Theilers Virus

Animal experiments have also questioned the hypothesis that demyelination alone is sufficient to explain permanent deficits in demyelinating diseases. Theiler's murine encephalomyelitis virus (TMEV) was isolated and identified by Theiler nearly 70 years ago as a picornavirus responsible for ubiquitous enteric infection and infrequent paralysis in mice (Theiler, 1937). Although initially used as a mouse model of polio, later work identified a strain of TMEV (the DA or Daniels' strain) that induced a chronic-progressive demyelinating disease in susceptible mice (Daniels et al., 1952). Further work in the 1970s suggested that Theiler's virus-induced demyelinating disease resembled human MS (Lipton, 1975; Lipton and Dal Canto, 1976a; 1976b; 1979), and numerous investigators have extended our understanding of MS using a variety of TMEV strains (Brahic 2002; Monteyne et al., 1997). After intracerebral injection of Theiler's virus, and during the first 10 to 12 days of infection, the virus replicates primarily in neurons of the hippocampus (Fig. 5), striatum, cortex, and anterior horn of the spinal cord, and then is rapidly cleared from the brain (Drescher et al., 1999). Oligodendrocytes and macrophages are also infected early (Njenga et al., 1997a).

In mice of resistant major histocompatibility complex (MHC) haplotypes (H-2b,d,k), no demyelination or viral persistence develops. However, in animals of susceptible MHC haplotypes (H-2s,q,r,v,f,p), the virus is cleared from neurons in the brain but persists in glial cells (Brahic et al., 1981; Rodriguez et al., 1983) and macrophages (Dal Canto and Lipton, 1982; Levy et al., 1992; Rossi et al., 1997) of the spinal cord white matter and brainstem (Fig. 6). This viral persistence is associated with chronic demyelination and stereotypical neurological impairment and paralysis due to the loss of axons (Drescher et al., 1997; Lipton 1975; Rodriguez and Miller, 1994) (Fig. 7). Demyelination in this model is in part mediated by a "dying-back" oligoden-

Figure 5 (A) High magnification view of a cell infected with Theiler's virus. Note the high density of dark, regularly shaped virions filling the cell. (B, C) Theiler's virus-infected neurons in the hippocampus (B) and spinal cord (C), as marked by immunostaining for viral antigens. Note the presence of viral antigen in the axons of these cells.

Figure 5 (A) High magnification view of a cell infected with Theiler's virus. Note the high density of dark, regularly shaped virions filling the cell. (B, C) Theiler's virus-infected neurons in the hippocampus (B) and spinal cord (C), as marked by immunostaining for viral antigens. Note the presence of viral antigen in the axons of these cells.

Figure 6 Immuno-electron micrograph evidence of Theiler's virus persistence in oligodendrocytes and myelin. (A) An area of demyelination in a longitudinal section, showing myelin injury and inflammatory cells. (B) Vibratome section of the region shown in (A) stained for viral antigen, demonstrating an infected oligodendrocyte ensheathing an axon. (C) Electron micrograph of cells shown in (B). Note the presence of viral antigen (electron-dense immunoperoxidase reaction product) in the inner and outer glial loops. The location of the viral antigen is consistent with the concept of "dying-back" oligodendrogliopathy. (D) Viral antigen present in the Schmidt-Lanterman clefts. The presence of labeled Schmidt-Lanterman incisures in Theiler's infected oligodendrocytes may represent an early response to virus-mediated injury.

Figure 6 Immuno-electron micrograph evidence of Theiler's virus persistence in oligodendrocytes and myelin. (A) An area of demyelination in a longitudinal section, showing myelin injury and inflammatory cells. (B) Vibratome section of the region shown in (A) stained for viral antigen, demonstrating an infected oligodendrocyte ensheathing an axon. (C) Electron micrograph of cells shown in (B). Note the presence of viral antigen (electron-dense immunoperoxidase reaction product) in the inner and outer glial loops. The location of the viral antigen is consistent with the concept of "dying-back" oligodendrogliopathy. (D) Viral antigen present in the Schmidt-Lanterman clefts. The presence of labeled Schmidt-Lanterman incisures in Theiler's infected oligodendrocytes may represent an early response to virus-mediated injury.

drogliopathy (Ludwin and Johnson, 1981) manifested by injury to the most distal extensions of the oligodendrocyte (Rodriguez, 1985).

Of the H-2 genes, it is the D locus that is of major importance for resistance vs. susceptibility. Resistance is a dominant trait that maps to H-2D, and genetic deletion or mutation of the D locus results in viral persistance and chronic demyelinating disease (Rodriguez et al., 1986). Specific introduction of H-2Db or H-2Dd genes into normally susceptible mice results in the acquisition of resistance to viral persistence (Rodriguez and David, 1995). This resistance is associated with a robust antiviral cytotoxic T-cell response that develops in the gray matter of infected C57BL6 mice (Pena Rossi et al., 1991), and immunological depletion of CD8+ T-cells or the genetic deletion of CD8+ T cells observed in p2-microglobulin knock-out mice results in viral persistence within otherwise resistant genetic backgrounds. Consistent with the genetics of resistance discussed previously, the cytotoxic T-cell response observed during the acute phase of Theiler's virus infection is restricted to the Db molecule (Lin et al., 1997). Moreover, after Theiler's virus infection of resistant mice of the H-2b haplotype, we have identified an immunodominant cyto-toxic T-cell population within the CNS that is specific for the VP2121-130 viral capsid peptide presented within the context of Db (Johnson et al., 1999). We have also previously demonstrated that cytotoxic T-cells appear to play a critical role in the injury of neurons and axons in both the acute (Howe and Rodriguez, unpublished observations) and chronic phases of Theiler's virus infection (Rivera-Quinones et al., 1998; Ure and Rodriguez, 2000; 2002).

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