Comparison of Theiler’s Murine Encephalomyelitis Virus Induced Spinal Cord and Peripheral Nerve Lesions Following Intracerebral and Intraspinal Infection

Hallmarks of Theiler’s murine encephalomyelitis virus (TMEV)-induced demyelinating disease (TMEV-IDD) include spinal cord (SC) inflammation, demyelination and axonal damage occurring approximately 5–8 weeks after classical intracerebral (i.c.) infection. The aim of this study was to elucidate the consequences of intraspinal (i.s.) TMEV infection and a direct comparison of classical i.c. and intraspinal infection. Swiss Jim Lambert (SJL)-mice were i.s. infected with the BeAn strain of TMEV. Clinical investigations including a scoring system and rotarod analysis were performed on a regular basis. Necropsies were performed at 3, 7, 14, 28 and 63 days post infection (dpi) following i.s. and at 4, 7, 14, 28, 56, 98, 147 and 196 dpi following i.c. infection. Serial sections of formalin-fixed, paraffin-embedded SC and peripheral nerves (PN) were investigated using hematoxylin and eosin (HE) and immunohistochemistry. I.s. infected mice developed clinical signs and a deterioration of motor coordination approximately 12 weeks earlier than i.c. infected animals. SC inflammation, demyelination and axonal damage occurred approximately 6 weeks earlier in i.s. infected animals. Interestingly, i.s. infected mice developed PN lesions, characterized by vacuolation, inflammation, demyelination and axonal damage, which was not seen following i.c. infection. The i.s. infection model offers the advantage of a significantly earlier onset of clinical signs, inflammatory and demyelinating SC lesions and additionally enables the investigation of virus-mediated PN lesions.

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Comparison of Reported Spinal Cord Lesions in Progressive Multiple Sclerosis with Theiler’s Murine Encephalomyelitis Virus Induced Demyelinating Disease

International Journal of Molecular Sciences ◽

10.3390/ijms20040989 ◽

2019 ◽

Vol 20 (4) ◽

pp. 989 ◽

Cited By ~ 4

Author(s):

Eva Leitzen ◽

Wen Jin ◽

Vanessa Herder ◽

Andreas Beineke ◽

Suliman Elmarabet ◽

...

Keyword(s):

Multiple Sclerosis ◽

Spinal Cord ◽

Axonal Degeneration ◽

Demyelinating Disease ◽

Progressive Multiple Sclerosis ◽

Axonal Damage ◽

Theiler's Murine Encephalomyelitis Virus ◽

Consistent Finding ◽

Theiler’S Murine Encephalomyelitis Virus ◽

Encephalomyelitis Virus

Background: Spinal cord (SC) lesions in Theiler’s murine encephalomyelitis virus induced demyelinating disease (TMEV-IDD) resemble important features of brain lesions in progressive multiple sclerosis (MS) including inflammation, demyelination, and axonal damage. The aim of the present study was a comparison of SC lesions in MS and TMEV-IDD focusing on spatial and temporal distribution of demyelination, inflammation, SC atrophy (SCA), and axonal degeneration/loss in major descending motor pathways. Methods: TMEV and mock-infected mice were investigated clinically once a week. SC tissue was collected at 42, 98, 147, and 196 days post infection, and investigated using hematoxylin and eosin (HE) staining, immunohistochemistry targeting myelin basic protein (demyelination), Mac3 (microglia/macrophages), phosphorylated neurofilaments (axonal damage) and transmission electron microscopy. Results: Demyelination prevailed in SC white matter in TMEV-IDD, contrasting a predominant gray matter involvement in MS. TMEV-infected mice revealed a significant loss of axons similar to MS. Ultrastructural analysis in TMEV-IDD revealed denuded axons, degenerative myelin changes, axonal degeneration, as well as remyelination. SCA is a consistent finding in the SC of MS patients and was also detected at a late time point in TMEV-IDD. Conclusion: This comparative study further indicates the suitability of TMEV-IDD as animal model also for the investigation of progressive SC lesions in MS.

