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

Abstract

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.

Figure 1

In vitro model of the BBB. Primary brain microvasulcar endothelial cells (BMECs) are cultured in a transwell above primary astrocytes and/or primary pericytes. Virus and/or exogenous cytokines are added to the upper chamber followed by measurement of trans-endothelial electrical resistance (TEER), virus crossing, and/or permeation of solutes into the lower chamber. BMECs also can be examined by immunofluoresence and confocal microscopy to assess expression and colocalization of tight junction proteins, which regulate permeability across BMEC monolayers.

Figure 2

Regulation of BBB integrity during viral infection. Pro-inflammatory cytokines (e.g., TNF-α, IL-1β, IL-6, IFN-γ, which are expressed either luminally or abluminally) act to open the BBB by causing breakdown of tight junctions. Astrocytes, pericytes, BMECs, leukocytes, and/or other cell types may produce these cytokines. MMPs disrupt BBB integrity during viral infection by directly degrading tight junctions. Collectively, the pro-inflammatory cytokines and MMPs facilitate viral crossing into the CNS parenchyma. By contrast, tight junction stabilization occurs in response to signals by type I IFNs (e.g., IFN-β) or type III IFN (IFN-λ). TAM receptor ligands induce signals that augment this effect by cooperating with type I IFN to activate Rac1, rearrange actin filaments, and stabilize endothelial tight junctions. Gut microbiota enhance BBB integrity as well, although its mechanistic role during neuroinvasive viral infection is yet to be defined.