scholarly journals A Protein Critical for a Theiler’s Virus-Induced Immune System-Mediated Demyelinating Disease Has a Cell Type-Specific Antiapoptotic Effect and a Key Role in Virus Persistence

1998 ◽  
Vol 72 (11) ◽  
pp. 8605-8612 ◽  
Author(s):  
Ghanashyam D. Ghadge ◽  
Li Ma ◽  
Shigeru Sato ◽  
Jong Kim ◽  
Raymond P. Roos
Keyword(s):  
Immune System ◽  
Demyelinating Disease ◽  
Central Nervous System Infection ◽  
Inflammatory Cells ◽  
Virus Persistence ◽  
Reading Frame ◽  
Virus Clearance ◽  
Encephalomyelitis Virus ◽  
A Cell ◽  
Apoptotic Activity

ABSTRACT TO subgroup strains of Theiler’s murine encephalomyelitis virus (TMEV) induce a persistent central nervous system infection and demyelinating disease in mice. This disease serves as an experimental model of multiple sclerosis (MS) because the two diseases have similar inflammatory white matter pathologies and because the immune system appears to mediate demyelination in both processes. We previously reported (H. H. Chen, W. P. Wong, L. Zhang, P. L. Ward, and R. P. Roos, Nat. Med. 1:927–931, 1995) that TO subgroup strains use an alternative initiation codon (in addition to the AUG used to synthesize the picornavirus polyprotein from one long open reading frame) to translate L*, a novel protein that is out of frame with the polyprotein and which plays a key role in the demyelinating disease. We now demonstrate that L* has antiapoptotic activity in macrophage cells and is critical for virus persistence. The antiapoptotic action of L* as well as the differential translation of L* and virion capsid proteins may foster virus persistence in macrophages and interfere with virus clearance. The regulation of apoptotic activity in inflammatory cells may be important in the pathogenesis of TMEV-induced demyelinating disease as well as MS.

Chromosome 14 Contains Determinants That Regulate Susceptibility to Theiler's Virus–Induced Demyelination in the Mouse

Genetics ◽  
1998 ◽  
Vol 148 (4) ◽  
pp. 1941-1949
Author(s):  
J-F Bureau ◽  
K M Drescher ◽  
L R Pease ◽  
T Vikoren ◽  
M Delcroix ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Major Histocompatibility Complex ◽  
Linkage Analysis ◽  
Demyelinating Disease ◽  
Theiler's Virus ◽  
Chromosome 14 ◽  
Virus Persistence ◽  
Histocompatibility Complex ◽  
Encephalomyelitis Virus ◽  
Two Peaks

Abstract Theiler's murine encephalomyelitis virus causes a chronic demyelinating disease in susceptible strains of mice that is similar to human multiple sclerosis. Several nonmajor histocompatibility complex–linked genes have been implicated as determinants of susceptibility or resistance to either demyelination or virus persistence. In this study, we used linkage analysis of major histocompatibility complex identical H-2d (DBA/2J × B10.D2) F2 intercross mice to identify loci associated with susceptibility to virus-induced demyelinating disease. In a 20-cM region on chromosome 14, we identified four markers, D14Mit54, D14Mit60, D14Mit61, and D14Mit90 that are significantly associated with demyelination. Because two peaks were identified, one near D14Mit54 and one near D14Mit90, it is possible that two loci in this region are involved in controlling demyelination.

scholarly journals Primary demyelination as a nonspecific consequence of a cell-mediated immune reaction.

1975 ◽  
Vol 141 (2) ◽  
pp. 346-359 ◽  
Author(s):  
H M Wisniewski ◽  
B R Bloom
Keyword(s):  
Mononuclear Cells ◽  
Demyelinating Disease ◽  
Inflammatory Cells ◽  
Polymorphonuclear Cells ◽  
Inflammatory Reactions ◽  
Purified Protein Derivative ◽  
Primary Demyelination ◽  
Tissue Antigens ◽  
A Cell ◽  
Constant Feature