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A hybrid between a resistant and a susceptible strain of mouse alters the pattern of Theiler's murine encephalomyelitis virus-induced white matter disease and favors oligodendrocyte-mediated remyelination

Multiple Sclerosis Journal ◽

10.1177/135245859500100207 ◽

1995 ◽

Vol 1 (2) ◽

pp. 95-103 ◽

Cited By ~ 3

Author(s):

MC Dal Canto ◽

RW Melvold ◽

BS Kim

Keyword(s):

Spinal Cord ◽

Demyelinating Disease ◽

Phenotypic Expression ◽

Theiler's Murine Encephalomyelitis Virus ◽

Pathological Lesions ◽

Theiler’S Murine Encephalomyelitis Virus ◽

Encephalomyelitis Virus ◽

Resistant Strains ◽

The Relationship ◽

Myelin Injury

Theiler's murine encephalomyelitis virus (TMEV) produces a chronic disease in its natural host, the mouse, characterised by primary inflammatory demyelination of the spinal cord. This viral infection is considered a very good model for human MS because the pathogenesis of myelin injury is mediated through the host immune response. Susceptibility and/or resistance to the demyelinating disease depend on multiple genes both in and outside the major histocompatibility complex (MHC). The pathological lesions in animals with different degrees of susceptibility vary in both their severity and in their ability to become remyelinated. In general, animals with intermediate levels of susceptibility show the best potential for remyelination. Most crosses of susceptible animals with resistant strains carrying the H-2b haplotype are resistant with only a couple of exceptions. One such exception is the (SJL/J × C57L/J)Fl hybrid, which is susceptible to the disease. To study whether the resistant genotype of C57L/J mice could modify the phenotypic expression of pathological lesions characteristic of the highly susceptible SJL/J mouse, we performed a light microscopical and ultrastructural study of the spinal cord of both parental strains and their Flprogeny. We focused particularly on the relationship between severity of inflammation, and especially macrophage infiltration, and the subsequent remyelinating potential of lesions. The results show a dramatic difference between the ability to remyelinate lesions by infected SJL/J mice vs similarly infected (SJL/L × C57L/J)Fl hybrids, and suggest an important influence by resistant genes in modulating the phenotypic expression of disease, including the ability to stimulate oligodendroglia-mediated remyelination.

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DNA Vaccination against Theiler’s Murine Encephalomyelitis Virus Leads to Alterations in Demyelinating Disease

Journal of Virology ◽

10.1128/jvi.73.2.993-1000.1999 ◽

1999 ◽

Vol 73 (2) ◽

pp. 993-1000 ◽

Cited By ~ 17

Author(s):

Neal D. Tolley ◽

Ikuo Tsunoda ◽

Robert S. Fujinami

Keyword(s):

Demyelinating Disease ◽

Clinical Symptoms ◽

Clinical Signs ◽

Dna Vaccination ◽

Model Systems ◽

Expression Vectors ◽

Virus Infections ◽

Theiler's Murine Encephalomyelitis Virus ◽

Theiler’S Murine Encephalomyelitis Virus ◽

Encephalomyelitis Virus

ABSTRACT Although the etiology of multiple sclerosis (MS) is not known, several factors play a role in this disease: genetic contributions, immunologic elements, and environmental factors. Viruses and virus infections have been associated with the initiation and/or enhancement of exacerbations in MS. Theiler’s murine encephalomyelitis virus (TMEV) infection of mice is one of the animal models used to mimic MS. In other animal model systems, DNA vaccination has been used to protect animals against a variety of virus infections. To explore the utility of DNA vaccination, we have constructed eukaryotic expression vectors encoding the TMEV capsid proteins VP1, VP2, and VP3. SJL/J mice were vaccinated intramuscularly once, twice, or three times with the different capsid protein cDNAs. This was followed by intracerebral TMEV infection to determine the effects of DNA vaccination on the course of TMEV-induced central nervous system (CNS) demyelinating disease. We found that vaccination of mice three times with cDNA encoding VP2 led to partial protection of mice from CNS demyelinating disease as determined by a decrease in clinical symptoms and histopathology. Vaccination of mice with cDNA encoding VP3 also led to a decrease in clinical symptoms. In contrast, mice vaccinated with cDNA encoding VP1 experienced a more severe disease with an earlier onset of clinical signs and enhanced histopathology compared with control mice. There was no correlation between anti-TMEV antibody titers and disease course. These results indicate that DNA immunization can modify chronic virus-induced demyelinating disease and may eventually lead to potential treatments for illnesses such as MS.

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