Theiler's murine encephalomyelitis virus infection of SJL/J and C57BL/6J mice: Models for multiple sclerosis and epilepsy

DePaula-Silva, Ana Beatriz; Hanak, Tyler J.; Libbey, Jane E.; Fujinami, Robert S.

doi:10.1016/j.jneuroim.2017.02.012

Cited by 65 publications

(102 citation statements)

References 183 publications

(234 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…and have ceased by day 10 p.i. [reviewed in (DePaula-Silva et al 2017)]. Previously, immunohistochemistry was used to show the presence of TMEV antigen in hippocampal neurons on days 6 and 7 p.i.…”

Section: Resultsmentioning

confidence: 99%

The immune response to picornavirus infection and the effect of immune manipulation on acute seizures

DePaula-Silva

Sonderegger²,

Libbey

et al. 2018

J. Neurovirol.

Self Cite

View full text Add to dashboard Cite

Viral infection of the central nervous system can result in encephalitis. About 20% of individuals who develop viral encephalitis go on to develop epilepsy. We have established an experimental model where virus infection of mice with Theiler's murine encephalomyelitis virus (TMEV) leads to acute seizures, followed by a latent period (no seizures/epileptogenesis phase) and then spontaneous recurrent seizures-epilepsy. Infiltrating macrophages (CD11bCD45) present in the brain at day 3 post-infection are an important source of interleukin-6, which contributes to the development of acute seizures in the TMEV-induced seizure model. Time course analysis of viral infection and inflammatory [CD11bCD45Ly-6C] and patrolling [CD11bCD45Ly-6C] monocyte and T cell infiltration into the brains of TMEV-infected C57BL/6J mice over the entire course of the acute viral infection was performed to elucidate the role of virus and the immune response to virus in seizures and viral clearance. The infiltrating inflammatory macrophages were present early following infection but declined over the course of acute viral infection, supporting a role in seizure development, while the lymphocyte infiltration increased rapidly and plateaued, advocating that they play a role in viral clearance. In addition, we showed for the first time that, while TMEV infection of RAG1 mice did not alter the number of mice experiencing acute seizures, TMEV infection of C57BL/6J mice depleted of macrophages resulted in a significant decrease in the number of mice experiencing seizures, again supporting a role for infiltrating macrophages in the development of acute seizures in the TMEV-induced seizure model.

show abstract

Section: Resultsmentioning

confidence: 99%

The immune response to picornavirus infection and the effect of immune manipulation on acute seizures

DePaula-Silva

Sonderegger²,

Libbey

et al. 2018

J. Neurovirol.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Histological analyses of the brain were mainly focused on the dorsal hippocampus, as this brain structure is mainly damaged due to a hippocampal tropism of TMEV in B6 mice and is also associated with development of seizures and epilepsy (DePaula-Silva et al, 2017). Additionally, thalamic, hypothalamic and cortical regions were screened for morphological alterations and staining positivity.…”

Section: Histologymentioning

confidence: 99%

“…We used PLX5622 in a model of viral encephalitis in mice, in which Theiler's virus (also termed Theiler's murine encephalomyelitis virus [TMEV]), a naturally occurring enteric pathogen of the mouse, is used for intracerebral infection (Vezzani et al, 2016;DePaula-Silva et al, 2017). Disease development following TMEV infection depends on the mouse strain.…”

Section: Introductionmentioning

confidence: 99%

“…The SJL/J mouse strain develops a multiple sclerosis-like progressive T cell-mediated autoimmune demyelinating disease, characterized by weakness of the hind limbs, which advances to a severe spastic paralysis, and inflammatory demyelination in the spinal cord, while the C57BL/6J (B6) mouse strain develops hippocampal damage and acute seizures, which progress to epilepsy (DePaula-Silva et al, 2017). The striking difference between the mouse strains seems to be partially due to the strong antiviral cytotoxic CD8 + T lymphocyte response observed in B6 mice, which is suppressed by the elevated induction of regulatory CD4 + T cells (Tregs) in SJL/J mice, resulting in viral persistence and demyelination (DePaula-Silva et al, 2017). We now report that elimination of microglia strikingly changes the disease phenotype of TMEV-infected B6 mice, indicating that microglia is much more important in this model of viral encephalitis than previously thought.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Microglia have a protective role in viral encephalitis-induced seizure development and hippocampal damage