Primary demyelination occurs in a variety of human and experimental diseases known to be associated with the presence of inflammatory cells. However, the mechanism of demyelination remains unclear. The possibility that myelin can be damaged as a nonspecific consequence of a specific delayed type of hypersensitivity reaction directed at nonnervous tissue antigens was investigated. Guinea pigs were sensitized to tuberculin with Freund's complete adjuvant, and were challenged in the central and peripheral nervous system either with live or killed sonicated tubercle bacilli, Old Tuberculin, or tuberculin purified protein derivative (PPD). Local inflammatory reactions were invariably produced and primary demyelination was a constant feature of the lesions. The morphological picture was rather similar to that observed in human neurotuberculosis and early tuberculoid leprosy, and in experimental allergic encephalomyelitis and distemper encephalitis in animals. The infiltrates consisted predominantly of mononuclear cells with some polymorphonuclear cells as well. Vesicular disruption of the myelin sheath in the immediate vicinity of the inflammatory cells and stripping of the myelin lamellae by the histiocytes without axonal damage were the leading features of the lesion. The results indicate that cell-mediated immune reactions to a variety of nonbrain antigens could be responsible for a component of the demyelination seen in some inflammatory demyelinating conditions, and suggest that this system may serve as a useful model for studying the immunopathology of demyelinating disease.

scholarly journals Virus Persistence in an Animal Model of Multiple Sclerosis Requires Virion Attachment to Sialic Acid Coreceptors

2004 ◽  
Vol 78 (16) ◽  
pp. 8860-8867 ◽  
Author(s):  
A. S. Manoj Kumar ◽  
Honey V. Reddi ◽  
Aisha Y. Kung ◽  
Mauro Dal Canto ◽  
Howard L. Lipton
Keyword(s):  
Multiple Sclerosis ◽  
Animal Model ◽  
Sialic Acid ◽  
Demyelinating Disease ◽  
Direct Role ◽  
Virus Persistence ◽  
Sialic Acid Binding ◽  
Relevant Animal Model ◽  
Encephalomyelitis Virus ◽  
The Central Nervous System

ABSTRACT Persistent Theiler's virus infection in the central nervous system (CNS) of mice provides a highly relevant animal model for multiple sclerosis. The low-neurovirulence DA strain uses sialic acid as a coreceptor for cell binding before establishing infection. During adaptation of DA virus to growth in sialic acid-deficient cells, three amino acid substitutions (G1100D, T1081I, and T3182A) in the capsid arose, and the virus no longer used sialic acid as a coreceptor. The adapted virus retained acute CNS virulence, but its persistence in the CNS, white matter inflammation, and demyelination were largely abrogated. Infection of murine macrophage but not oligodendrocyte cultures with the adapted virus was also significantly reduced. Substitution of G1100D in an infectious DA virus cDNA clone demonstrated a major role for this mutation in loss of sialic acid binding and CNS persistence. These data indicate a direct role for sialic acid binding in Theiler's murine encephalomyelitis virus persistence and chronic demyelinating disease.

scholarly journals Theiler's Murine Encephalomyelitis Virus L* Amino Acid Position 93 Is Important for Virus Persistence and Virus-Induced Demyelination

2009 ◽  
Vol 84 (3) ◽  
pp. 1348-1354 ◽  
Author(s):  
Spyridon Stavrou ◽  
Gleb Baida ◽  
Ekaterina Viktorova ◽  
Ghanashyam Ghadge ◽  
Vadim I. Agol ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Sequence ◽  
Demyelinating Disease ◽  
Infectious Clone ◽  
Central Nervous System Infection ◽  
Mutant Virus ◽  
Full Length ◽  
Theiler's Murine Encephalomyelitis Virus ◽  
Theiler’S Murine Encephalomyelitis Virus ◽  
Encephalomyelitis Virus

ABSTRACT The DA strain and other members of the TO subgroup of Theiler's murine encephalomyelitis virus (TMEV) induce a persistent central nervous system infection associated with an inflammatory white matter demyelinating disease. TO subgroup strains synthesize an 18-kDa protein, L*, out of frame with the polyprotein from an initiation codon 13 nucleotides downstream from the polyprotein's AUG codon. We previously generated a mutant virus from our infectious DA full-length clone that has a change of the L* AUG codon to ACG (with no change in the polyprotein's amino acid sequence). Studies of this mutant virus showed that L* was key to the TO subgroup phenotype because the mutant had a decreased ability to persist and demyelinate. This work was initially called into question because a similar mutant derived from a different full-length DA infectious clone persisted and demyelinated similarly to wild-type DA virus (O. van Eyll and T. Michiels, J. Virol. 74:9071-9077, 2000). We now report that (i) the sequence of the L* coding region differs in the two infectious clones, resulting in a Ser or Leu as the predicted amino acid at position 93 of L* (with no change in the polyprotein's amino acid sequence), (ii) the difference in this amino acid is key to the phenotypic differences between the two mutants, and (iii) the change in amino acid 93 may affect L* phosphorylation. It is of interest that this amino acid only appears critical in determining the virus phenotype when L* is present in a significantly reduced amount (i.e., following translation from an ACG initiating codon).

