Theiler's Murine Encephalomyelitis Virus (theiler + murine_encephalomyelitis_virus)

Distribution by Scientific Domains

Selected Abstracts

Structural requirements for initiation of cross-reactivity and CNS autoimmunity with a PLP139,151 mimic peptide derived from murine hepatitis virus

Ludovic Croxford
Abstract MS is an autoimmune CNS demyelinating disease in which infection appears to be an important pathogenic factor. Molecular mimicry, the cross-activation of autoreactive T cells by mimic peptides from infectious agents, is a possible explanation for infection-induced autoimmunity. Infection of mice with a non-pathogenic strain of Theiler's murine encephalomyelitis virus (TMEV) engineered to express an epitope from Haemophilus influenzae (HI) sharing 6/13 amino acids with the dominant proteolipid protein (PLP) epitope, PLP139,151, can induce CNS autoimmune disease. Here we demonstrate that another PLP139,151 mimic sequence derived from murine hepatitis virus (MHV) which shares only 3/13 amino acids with PLP139,151 can also induce CNS autoimmune disease, but only when delivered by genetically engineered TMEV, not by immunization with the MHV peptide. Further, we demonstrate the importance of proline at the secondary MHC class,II contact residue for effective cross-reactivity, as addition of this amino acid to the native MHV sequence increases its ability to cross-activate PLP139,151 -specific autoreactive T cells, while substitution of proline in the HI mimic peptide has the opposite effect. This study describes a structural requirement for potential PLP139,151 mimic peptides, and provides further evidence for infection-induced molecular mimicry in the pathogenesis of autoimmune disease. [source]

Replication of Theiler's virus requires NF-,B-activation: Higher viral replication and spreading in astrocytes from susceptible mice

GLIA, Issue 9 2008
Min Hyung Kang
Abstract To investigate viral replication and cell,cell spreading in astrocytes, recombinant Theiler's murine encephalomyelitis virus (TMEV) expressing green fluorescent protein (GFP) during the replication was generated. GFP and TMEV proteins were processed correctly in infected cells and production of viral proteins could be tracked by fluorescent microscopy. Viral replication of both wild-type TMEV and GFP-TMEV was dependent on the activation of NF-,B and partially MAP kinase, based on chemical inhibition studies. Viral replication was significantly reduced in primary astrocytes from NF-,B1 (p105)-deficient mice compared with that from wild-type control mice, whereas cytokine production was enhanced. These results suggest an association of canonical NF-,B subunits in viral replication, but not cytokine production. Viral replication was also suppressed in both IKK, and IKK,-deficient mouse embryonic fibroblasts (MEFs), compared with that in wild-type MEF. However, the inhibition was significantly greater in IKK,-deficient MEF, suggesting that IKK, plays a stronger role in supporting viral replication. Interestingly, viral replication and spreading in primary astrocytes from susceptible SJL/J mice were several-fold higher than those in astrocytes from resistant C57BL/6 mice, suggesting that higher viral replication levels in astrocytes may also contribute to the viral persistence in the central nervous system (CNS) of susceptible SJL/J mice. A relatively higher level of activated NF-,B was found in the nuclei of virus-infected SJL astrocytes compared with C57BL/6 astrocytes suggest that the NF-,B activation level affects on viral replication. 2008 Wiley-Liss, Inc. [source]

Distinct roles of protein kinase R and toll-like receptor 3 in the activation of astrocytes by viral stimuli

GLIA, Issue 3 2007
Pamela A. Carpentier
Abstract Impaired immune surveillance and constitutive immunosuppressive properties make the central nervous system (CNS) a particular challenge to immune defense, and require that CNS-resident cells be capable of rapidly recognizing and responding to infection. We have previously shown that astrocytes respond to treatment with a TLR3 ligand, poly I:C, with the upregulation of innate immune functions. In the current study, we examine the activation of innate immune functions of astrocytes by Theiler's murine encephalomyelitis virus (TMEV), a picornavirus, which establishes a persistent infection in the CNS of susceptible strains of mice and leads to the development of an autoimmune demyelinating disease that resembles human multiple sclerosis. Astrocytes infected with TMEV are activated to produce type I interferons, the cytokine IL-6, and chemokines CCL2 and CXCL10. We further examined the mechanisms that are responsible for the activation of astrocytes in response to direct viral infection and treatment with poly I:C. We found that the cytoplasmic dsRNA-activated kinase PKR is important for innate immune responses to TMEV infection, but has no role in their induction by poly I:C delivered extracellularly. In contrast, we found that TLR3 has only a minor role in responses to TMEV infection, but is important for responses to poly I:C. These results highlight the differences between responses induced by direct, nonlytic virus infection and extracellular poly I:C. The activation of astrocytes through these different pathways has implications for the initiation and progression of viral encephalitis and demyelinating diseases such as multiple sclerosis. 2006 Wiley-Liss, Inc. [source]