Waltl

Käufer

Gerhauser

et al. 2018

Brain, Behavior, and Immunity

113

View full text Add to dashboard Cite

In the central nervous system (CNS), innate immune surveillance is mainly coordinated by microglia. These CNS resident myeloid cells are assumed to help orchestrate the immune response against infections of the brain. However, their specific role in this process and their interactions with CNS infiltrating immune cells, such as blood-borne monocytes and T cells are only incompletely understood. The recent development of PLX5622, a specific inhibitor of colony-stimulating factor 1 receptor that depletes microglia, allows studying the role of microglia in conditions of brain injury such as viral encephalitis, the most common form of brain infection. Here we used this inhibitor in a model of viral infection-induced epilepsy, in which C57BL/6 mice are infected by a picornavirus (Theiler's murine encephalomyelitis virus) and display seizures and hippocampal damage. Our results show that microglia are required early after infection to limit virus distribution and persistence, most likely by modulating T cell activation. Microglia depletion accelerated the occurrence of seizures, exacerbated hippocampal damage, and led to neurodegeneration in the spinal cord, which is normally not observed in this mouse strain. This study enhances our understanding of the role of microglia in viral encephalitis and adds to the concept of microglia-T cell crosstalk.

show abstract

“…The neurological effects of TMEV seem to be mediated by the activation of T-lymphocytes, such as the CD8 + T-cells, rather than by a direct interaction of the virus with the myelin proteins; moreover, the permanence of the virus in the central nervous system seems to depend on the astrocyte activity that supports viral replication (67). In summary, TMEV is useful to reproduce acute or chronic/progressive phases of the disease (64,68).…”

Section: Theiler's Murine Encephalomyelitis Virusmentioning

confidence: 99%

Experimental In Vivo Models of Multiple Sclerosis: State of the Art

Palumbo

Pellegrini

2017

Multiple Sclerosis: Perspectives in Treatment and Pathogenesis

View full text Add to dashboard Cite

Abstract:Multiple sclerosis is a multifactorial and heterogeneous neurological disease; hence, several experimental animal models had to be developed to mimic the different features of human pathology. Three main classes of animal models have been developed:experimental autoimmune encephalomyelitis (EAE), cuprizone intoxication, and Theiler' s murine encephalomyelitis virus (TMEV) infection. The EAE model is the most versatile as it allows the reproduction of different patterns of multiple sclerosis; it is mostly relevant for relapsing-remitting multiple sclerosis and has allowed the development of several first-line, disease-modifying drugs for the treatment of multiple sclerosis. The other two models are less flexible than the EAE model and, to date, have not led to the discovery of any clinically relevant therapies. The cuprizone model mostly mimics the acute and chronic courses of multiple sclerosis, and it may represent a useful tool to develop novel therapies to protect oligodendrocytes and stimulate remyelination. Finally, the TMEV infection is the reference model to specifically study viral-mediated mechanisms of acute and primary progressive multiple sclerosis. In Vivo Models of Multiple Sclerosis 174

show abstract

Theiler's murine encephalomyelitis virus infection of SJL/J and C57BL/6J mice: Models for multiple sclerosis and epilepsy

Cited by 65 publications

References 183 publications

The immune response to picornavirus infection and the effect of immune manipulation on acute seizures

The immune response to picornavirus infection and the effect of immune manipulation on acute seizures

Microglia have a protective role in viral encephalitis-induced seizure development and hippocampal damage

Experimental In Vivo Models of Multiple Sclerosis: State of the Art

Contact Info

Product

Resources

About