Immune responses to RNA-virus infections of the CNS

Abstract

A successful outcome for the host of virus infection of the central nervous system (CNS) requires the elimination of the virus without damage to essential non-renewable cells, such as neurons. As a result, inflammatory responses must be tightly controlled, and many unique mechanisms seem to contribute to this control. In addition to being important causes of human disease, RNA viruses that infect the CNS provide useful models in which to study immune responses in the CNS. Recent work has shown the importance of innate immune responses in the CNS in controlling virus infection. And advances have been made in assessing the relative roles of cytotoxic T cells, antibodies and cytokines in the clearance of viruses from neurons, glial cells and meningeal cells.

Figure 1. Changes that occur in the CNS during the immune response to a neuronal virus infection.

a | In the normal uninfected central nervous system (CNS), endothelial cells express few adhesion molecules. Neurons maintain microglia in a quiescent state through CD200–CD200 receptor (CD200R) interactions and astrocytes contribute by the production of neurotrophins, such as brain-derived neurotrophic factor (BDNF), nerve-growth factor (NGF) and neurotrophin 3 (NT3), that interact with p75, a low-affinity neurotrophin receptor. Gangliosides are abundant and transforming growth factor-β (TGF-β) is constitutively produced by neurons and astrocytes. Activated T cells enter the CNS routinely through interaction with low levels of P-selectin expressed by endothelial cells, but leave or die soon thereafter. b | Virus infection of neurons initiates the early production of interferon-β (IFN-β), chemokines and pro-inflammatory cytokines, which results in further activation of microglia and increased expression of adhesion molecules, such as vascular-cell adhesion molecule 1 (VCAM1) and intercellular adhesion molecule 1 (ICAM1), by endothelial cells. c | By three to four days after infection, inflammatory cells — such as natural killer (NK) cells, macrophages and lymphocytes — that are activated in secondary lymphoid tissue begin to enter the CNS at regions where virus replication is occurring and chemokines, such as CCL19 and CCL21, are expressed by endothelial cells. T cells produce additional cytokines, such as interleukin-4 (IL-4) and IFN-γ, and the B cells produce antibody, which initiates clearance of virus from infected cells. TNF, tumour-necrosis factor.

Figure 2. Mechanisms of virus clearance from neurons and microglia.

a | In neurons that survive infection with RNA viruses, infection is controlled initially by interferon-β (IFN-β) and subsequently by virus-specific antibody and IFN-γ produced by T cells and possibly neurons. This effectively inhibits the production of new virus, but does not necessarily eliminate virus RNA from the cell. CD4⁺ T cells that secrete cytokines, such as IFN-γ, and antibody-secreting B cells are resident for prolonged periods of time in the nervous system and probably have a role in long-term control of virus replication. b | Initial control of virus replication in infected glial cells involves IFN-β. Clearance involves cytolytic CD8⁺ T cells. CD4⁺ T cells supply help for CD8⁺ T cells and both subsets of T cells produce IFN-γ, which has an independent role in virus clearance from cells that survive. Long-term control of virus replication requires the local production of virus-specific antibody and possibly T cells.