Antiviral Type I and Type III Interferon Responses in the Central Nervous System

Abstract

The central nervous system (CNS) harbors highly differentiated cells, such as neurons that are essential to coordinate the functions of complex organisms. This organ is partly protected by the blood-brain barrier (BBB) from toxic substances and pathogens carried in the bloodstream. Yet, neurotropic viruses can reach the CNS either by crossing the BBB after viremia, or by exploiting motile infected cells as Trojan horses, or by using axonal transport. Type I and type III interferons (IFNs) are cytokines that are critical to control early steps of viral infections. Deficiencies in the IFN pathway have been associated with fatal viral encephalitis both in humans and mice. Therefore, the IFN system provides an essential protection of the CNS against viral infections. Yet, basal activity of the IFN system appears to be low within the CNS, likely owing to the toxicity of IFN to this organ. Moreover, after viral infection, neurons and oligodendrocytes were reported to be relatively poor IFN producers and appear to keep some susceptibility to neurotropic viruses, even in the presence of IFN. This review addresses some trends and recent developments concerning the role of type I and type III IFNs in: i) preventing neuroinvasion and infection of CNS cells; ii) the identity of IFN-producing cells in the CNS; iii) the antiviral activity of ISGs; and iv) the activity of viral proteins of neurotropic viruses that target the IFN pathway.

The brain parenchyma has a type I interferon response that can limit virus spread

“…A similar study with LACV found nearly no type I IFN-expressing neurons but rather that glia expressed type I IFN (9). In addition, other innate immune pathways, such as the type II and III IFN responses (10,11), and inflammation (12), are activated by viral infection. These observations suggest a great deal of complexity in the brain's response to viral infection and raise several issues in need of clarification.…”

Abortively Infected Astrocytes Appear To Represent the Main Source of Interferon Beta in the Virus-Infected Brain

“…Thus, brain-resident cells must produce substantial amounts of IFN after virus infection. It appears that all brain cells are capable of producing IFN, although to greatly differing extents (6,7). Most experimental attempts to identify IFN-producing cells in the brain have been in vitro approaches, and only a few of those studies have given insights into the in vivo situation.…”

Upon Intranasal Vesicular Stomatitis Virus Infection, Astrocytes in the Olfactory Bulb Are Important Interferon Beta Producers That Protect from Lethal Encephalitis

“…Typically, neurotropic viruses may reach the central nervous system (CNS) by (i) the olfactory route, (ii) via the blood-brain barrier, (iii) by infecting infiltrating cells, or (iv) by axonal transport (1). Viral clearance in non-neuronal tissues often involves cytolytic elimination of infected cells.…”