Interleukin-4 and interleukin-10 modulate nuclear factor ,B activity and nitric oxide synthase-2 expression in Theiler's virus-infected brain astrocytes

Eduardo Molina-Holgado
Abstract In brain astrocytes, nuclear factor ,B (NF-,B) is activated by stimuli that produce cellular stress causing the expression of genes involved in defence, including the inducible nitric oxide synthase (NOS-2). Theiler's murine encephalomyelitis virus (TMEV) induces a persistent CNS infection and chronic immune-mediated demyelination, similar to human multiple sclerosis. The cytokines interleukin (IL)-4 and IL-10 inhibit the expression of proinflammatory cytokines, counteracting the inflammatory process. Our study reports that infection of cultured astrocytes with TMEV resulted in a time-dependent phosphorylation of I,B,, degradation of I,B, and I,B,, activation of NF-,B and expression of NOS-2. The proteasome inhibitor MG-132 blocked TMEV-induced nitrite accumulation, NOS-2 mRNA expression and phospho-I,B, degradation, suggesting NF-,B-dependent NOS-2 expression. Pretreatment of astrocytes with IL-4 or IL-10 decreased p65 nuclear translocation, NF-,B binding activity and NOS-2 transcription. IL-4 and IL-10 caused an accumulation of I,B, in TMEV-infected astrocytes without affecting I,B, levels. The I,B kinase activity and the degradation rate of both I,Bs were not modified by either cytokine, suggesting de novo synthesis of I,B,. Indeed, IL-4 or IL-10 up-regulated I,B, mRNA levels after TMEV infection. Therefore, the accumulation of I,B, might impair the translocation of the NF-,B to the nucleus, mediating the inhibition of NF-,B activity. Overall, these data suggest a novel mechanism of action of IL-4 and IL-10, which abrogates NOS-2 expression in viral-infected glial cells. [source]

CD40L is Critical for Protection from Demyelinating Disease and Development of Spontaneous Remyelination in a Mouse Model of Multiple Sclerosis

Kristen M. Drescher
Theiler's murine encephalomyelitis virus (TMEV) induces acute neuronal disease followed by chronic demyelination in susceptible strains of mice. In this study we examined the role of a limited immune defect (deletion or blocking of CD40 ligand [CD40L]) on the extent of brain disease, susceptibility to demyelination, and the ability of demyelinated mice to spontaneously remyelinate following TMEV infection. We demonstrated that CD40L-dependent immune responses participate in pathogenesis in the cerebellum and the spinal cord white matter but protect the striatum of susceptible SJL/J mice. In mice on a background resistant to TMEV-induced demyelination (C57BL/6), the lack of CD40L resulted in increased striatal disease and meningeal inflammation. In addition, CD40L was required to maintain resistance to demyelination and clinical deficits in H-2b mice. CD40L-mediated interactions were also necessary for development of protective H-2b -restricted cytotoxic T cell responses directed against the VP2 region of TMEV as well as for spontaneous remyelination of the spinal cord white matter. The data presented here demonstrated the critical role of this molecule in both antibody- and cell-mediated protective immune responses in distinct phases of TMEV-mediated pathology. [source]

Pathogenesis of Theiler's murine encephalomyelitis virus-induced disease

Raymond P. Roos
Abstract Theiler's murine encephalomyelitis virus (TMEV) is a member of the Cardiovirus genus of the Picornaviridae family. Interest in TMEV is at least partly related to the fact that the Daniels (DA) strain and other members of Theiler's original (TO) subgroup induce an inflammatory demyelinating disease in which the virus persists for the life of the mouse. This disease resembles multiple sclerosis because of the similar pathology and because the immune system seems to play an important role in both. The present review describes features of TMEV and the importance of both virus persistence as well as the immune system in the pathogenesis of DA virus-induced demyelinating disease. (Clin. Exp. Neuroimmunol. doi: 10.1111/j.1759-1961.2010.00008.x, 2010) [source]