Chapter 26 : Theiler’s Virus Central Nervous System Infection

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The genus is divided into two species: the species, which includes encephalomyocarditis virus (EMCV) and mengovirus, and the species, which includes Theiler’s murine encephalomyelitis virus (TMEV), Vilyuisk human encephalomyelitis virus (VHEV), and Saffold virus (SAFV). This chapter discusses members of the genus and distinctive characteristics of these viruses. It focuses on the pathogenesis of TMEV-induced disease because of the extensive investigations of this topic as well as the remarkable ability of this virus to establish lifelong infection of the central nervous system (CNS) and to produce an immune-mediated demyelinating disease. There are many features of cardioviruses, and especially TMEV, that make them attractive for pathogenesis studies, including the following: the unusual and rather unique characteristics of TMEV strains and TMEV-induced diseases (neurovirulent versus persistent strains, acute versus chronic disease, virus-induced versus immune-mediated pathology); the ability of some strains to persist in the host in the absence of latency or genome integration; the substantial knowledge concerning cardioviruses along with powerful tools for their study; the experimental model system of TMEV (and EMCV) infection in the mouse, which is the virus’ natural host. The recent identification of SAFV infection as a frequent one in humans has focused attention on whether this virus causes disease in humans. Furthermore, the identification of the human SAFV indicates that efforts investigating the involvement of cardioviruses as a cause of Vilyuisk encephalomyelitis should be renewed.

Citation: Michiels T, Roos R. 2010. Theiler’s Virus Central Nervous System Infection, p 411-428. In Ehrenfeld E, Domingo E, Roos R (ed), The Picornaviruses. ASM Press, Washington, DC. doi: 10.1128/9781555816698.ch26
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Image of Figure 1.
Figure 1.

Phylogenetic tree of the P1 capsid coding sequences of the genus. Three of the eight lineages of SAFV are shown. Note: sequences closest to SAFV isolates are those of TRV; VHEV is phylogenetically related to TMEV strains. (The figure was kindly provided by Nick Knowles.)

Citation: Michiels T, Roos R. 2010. Theiler’s Virus Central Nervous System Infection, p 411-428. In Ehrenfeld E, Domingo E, Roos R (ed), The Picornaviruses. ASM Press, Washington, DC. doi: 10.1128/9781555816698.ch26
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Image of Figure 2.
Figure 2.

Schematic representation of genomes of representative cardioviruses EMCV, SAFV, and TMEV. Features that differ from the prototypic poliovirus are outlined: structures of the 5′ and 3′ NCRs, CRE in the VP2 region, L, and protein 2A promoting a “ribosomal skip” and hence primary cleavage of the polyprotein at the NPG/P sequence of the 2A-2B boundary. Note that EMCV has a poly(C) tract in the 5′ NCR. TMEV (but not SAFV) encodes the L* protein from an ORF that overlaps the L, VP2, and VP4 coding regions.

Citation: Michiels T, Roos R. 2010. Theiler’s Virus Central Nervous System Infection, p 411-428. In Ehrenfeld E, Domingo E, Roos R (ed), The Picornaviruses. ASM Press, Washington, DC. doi: 10.1128/9781555816698.ch26
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Image of Figure 3.
Figure 3.

Alignment of predicted L protein sequences from EMCV (mengovirus), SAFV, TMEV (the neurovirulent GDVII strain), and TMEV (the persistent DA strain). The domains identified in the sequence are indicated. The boxed Y and T residues in the mengovirus sequence show putative phosphorylation sites.

Citation: Michiels T, Roos R. 2010. Theiler’s Virus Central Nervous System Infection, p 411-428. In Ehrenfeld E, Domingo E, Roos R (ed), The Picornaviruses. ASM Press, Washington, DC. doi: 10.1128/9781555816698.ch26
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Image of Figure 4.
Figure 4.

Trafficking and persistence of TMEV in the CNS. Cell-to-cell trafficking of the virus between neurons and oligoden-drocytes may represent a novel strategy to escape local CTL responses as well as neutralization by antibodies. (1) Infection of neuron; (2) slow replication in neurons and axonal transport; (3) noncytolytic passage from neuron to myelin; (4) trafficking through cytoplasmic channels within oligodendrocytes; (5) passage from myelin to neuron (which can be remote from the previously infected neuron); (6) some infected oligodendrocytes release viral particles; (7) infection of macrophages (with a constant infiltration of macrophages from peripheral monocytes). BBB, blood-brain barrier.

Citation: Michiels T, Roos R. 2010. Theiler’s Virus Central Nervous System Infection, p 411-428. In Ehrenfeld E, Domingo E, Roos R (ed), The Picornaviruses. ASM Press, Washington, DC. doi: 10.1128/9781555816698.ch26
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Table 1.

Functions of L, L*, and 2A nonstructural proteins of TMEV and EMCV

Citation: Michiels T, Roos R. 2010. Theiler’s Virus Central Nervous System Infection, p 411-428. In Ehrenfeld E, Domingo E, Roos R (ed), The Picornaviruses. ASM Press, Washington, DC. doi: 10.1128/9781555816698.ch26
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Table 2.

Effectors of the TMEV immune response and demyelination

Citation: Michiels T, Roos R. 2010. Theiler’s Virus Central Nervous System Infection, p 411-428. In Ehrenfeld E, Domingo E, Roos R (ed), The Picornaviruses. ASM Press, Washington, DC. doi: 10.1128/9781555816698.ch26

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