scholarly journals Different Strains of Theiler's Murine Encephalomyelitis Virus Antagonize Different Sites in the Type I Interferon Pathway

2010 ◽  
Vol 84 (18) ◽  
pp. 9181-9189 ◽  
Author(s):  
Spyridon Stavrou ◽  
Zongdi Feng ◽  
Stanley M. Lemon ◽  
Raymond P. Roos
Keyword(s):  
Gene Transcription ◽  
Demyelinating Disease ◽  
Viral Proteins ◽  
Type I ◽  
Theiler's Murine Encephalomyelitis Virus ◽  
Virus Persistence ◽  
Multifunctional Protein ◽  
Theiler’S Murine Encephalomyelitis Virus ◽  
Encephalomyelitis Virus ◽  
Different Strains

ABSTRACT The DA strain of Theiler's murine encephalomyelitis virus (TMEV), a member of the Cardiovirus genus of the family Picornaviridae, causes persistent infection in susceptible mice, associated with restricted expression of viral proteins, and induces a demyelinating disease of the central nervous system. DA-induced demyelinating disease serves as a model of human multiple sclerosis because of similarities in pathology and because host immune responses contribute to pathogenesis in both disorders. In contrast, the GDVII strain of TMEV causes acute lethal encephalitis with no virus persistence. Cardiovirus L is a multifunctional protein that blocks beta interferon (IFN-β) gene transcription. We show that both DA L and GDVII L disrupt IFN-β gene transcription induction by IFN regulatory factor 3 (IRF-3) but do so at different points in the signaling pathway. DA L blocks IFN-β gene transcription downstream of mitochondrial antiviral signaling protein (MAVS) but upstream of IRF-3 activation, while GDVII L acts downstream of IRF-3 activation. Both DA L and GDVII L block IFN-β gene transcription in infected mice; however, IFN-β mRNA is expressed at low levels in the central nervous systems of mice persistently infected with DA. The particular level of IFN-β mRNA expression set by DA L as well as other factors in the IRF-3 pathway may play a role in virus persistence, inflammation, and the restricted expression of viral proteins during the late stage of demyelinating disease.

scholarly journals Alternative Translation Initiation of Theiler’s Murine Encephalomyelitis Virus

1999 ◽  
Vol 73 (10) ◽  
pp. 8519-8526 ◽  
Author(s):  
Kenji Yamasaki ◽  
Conrad C. Weihl ◽  
Raymond P. Roos
Keyword(s):  
Translation Initiation ◽  
Demyelinating Disease ◽  
Stop Codon ◽  
Initiation Codon ◽  
Site Mutation ◽  
Entry Site ◽  
Theiler's Murine Encephalomyelitis Virus ◽  
Reading Frame ◽  
Theiler’S Murine Encephalomyelitis Virus ◽  
Encephalomyelitis Virus

ABSTRACT DA strain and other members of the TO subgroup of Theiler’s murine encephalomyelitis virus (TMEV) produce a chronic demyelinating disease in which the virus persists but has a restricted expression. We previously reported that TO subgroup strains, in addition to synthesizing the picornaviral polyprotein, use an alternative initiation codon just downstream from the polyprotein’s AUG to translate an 18-kDa protein called L* that is out of frame with the polyprotein (H. H. Chen et al., Nat. Med. 1:927–931, 1995; W. P. Kong and R. P. Roos, J. Virol. 65:3395–3399, 1991). L* is critically important for virus persistence and the induction of the demyelinating disease (Chen et al., 1995; G. D. Ghadge et al. J. Virol. 72:8605–8612, 1998). We have proposed that variations in the amount of translation initiation from the L* AUG versus the polyprotein AUG may occur in different cell types and therefore affect the degree of expression of viral capsid proteins. We now demonstrate that ribosomal translation initiation at the polyprotein’s initiation codon affects initiation at the L* AUG, suggesting that ribosomes land at the polyprotein’s initiation codon before scanning downstream and initiating at the L* AUG. We also find that the viral 5′ untranslated region affects utilization of the L* AUG. Surprisingly, mutant DA cDNAs were found to be infectious despite the presence of mutations of the polyprotein initiation codon or placement of a stop codon upstream of the L* AUG in the polyprotein’s reading frame. Sequencing studies showed that these viruses had a second site mutation, converting the reading frame of L* into the polyprotein’s reading frame; the results suggest that translation of the polyprotein during infection of these mutant viruses can be initiated at the L* AUG. These data are important in our understanding of translation initiation of TMEV and other RNAs that contain an internal ribosome entry site.

