Role of Dendritic Cells in Viral Brain Infections

Abstract

To gain access to the brain, a so-called immune-privileged organ due to its physical separation from the blood stream, pathogens and particularly viruses have been selected throughout evolution for their use of specific mechanisms. They can enter the central nervous system through direct infection of nerves or cerebral barriers or through cell-mediated transport. Indeed, peripheral lymphoid and myeloid immune cells can interact with the blood-brain and the blood-cerebrospinal fluid barriers and allow viral brain access using the "Trojan horse" mechanism. Among immune cells, at the frontier between innate and adaptive immune responses, dendritic cells (DCs) can be pathogen carriers, regulate or exacerbate antiviral responses and neuroinflammation, and therefore be involved in viral transmission and spread. In this review, we highlight an important contribution of DCs in the development and the consequences of viral brain infections.

Keywords: blood–brain barrier; blood–cerebrospinal barrier; dendritic cell; neuroinfections; neuroinflammation; viral infection.

Figure 1

Different viral modes of access to the central nervous system (CNS). (A) Viruses can be up taken by nerve terminals at the olfactory bulb to gain access to the CNS. (B) They also can infect peripheral neurons and use long-range retrograde axonal transport. (C) At the blood–brain barrier (BBB), (1) viruses can directly cross the endothelium (by paracellular or transcellular ways), (2) they can infect and replicate in brain endothelial cells and be released in the CNS, (3) and finally they can pass through the BBB by infecting immune cells that cross the endothelium through the “Trojan horse” mechanism. (D) At the blood–cerebrospinal fluid barrier, (1) viruses can directly cross the endothelium, (2) they can also infect, replicate, and be released from endothelial cells, pericytes, or epithelial cells of the choroid plexus, (3) and finally infected immune cells can also cross this barrier and deliver viruses in the CNS. Created with SMART Servier Medical Art.

Figure 2

Effects of neuroinfections in the CNS. Viral brain infections will trigger multiple molecular and cellular mechanisms in the various CNS cell types that can lead to apoptosis of neuronal cells, release of pro-inflammatory factors, disruption of brain barriers, and immune cell recruitment, which ultimately will exacerbate neuroinflammation. Created with SMART Servier Medical Art.

Figure 3

Interaction of dendritic cells with the blood–brain barrier. Through the neuroinfection and the release of pro-inflammatory factors, DCs can produce type I interferon to regulate viral replication. Infected DCs can also act as antigen-presenting cells and stimulate T cells. (A) DCs are chemoattracted to brain barriers by circulating chemokines (such as CCL2); a firm contact is established by interaction of cellular adhesion molecules expressed by endothelial cells that facilitate rolling and adhesion. Transmigration occurs as an interaction of cellular adhesion molecules and integrins. (B) The recruitment of mature DCs is facilitated by expression of CCR7 and IL-1R that increases attraction by secreted CCL19, CCL21 or IL-1α and IL-1β, respectively. (C) Immature DCs can also be attracted by interaction of IL-1α or IL-1β with IL-1R, but their expression of CCR2, CCR3, and CCR5 increases the interactions with CCL2, CCL3, and CCL5. Created with SMART Servier Medical Art.