized neuroinfection model will allow us to study the main role of astrocytes and microglia cells in the neuro-DENV pathogenesis and permit us to study pharmacological approaches to manage the neurological signs occurring during DENV infection.