Demyelinating lesions due to Theiler's virus are associated with ongoing central nervous system infection

Chamorro, M; Aubert, C; Brahic, Michel

doi:10.1128/jvi.57.3.992-997.1986

Cited by 84 publications

(32 citation statements)

References 12 publications

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“…TMEV-induced demyelinating disease (TMEV-IDD) is a relevant model for human multiple sclerosis (MS) because many of the clinical symptoms and pathologic correlates are similar, including CD4 + T cell and mononuclear phagocyte infiltration into the CNS, primary demyelination and spastic hindlimb paralysis (Dal Canto and Lipton, 1975;Hafler, 2004;Lipton, 1975). In contrast, resistant mice are able to efficiently clear TMEV from the CNS and do not progress to demyelinating disease (Chamorro et al, 1986).…”

Section: Introductionmentioning

confidence: 99%

Pro-inflammatory functions of astrocytes correlate with viral clearance and strain-dependent protection from TMEV-induced demyelinating disease

2008

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Intracerebral infection of susceptible strains of mice, e.g. SJL/J, with Theiler's murine encephalomyelitis virus (TMEV) leads to a persistent CNS infection accompanied by development of a chronic-progressive inflammatory CNS autoimmune demyelinating disease which is clinically and pathologically similar to human multiple sclerosis. In contrast, resistant strains of mice, e.g. C57BL/6 (B6), effectively clear TMEV from the CNS and do not develop demyelinating disease. Although CD8(+) T cells are crucial for viral clearance in B6 mice, SJL mice also mount potent CD8(+) T cell responses against virus, thus the reason for the viral persistence in the CNS in these mice is unclear. Here, we examined innate anti-viral responses of CNS-resident astrocytes as a potential determinant of viral persistence and disease susceptibility. We demonstrate that B6 astrocytes produce significantly higher levels of cytokines, chemokines and adhesion molecules in response to TMEV infection, or stimulation with IFN-gamma and TNF-alpha or poly I:C than SJL mice. In addition, TMEV more effectively induces MHC I molecules on B6 astrocytes than SJL, corresponding with an increased ability to activate TMEV-specific CD8(+) T cells directly ex vivo. These results suggest that enhanced anti-viral responses of B6 astrocytes contribute to the ability of these mice to clear TMEV from the CNS and therefore to their resistance to the development of autoimmune demyelinating disease.

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Section: Introductionmentioning

confidence: 99%

Pro-inflammatory functions of astrocytes correlate with viral clearance and strain-dependent protection from TMEV-induced demyelinating disease

2008

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“…In the second group, different viruses can infect glial cells and cause CNS demyelination. Among the RNA viruses, a mouse picornavirus causes demyelination during Theiler's murine encephalomyelitis (Aubert et al, 1987;Chamorro et al, 1986;Lipton and Dal Canto, 1976). In this model, virus persists at the sites of the lesions although at low levels, and infected cells appear to survive for prolonged periods of time.…”

Section: Introductionmentioning

confidence: 99%

Expression of viral and myelin gene transcripts in a murine CNS demyelinating disease caused by a coronavirus

Jordan

Friedrich

Godfraind

et al. 1989

Glia

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C57BI/6N mice develop a CNS demyelinating disease when inoculated intracranially at 4 weeks of age with the A59 strain of mouse hepatitis virus (MHV-A59). In order to explore the virus-host interactions, the histological features of the demyelinating disease were correlated with the spatial and temporal distribution of viral transcripts and the expression of oligodendrocyte-specific genes (myelin basic protein, proteolipid protein, myelin-associated glycoprotein, and 2',3' cyclic nucleotide 3'-phosphohydrolase) in the spinal cord of diseased mice. Three distinct phases in the disease were identified. In the first phase, 1 week postinfection (1 WPI), virus replication was widespread in both gray and white matter but was preferentially occurring in glial cells. In the ventral and dorsal root zones where viral transcripts were most abundant, all myelin gene transcripts were decreased before demyelination was seen. During the second phase of the disease (2-3 WPI), viral transcripts decreased in abundance and became restricted to the white matter. Numerous demyelinating lesions were observed and were characterized by inflammatory cells, paucity of oligodendrocytes, and a profound decrease of all myelin gene transcripts. In the third phase of the disease (4-6 WPI) no viral transcripts were detected, and remyelination began. In the lesions and the tissue surrounding them, transcripts of all myelin genes increased to levels above normal. The increased expression of myelin gene transcripts occurred in a synchronized manner and with a cellular distribution reminiscent of that seen in developmental myelination. These molecular events correlated with efficient remyelination and clinical recovery in this murine demyelinating disease.

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“…Infected C57BL/6 mice do develop an acute disease, and have the ability to clear the virus. These mice do not go on to develop the late disease (Lipton & Dal Canto, 1979; Chamorro et al., 1986; Lindsley & Rodriguez, 1989; Pena‐Rossi et al., 1991). We previously reported that more than 50% of C57BL/6 mice infected with TMEV develop acute seizures between days 3 and 10 p.i.…”

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confidence: 99%

Innate but not adaptive immune responses contribute to behavioral seizures following viral infection

Kirkman¹,

Libbey²,

et al. 2010

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Summary Purpose: To examine the role of innate immunity in a novel viral infection–induced seizure model. Methods: C57BL/6 mice, mouse strains deficient in interleukin (IL)‐1RI, IL‐6, tumor necrosis factor (TNF)‐RI, or myeloid differentiation primary response gene 88 (MyD88), or transgenic mice (OT‐I) were infected with Theiler’s murine encephalomyelitis virus (TMEV) or were mock infected. Mice were followed for acute seizures. Tissues were examined for neuron loss, the presence of virus (viral RNA and antigen), perivascular cuffs, macrophages/microglia, and gliosis, and mRNA expression of IL‐1, TNF‐α, and IL‐6. Results: IL‐1 does not play a major role in seizures, as IL‐1RI‐ and MyD88‐deficient mice displayed a comparable seizure frequency relative to controls. In contrast, TNF‐α and IL‐6 appear to be important in the development of seizures, as only 10% and 15% of TNF‐RI‐ and IL‐6‐deficient mice, respectively, showed signs of seizure activity. TNF‐α and IL‐6 mRNA levels also increased in mice with seizures. Inflammation (perivascular cuffs, macrophages/microglia, and gliosis) was greater in mice with seizures. OT‐I mice (virus persists) had a seizure rate that was comparable to controls (no viral persistence), thereby discounting a role for TMEV‐specific T cells in seizures. Discussion: We have implicated the innate immune response to viral infection, specifically TNF‐α and IL‐6, and concomitant inflammatory changes in the brain as contributing to the development of acute seizures. This model is a potential infection‐driven model of mesial temporal lobe epilepsy with hippocampal sclerosis.

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Demyelinating lesions due to Theiler's virus are associated with ongoing central nervous system infection

Cited by 84 publications

References 12 publications

Pro-inflammatory functions of astrocytes correlate with viral clearance and strain-dependent protection from TMEV-induced demyelinating disease

Pro-inflammatory functions of astrocytes correlate with viral clearance and strain-dependent protection from TMEV-induced demyelinating disease

Expression of viral and myelin gene transcripts in a murine CNS demyelinating disease caused by a coronavirus

Innate but not adaptive immune responses contribute to behavioral seizures following viral infection

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