Viral Hyperinfection of the Central Nervous System and High Mortality After Hematopoietic Stem Cell Transplantation for Treatment of Theiler’s Murine Encephalomyelitis Virus-Induced Demyelinating Disease

Blood ◽  
1999 ◽  
Vol 94 (8) ◽  
pp. 2915-2922 ◽  
Author(s):  
Richard K. Burt ◽  
Josette Padilla ◽  
Mauro C. Dal Canto ◽  
Stephen D. Miller
Keyword(s):  
Central Nervous System ◽  
Bone Marrow ◽  
Nervous System ◽  
Immune System ◽  
Autoimmune Disease ◽  
Demyelinating Disease ◽  
Cytopathic Effects ◽  
Immune Mediated ◽  
Encephalomyelitis Virus ◽  
The Central Nervous System

Theiler’s murine encephalomyelitis virus (TMEV) establishes a persistent infection in the central nervous system (CNS) leading to an inflammatory demyelinating disease of the CNS in which the histology and clinical course is similar to multiple sclerosis (MS). Disease pathogenesis is primarily due to T-cell–mediated destruction of myelin, which has been attributed to cytopathic effects of the virus, but immune-mediated destruction of myelin mediated via both virus-specific and myelin-specific T cells appear to play the major role. To determine if bone marrow transplantation would be an effective therapy for a virus-initiated autoimmune disease and to better separate viral cytopathic effects from immune-mediated demyelination, we ablated the immune system of TMEV-infected animals with 1,100 cGy total body irradiation, and then the animal’s immunity was reconstituted by transplantation of disease-susceptible SJL/J mice with syngeneic marrow or disease-susceptible DBA/2J with marrow from disease-resistant (C57Bl/6 × DBA/2)F1 (B6D2) donors. Hematopoietic transplant performed after onset of disease resulted in 42% mortality in SJL/J syngeneic transplants, 47% mortality in diseased DBA2 recipients restored with marrow from naive B6D2 donors, and 12% in diseased DBA2 recipients receiving marrow from B6D2 donors previously infected with TMEV. Delayed type hypersensitivity (DTH) to both virion and myelin proteins was decreased in surviving mice that underwent transplantation; however, CNS viral titers were significantly elevated compared with nontransplanted controls. We conclude that a functional immune system with appropriate T-cell responses are important in prevention of lethal cytopathic CNS effects from TMEV. Relevant to the clinical use of bone marrow transplantation, attempts to ablate the immune system in viral-mediated immune diseases or virus-initiated autoimmune disease may have acute and lethal consequences. Our results raise concern about the attempted use of autologous hematopoietic transplantation in patients with MS, an autoimmune disease with a suspected virus etiology, particularly if the graft is aggressively depleted of lymphocytes.

scholarly journals During Infection, Theiler's Virions Are Cleaved by Caspases and Disassembled into Pentamers

2016 ◽  
Vol 90 (7) ◽  
pp. 3573-3583 ◽  
Author(s):  
Sevim Yildiz Arslan ◽  
Kyung-No Son ◽  
Howard L. Lipton
Keyword(s):  
Demyelinating Disease ◽  
Cell Infection ◽  
Theiler's Murine Encephalomyelitis Virus ◽  
Virus Persistence ◽  
Caspase Cleavage ◽  
Murine Macrophages ◽  
Theiler’S Murine Encephalomyelitis Virus ◽  
Viral Spread ◽  
Encephalomyelitis Virus

