Mechanisms of restriction of viral neuroinvasion at the blood–brain barrier

• Neurotropic viruses invade the CNS via several routes including direct transit across the blood–brain barrier (BBB).
• Pro-inflammatory cytokines promote BBB breakdown during viral infection.
• IFN-β, IFN-λ, and TAM receptor signaling enhance BBB integrity.
• Gastrointestinal microbiota modulate BBB function.

The blood–brain barrier (BBB) consists of highly specialized cells including brain microvascular endothelial cells, astrocytes, microglia, pericytes, and neurons, which act in concert to restrict the entry of pathogens, immune cells, and soluble molecules into the central nervous system (CNS). If pathogens manage to cross the BBB and establish infection within the CNS, the BBB can open in a regulated manner to allow leukocyte transmigration into the CNS so that microbes, infected cells, and debris can be cleared. This review highlights how different inflammatory cytokines or signaling pathways disrupt or enhance BBB integrity in a way that regulates entry of neurotropic viruses into the CNS.