Pathogenesis of Theiler's Murine Encephalomyelitis Virus

Depending on the strain, Theiler murine encephalomyelitis virus (TMEV) may cause acute encephalitis or chronic demyelinating disease, which is associated with viral persistence in mice. Persistent central nervous system infection and demyelination by the less-virulent TMEV has provided a useful animal model for the human demyelinating disease multiple sclerosis. The less-virulent BeAn strain of TMEV was crystallized and its atomic structure was determined by x-ray crystallography. The a-carbon coordinates of the closely related Mengo virus were used to calculate the initial phases to 3.5 A resolution and the interpretable electron density map was produced by 10 cycles of30-fold noncrystallographic molecular replacement averaging. The structure revealed a high degree of overall structural similarity to Mengo virus as well as substantial differences in the surface loops. These structural changes might be correlated with TMEV host-specific recognition, pH-related stability, and neurovirulence.

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“…Fig. 3 (24). Cluster B region has been indirectly shown to be a potential antigenic site and neurovirulence determinant (25).…”

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Three-dimensional structure of Theiler murine encephalomyelitis virus (BeAn strain).

Luo

Toth

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

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“…Other antibodies are poorly pathogenic when given to normal animals but significantly augment tissue injury in the presence of virus (8). Various picornaviruses, including coxsackieviruses, contain mimicking epitopes in their structural proteins to selfmolecules in the heart and other organs (8,10,11,(13)(14)(15) (22). In the present work, we used three anti-streptococcal mAbs to select new CVB3 variants which were evaluated for changes in their ability to induce myocarditis in inbred strains of mice.…”

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confidence: 99%

“…Antigenic mimicry has been demonstrated between a wide range of infectious agents and normal tissue antigens (4)(5)(6)(7)(8)(9)(10)(11), and antibodies to these crossreactive epitopes can often be obtained (7). These autoreactive antibodies frequently have variable effects on disease pathogenicity (7,8,11,12).…”

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confidence: 99%

“…Some monoclonal antibodies (mAbs) to crossreactive epitopes directly cause tissue injury in vivo (7,11). Other antibodies are poorly pathogenic when given to normal animals but significantly augment tissue injury in the presence of virus (8). Various picornaviruses, including coxsackieviruses, contain mimicking epitopes in their structural proteins to selfmolecules in the heart and other organs (8,10,11,(13)(14)(15).…”

mentioning

confidence: 99%

“…Other antibodies are poorly pathogenic when given to normal animals but significantly augment tissue injury in the presence of virus (8). Various picornaviruses, including coxsackieviruses, contain mimicking epitopes in their structural proteins to selfmolecules in the heart and other organs (8,10,11,(13)(14)(15). Cunningham et al (16) demonstrated that mAbs identifying shared epitopes between group A streptococcal M5 protein and heart antigens also possessed significant neutralizing activity to coxsackievirus group B type 3 (CVB3).…”

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Alterations in major histocompatibility complex association of myocarditis induced by coxsackievirus B3 mutants selected with monoclonal antibodies to group A streptococci.

Huber

Moraska

Cunningham

1994

Proc. Natl. Acad. Sci. U.S.A.

