Knocking on Closed Doors: Host Interferons Dynamically Regulate Blood-Brain Barrier Function during Viral Infections of the Central Nervous System

Abstract

The central nervous system (CNS) is among the most important organ systems, integrating information inputs and coordinating the activity of all other body systems. Like many organ systems, the CNS is susceptible to infection by pathogenic microorganisms, including many arboviruses that are considered neurotropic because they are able to achieve robust replication in neural cells. Neurotropic arboviruses capable of infecting the CNS include members of the Flaviviridae (e.g., West Nile and Japanese encephalitis viruses), Bunyaviridae (La Cross and Rift Valley Fever viruses), and Togaviridae (Alphavirus species) families, all RNA viruses that are maintained in complex life cycles involving a nonhuman primary vertebrate and a primary arthropod vector [1]. A variety of mechanisms exist to protect the CNS from the entry and infection of neurotropic viruses, including innate immune responses and multilayer barriers formed by diverse host cell types [2]. However, many arboviruses gain access to the CNS either as free virions, within motile infected cells, and/or by using axonal transport mechanisms of peripheral nerves that directly enter or form synapses within the CNS. Viruses that enter via the bloodstream must cross CNS endothelial barriers that exhibit unique specializations, collectively termed the blood-brain barrier (BBB).