New advances in CNS immunity against viral infection

Abstract

The central nervous system (CNS) is an immunologically specialized organ where restrictive barrier structures protect the parenchyma from inflammation and infection. This protection is important in preventing damage to non-renewable resident cell populations, such as neurons, responsible for functions ranging from executive to autonomic. Despite these barriers, the CNS can be infected through several entry portals, giving rise to meningitis and encephalitis. Following infection, resident cells recruit peripherally derived immune cells to sites of viral infection. In this review, we discuss recent advances in immune recruitment and entry at barrier structures as well as current immunotherapeutic strategies for the treatment of persistent viral infections.

Figure 1

Sagittal view of the central nervous system and its barrier structures. The CNS is protected by several anatomically restrictive barrier structures that include the choroid plexus (Figure 2), meninges (Figure 3), blood–brain barrier (Figure 4), and olfactory epithelium (Figure 5). These barrier structures protect the CNS infection but can also serve as an entry point for pathogens and/or immune cells.

Figure 2

Choroid plexus. The choroid plexus resides in ventricular spaces of the brain and is responsible for creating cerebral spinal fluid (CSF). The choroid plexus is a dynamic barrier structure home to many immune cells, including choroid plexus macrophages. Unlike the BBB, but similar to the dura mater, choroid plexus blood vessels are fenestrated and do not express tight junctions, which provides easier access to pathogens and immune cells into the stromal space. Choroid plexus epithelia (ependyma) serve as a barrier between fenestrated blood vessels and the CSF. Expression of tight junctional proteins between individual epithelial cells protects the CSF by restricting solute and cellular movement. During infection, the choroid plexus can serve as a gateway for immune recruitment and entry into the CSF. Immune cells must first enter the choroid plexus stroma before traversing the epithelial barrier.

Figure 3

Meninges. The meninges consist of three layers that envelope the brain and spinal cord. The dura mater, the outermost layer, is vascularized by fenestrated vessels and is home to a repertoire of immune cells, including meningeal macrophages that line the vessels. Interior to the dura lies the arachnoid mater. The arachnoid, its trabecula and the pia mater form the subarachnoid space, a compartment where cerebrospinal fluid (CSF) freely flows. The arachnoid mater also contains tight junctions that help keep materials in the dura mater separate from the subarchnoid space. Within the subarachnoid space resides pial vessels that dive into the CNS parenchyma. Pial vessels are non-fenestrated and express tight junctions. The spaces between these vessels and the parenchyma (referred to as perivascular spaces) are inhabited by perivascular macrophages. The final layer, which lies beneath pia mater, is referred to as the glia limitans — a layer of surface-associated astrocytes that protect the brain and prevent migration of solutes and cells from the CSF into the parenchyma. During states of infection, the meninges can serve as an entry point for extravasating immune cells. Dural vessels are especially susceptible to immune cell and pathogen entry because they are fenestrated and do not express tight junctions.

Figure 4

Blood–brain barrier (BBB). The blood brain barrier creates a selective interface between the blood and CNS parenchyma. It consists of endothelial cells and their tight junction proteins, basement membrane, pericytes and astrocytic end feet. In conjunction with barrier function, the BBB can also modulate cerebral blood flow through the neuro-vascular unit, a connection involving neurons, pericytes, astrocytes, and the blood–brain barrier. This allows neural and astrocytic activity to modulate blood vessel tone, resulting in an increase or decrease of regional perfusion. During infection, the BBB is permissive to immune extravasation from the blood into the perivascular spaces. Immune cells usually enter the perivascular spaces before gaining access to the parenchyma. These spaces are inhabited by perivascular macrophages.

Figure 5

Olfactory epithelium and bulb. The olfactory epithelium forms part of the nasal airway and serves as a direct interface between the peripheral nervous system (PNS) and CNS. Olfactory sensory neurons within the olfactory epithelium are surrounded by support cells including basal, sustentacular, and microvillar cells. These neurons extend axon fibers that cross the cribriform plate and synapse in the olfactory bulb of the CNS. Because the dendrites of olfactory sensory neurons extend directly into the airways, these cells can be infected by viruses. Viruses that infect olfactory sensory neurons often hijack axonal transport machinery to invade the CNS. Other pathogens, such as bacteria and amoeba, can also access the CNS by traversing the olfactory epithelium and entering holes in the cribriform plate.