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Three monoclonal antibodies (mAbs), 49. Evidence increasingly implicates virus and microbial infections as triggers of autoimmune diseases (1-3). Antigenic mimicry has been demonstrated between a wide range of infectious agents and normal tissue antigens (4-11), and antibodies to these crossreactive epitopes can often be obtained (7). These autoreactive antibodies frequently have variable effects on disease pathogenicity (7,8,11,12). Some monoclonal antibodies (mAbs) to crossreactive epitopes directly cause tissue injury in vivo (7,11). Other antibodies are poorly pathogenic when given to normal animals but significantly augment tissue injury in the presence of virus (8). Various picornaviruses, including coxsackieviruses, contain mimicking epitopes in their structural proteins to selfmolecules in the heart and other organs (8,10,11,(13)(14)(15) (22). In the present work, we used three anti-streptococcal mAbs to select new CVB3 variants which were evaluated for changes in their ability to induce myocarditis in inbred strains of mice. This study demonstrates that viruses altered by antibodies to crossreactive epitopes shared between an infectious agent and host tissue can substantially shift the genetic susceptibility associations of virus-induced diseases. These epitopes may disturb the interaction between infections and the immune system, resulting in autoimmune destruction in genetically susceptible individuals.MATERIALS AND METHODS Mice. Male DBA/2, A/J, CBA/J, C57BL/Snl0J (B10), B1O.D2/nJ, B10.A, B10.A(2R), and B10.BR mice 5-7 weeks of age were purchased from Jackson Laboratories, Bar Harbor, ME.Viruses. A plaque-purified CVB3 variant (H3) was isolated as described (23). Antibody-selected variant viruses were obtained by culturing 106 plaque-forming units (pfu) of H3 virus with 100 ,g of mAb on HeLa cells. After culture for 20 hr, the HeLa cells were homogenized, mixed with 100 pg of the mAb, and added to fresh HeLa cell cultures. This process (blind passage) was repeated up to two more times until the supernatants produced >50%o lysis of HeLa cell monolayers. The new CVB3 variants designated H3-36, H3-49, and H3-54 were derived by using mAbs 36.2.2, 49.8.9 and 54.2.8, respectively, and were plaque purified (23) and purified by ultracentrifugation on sucrose gradients (24).Antibodies. Production, maintenance, and antigen specificities of murine IgM mAbs to M-type-5 Streptococcus pyogenes have been described (25,26 (25)(26)(27). A hyperimmune horse anti-CVB3 was purchased from the American Type Culture Collection. Hybridoma clones GK 1.5 (anti-L3T4), 2.43 (anti-Lyt-2.2), and 30-H12 (anti-Thy-1.2) were purchased from the American Type Culture Collection. mAbs from these clones were isolated as described (29).Organ Virus Titers and Virus Neutralization Assays. These procedures were performed as described (30).Abbreviations: CVB3, coxsackievirus B3; mAb, monoclonal antibody; MHC, major histocompatibility complex; pfu, plaque-forming unit(s). tTo whom reprint requests should be addressed. 5543The publicat...

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Altered Cell Growth and Morphology in a BHK-21 Cell Mutant That Lacks a Receptor for Theiler's Murine Encephalomyelitis Virus

2002

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The receptor for Theiler's murine encephalomyelitis virus (TMEV) remains unknown. In vitro, BHK-21 cells are permissive to infection by TMEV. Selecting mutants of BHK-21 cells produced a cell line (BHKR-) resistant to infection by TMEV. Viral persistence was ruled out by immunofluorescent staining for viral antigens. BHKR- cells were nonpermissive to infection even at high multiplicities of infection. In contrast, cells were able to support one round of virus replication when transfected with infectious TMEV RNA. Binding studies indicated that TMEV was unable to attach to these cells. These data are consistent with the BHKR- cells lacking a receptor for TMEV. Interestingly, BHKR- cells were larger in size and had a significant lag in growth after subculture versus BHK-21 cells. This suggests that the TMEV receptor on BHK-21 cells could play an important role in cell growth and morphology under physiologic conditions. BHKR- cells should facilitate the search for TMEV receptors.

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Pathogenesis of Theiler's Murine Encephalomyelitis Virus

Cited by 27 publications

References 116 publications

Three-dimensional structure of Theiler murine encephalomyelitis virus (BeAn strain).

Three-dimensional structure of Theiler murine encephalomyelitis virus (BeAn strain).

Alterations in major histocompatibility complex association of myocarditis induced by coxsackievirus B3 mutants selected with monoclonal antibodies to group A streptococci.

Altered Cell Growth and Morphology in a BHK-21 Cell Mutant That Lacks a Receptor for Theiler's Murine Encephalomyelitis Virus

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