ABSTRACTInfected macrophages in spinal cords of mice persistently infected with Theiler's murine encephalomyelitis virus (TMEV) undergo apoptosis, resulting in restricted virus yields, as do infected macrophages in culture. Apoptosis of murine macrophages in culture occurs via the intrinsic pathway later in infection (>10 h postinfection [p.i.]) after maximal virus titers (150 to 200 PFU/cell) have been reached, with loss of most infectious virus (<5 PFU/cell) by 20 to 24 h p.i. Here, we show that BeAn virus RNA replication, translation, polyprotein processing into final protein products, and assembly of protomers and pentamers in infected M1-D macrophages did not differ from those processes in TMEV-infected BHK-21 cells, which undergo necroptosis. However, the initial difference from BHK-21 cell infection was seen at 10 to 12 h p.i., where virions from the 160S peak in sucrose gradients had incompletely processed VP0 (compared to that in infected BHK-21 cells). Thereafter, there was a gradual loss of the 160S virion peak in sucrose gradients, with replacement by a 216S peak that was observed to contain pentamers among lipid debris in negatively stained grids by electron microscopy. After infection or incubation of purified virions with activated caspase-3in vitro, 13- and 17-kDa capsid peptide fragments were observed and were predicted by algorithms to contain cleavage sites within proteins by cysteine-dependent aspartate-directed proteases. These findings suggest that caspase cleavage of sites in exposed capsid loops of assembled virions occurs contemporaneously with the onset and progression of apoptosis later in the infection.IMPORTANCETheiler's murine encephalomyelitis virus (TMEV) infection in mice results in establishment of virus persistence in the central nervous system and chronic inflammatory demyelinating disease, providing an experimental animal model for multiple sclerosis. Virus persistence takes place primarily in macrophages recruited into the spinal cord that undergo apoptosis and in turn may facilitate viral spread via infected apoptotic blebs. Infection of murine macrophages in culture results in restricted virus yields late in infection. Here it is shown that the early steps of the virus life cycle in infected macrophagesin vitrodo not differ from these processes in TMEV-infected BHK-21 cells, which undergo necroptosis. However, the findings late in infection suggest that caspases cleave sites in exposed capsid loops and possibly internal sites of assembled virions occurring contemporaneously with onset and progression of apoptosis. Mechanistically, this would explain the dramatic loss in virus yields during TMEV-induced apoptosis and attenuate the virus, enabling persistence.

scholarly journals Mutations That Affect the Tropism of DA and GDVII Strains of Theiler's Virus In Vitro Influence Sialic Acid Binding and Pathogenicity

2002 ◽  
Vol 76 (16) ◽  
pp. 8138-8147 ◽  
Author(s):  
Karima Jnaoui ◽  
Muriel Minet ◽  
Thomas Michiels
Keyword(s):  
Sialic Acid ◽  
Demyelinating Disease ◽  
Binding Capacity ◽  
Single Amino Acid ◽  
Sialic Acid Binding ◽  
Encephalomyelitis Virus ◽  
The Central Nervous System ◽  
Different Strains ◽  
Single Amino Acid Mutation

ABSTRACT Theiler's murine encephalomyelitis virus (TMEV) is a natural pathogen of the mouse. The different strains of TMEV are divided into two subgroups according to the pathology they provoke. The neurovirulent strains GDVII and FA induce an acute fatal encephalitis, while persistent strains, like DA and BeAn, cause a chronic demyelinating disease associated with viral persistence in the central nervous system. Different receptor usage was proposed to account for most of the phenotype difference between neurovirulent and persistent strains. Persistent but not neurovirulent strains were shown to bind sialic acid. We characterized DA and GDVII derivatives adapted to grow on CHO-K1 cells. Expression of glycosaminoglycans did not influence infection of CHO-K1 cells by parental and adapted viruses. Mutations resulting from adaptation of DA and GDVII to CHO-K1 cells notably mapped to the well-characterized VP1 CD and VP2 EF loops of the capsid. Adaptation of the DA virus to CHO-K1 cells correlated with decreased sialic acid usage for entry. In contrast, adaptation of the GDVII virus to CHO-K1 cells correlated with the appearance of a weak sialic acid usage for entry. The sialic acid binding capacity of the GDVII variant resulted from a single amino acid mutation (VP1-51, Asn→Ser) located out of the sialic acid binding region defined for virus DA. Mutations affecting tropism in vitro and sialic acid binding dramatically affected the persistence and neurovirulence of the viruses.

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