Virus-triggered spinal cord demyelination is followed by a peripheral neuropathy resembling features of Guillain-Barr\xe9 Syndrome

Eva Leitzen,Sandra Goebbels,Florian Hansmann,Barbara B Raddatz,Klaus-Armin Nave,Wolfgang Baumgärtner,Wen Jin

doi:10.1038/s41598-019-40964-1

Abstract

Theiler’s murine encephalomyelitis virus (TMEV)-induces a demyelinating disease in the spinal cord (SC) of susceptible but not in resistant (B6) mouse strains. The aim of the present study was to induce SC demyelination and a peripheral neuropathy in resistant mice by switching the infection site from cerebrum to SC. B6 mice were intraspinally inoculated with TMEV. Infected mice showed clinical signs starting at 7 days post infection (dpi). Histopathology revealed a mononuclear myelitis, centred on the injection site at 3 dpi with subsequent antero- and retrograde spread, accompanied by demyelination and axonal damage within the SC. Virus protein was detected in the SC at all time points. SC inflammation decreased until the end of the investigation period (28 dpi). Concurrent with the amelioration of SC inflammation, the emergence of a peripheral neuropathy, characterized by axonal damage, demyelination and macrophage infiltration, contributing to persistent clinical sings, was observed. Intraspinal TMEV infection of resistant mice induced inflammation, demyelination and delayed viral clearance in the spinal cord and more interestingly, subsequent, virus-triggered inflammation and degeneration within the PN associated with dramatic and progressive clinical signs. The lesions observed in the PN resemble important features of Guillain-Barré syndrome, especially of acute motor/motor-sensory axonal forms.

Highlights

Theiler’s murine encephalomyelitis virus (TMEV) was firstly described as a neuropathogenic virus and causative agent of Theiler’s murine encephalitis (TME) in the 1930s by Max Theiler[1,2]
Significant differences regarding the immune response and glial cell reaction within brain and spinal cord exist which are attributed to various factors including differences between blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) as well as different reaction patterns of microglia/macrophages[19–22]
The hypothesis of the present study is that direct intraspinal (i.s.) TMEV infection of resistant B6 mice will lead to demyelination in the SC as a result of a more pronounced inflammatory response compared to intracerebral infection

Summary

Introduction

Theiler’s murine encephalomyelitis virus (TMEV) was firstly described as a neuropathogenic virus and causative agent of Theiler’s murine encephalitis (TME) in the 1930s by Max Theiler[1,2]. Genetic factors contributing to resistance of B6 mice to the development of TMEV-induced demyelinating disease are well known including a more efficient antiviral immune response[12–15]. In this context, numerous studies describe a compartmentalization of the immune response between CNS and periphery during infectious as well as inflammatory diseases[16–18]. The hypothesis of the present study is that direct intraspinal (i.s.) TMEV infection of resistant B6 mice will lead to demyelination in the SC as a result of a more pronounced inflammatory response compared to intracerebral infection This would provide a reproducible mouse model to study virus-induced de- and remyelination at early time points mimicking lesions in susceptible mice during the late phase of TME. The aims of this study were (1) to investigate TMEV-induced de- and remyelination in the SC of a resistant mouse strain, (2) to test the hypothesis of TMEV being capable of spreading to the PNS as well as (3) inducing a peripheral neuropathy after i.s. infection

Objectives

Methods

Results

Discussion

Conclusion