The Biology of Persistent Infection: Inflammation and Demyelination following Murine Coronavirus Infection of the Central Nervous System

Abstract

Multiple Sclerosis (MS) is an immune-mediated demyelinating disease of humans. Although causes of MS are enigmatic, underlying elements contributing to disease development include both genetic and environmental factors. Recent epidemiological evidence has pointed to viral infection as a trigger to initiating white matter damage in humans. Mouse hepatitis virus (MHV) is a positive strand RNA virus that, following intracranial infection of susceptible mice, induces an acute encephalomyelitis that later resolves into a chronic fulminating demyelinating disease. Immune cell infiltration into the central nervous system is critical both to quell viral replication and instigate demyelination. Recent efforts by our laboratory and others have focused upon strategies capable of enhancing remyelination in response to viral-induced demyelination, both by dampening chronic inflammation and by surgical engraftment of remyelination - competent neural precursor cells.

Figure 1. Kinetics of viral replication and neuroinflammation following MHV infection of the CNS

(A) Following intracranial infection of mice, MHV replicates initially within ependymal cells and later disseminates to astrocytes, oligodendrocytes, and microglia, quickly reaching peak load between 4–6 days post – infection [38, 68]. Cells of the innate immune system e.g. neutrophils, NK cells, and macrophages are rapidly recruited to the CNS within the first few days following infection [59, 60]. While neutrophils are important for permeabilizing the blood brain barrier, cellular components of the innate immune response are incapable of controlling viral replication. Beginning at 5 days post – infection, virus – specific T cells enter the CNS [45, 64] and control viral replication through perforin-mediated cytolysis and IFN-γ secretion. By two weeks post-infection MHV is generally undetectable in the CNS by plaque assay, however T cells and macrophages persist within the CNS [–48]. Neutralizing antibody, while detectable during acute infection does not play any appreciable role in viral clearance; rather virus-specific antibody is responsible for preventing viral recrudescence during chronic infection [–79]. (B) Even though replicating virus is undetectable in the CNS at later stages of infection, both viral antigen and/or RNA persist within the CNS for up to a year. Viral persistence is responsible for continued T cell and macrophage infiltration into the CNS that leads to chronic demyelination [40, 80]. Data depicted in panels A and B are schematic curves representative of published results.

Figure 2. Demyelination in mice persistently infected with MHV

Following acute disease, MHV will persist primarily in astrocytes and oligodendrocytes. Activated astrocytes secrete the T cell and macrophage chemokines CXCL10 and CCL5, serving to attract CD4⁺ T cells, CD8⁺ T cells, and macrophages to migrate across the blood brain barrier and into the perivascular space. CD4⁺ T cells are also capable of secreting CCL5, further enhancing macrophage accumulation. Both CD4⁺ and CD8⁺ T cells secrete IFN-γ, activating macrophages and aiding in viral clearance from persistently infected oligodendrocytes. Activated macrophages in turn digest myelin debris and enhance the immune – mediated demyelination. Targeted neutralization of either CXCL10 [48] or CCL5 [92] prevents the accumulation of CD4+ T cells or macrophages, respectively, muting chronic inflammation within the CNS and allowing remyelination to occur. Engrafted neural precursor cells also enhance remyelination, presumably by directly myelinating axons [149, 150].