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M Brahic

Publications and source records attributed to M Brahic.

At least 37 records · Page 2Linked to original sources
PubMed1998

The neurovirulence of the DA and GDVII strains of Theiler's virus correlates with their ability To infect cultured neurons.

The strains of Theiler's murine encephalomyelitis virus, a picornavirus, are divided into two groups according to their neurovirulence after intracerebral inoculation. The highly virulent GDVII strain causes an acute, fatal encephalomyelitis, whereas the DA strain causes a mild encephalomyelitis followed by a chronic inflammatory demyelinating disease associated with viral persistence. Studies with recombinant viruses showed that the capsid plays the major role in determining these phenotypes. However, the molecular basis for the effect of the capsid on neurovirulence is still unknown. In this paper, we describe a large difference in the patterns of infection of primary neuron cultures by the GDVII and DA strains. Close to 90% of the neurons were infected 12 h after inoculation with the GDVII strain, and the cytopathic effect was complete 24 h postinoculation. In contrast, with the DA strain, viral antigens were not detected in neurons until 24 h postinoculation. Infected neurons accounted for only 2% of the total number of neurons, even 6 days after inoculation. No cytopathic effect was visible, and the cultures could be kept for the same length of time as the noninfected controls. Because the neurovirulence of the GDVII strain has been mapped to the capsid, we examined the role of the capsid in this difference of phenotype. We showed, using recombinant viruses, that the capsid was indeed responsible for the pattern of infection observed in vitro, most likely through its role in viral entry. Thus, the levels of neurovirulence of the GDVII and DA strains correlate with their abilities to infect cultured neurons, and this ability is controlled by the capsid.

Animals↗
PubMed1997

Infection of choroid plexus cells by human T cell leukaemia virus type I.

Very little is known about the factors that determine the outcome of infection by human T cell leukaemia virus type I (HTLV-I) and the neurotropism of this virus is still a controversial point. In transgenic mice, the HTLV-I LTR is active mainly in the central nervous system (CNS), in parenchyma as well as in ependymal and choroid plexus cells. The latter are of particular interest and could represent the way of entry of the virus into the CNS. In this study we show that primary cultures of sheep choroid plexus can be infected with HTLV-I, leading to characteristic multinucleated syncytial cells containing virus RNA and proteins. HTLV-I p24 Gag protein was detected in the culture medium and the presence of virus particles was observed by electron microscopy 40 days after infection. At this time post-infection HTLV-I could be transmitted to human cord blood cells.

Animals↗
PubMed1997

The infection of mouse by Theiler's virus: from genetics to immunology.

Theiler's virus is a picornavirus of mouse which causes an acute encephalomyelitis followed by a persistent infection of the white matter of the spinal cord with chronic inflammation and demyelination. This late disease is studied as a model for multiple sclerosis. Inbred strains of mice differ in their susceptibility to persistent infection and demyelination. Resistant strains clear the infection after the acute encephalomyelitis. This observation is the basis of genetic studies which we used as a thread for this review. The H-2D locus has a major effect on susceptibility. The H-2Db gene is involved in a fast and intense CTL response which confers resistance. The Tcrb locus is also implicated, although there is no proof that the susceptibility gene in this region codes for the T-cell receptor. A complete screen of the genome uncovered the role of the Ifng locus and led to the demonstration that IFN-gamma limits viral spread in the white matter. The roles of NK cells and B cells in limiting the infection are discussed. CD4+ T cells participate both in protection against the infection and in demyelination. Finally, the effect of non-immune factors in resistance is illustrated by mice with mutations in the MBP or PLP gene.

Animals↗
PubMed1997

In vivo administration of interleukin-2 protects susceptible mice from Theiler's virus persistence.

In vivo administration of interleukin-2 (IL-2)-secreting tumor cells results in complete protection against persistent infection by Theiler's murine encephalomyelitis virus (TMEV) in susceptible DBA/2 mice. The IL-2-mediated protection was found to depend on the inoculum size as well as the timing of IL-2 administration. IL-2-treated and TMEV-infected mice displayed a three- to fourfold relative increase in virus-specific cytotoxic T-lymphocyte (CTL) precursors. Thus, we postulate that the persistence of TMEV infection in susceptible mice reflects limited numbers of relevant CTL precursors and their time course of induction and activation.

Animals↗
PubMed1997

An early, abundant cytotoxic T-lymphocyte response against Theiler's virus is critical for preventing viral persistence.

In genetically susceptible strains of mice, the DA strain of Theiler's virus, a picornavirus, causes a persistent infection of the white matter of the spinal cord associated with chronic demyelination. In resistant strains, on the other hand, the infection is cleared within 1 to 2 weeks. In this article, we show that Theiler's virus induces a rapid and abundant cytotoxic T lymphocyte (CTL) response in resistant C57BL/6 mice, while the response remains low throughout infection in susceptible SJL/J mice. This difference can be referred to a higher number of virus-specific CTL precursors in C57BL/6 mice. These observations indicate that the efficient induction of virus-specific CTL precursors is critical for avoiding the establishment of a persistent picornaviral infection.

Animals↗
PubMed1997

Role of macrophages during Theiler's virus infection.

Theiler's virus, a murine picornavirus, causes a persistent infection of the central nervous system with chronic inflammation and primary demyelination. We examined the nature of infected cells at different times postinoculation (p.i.) with a combined immunocytochemistry-in situ hybridization assay. The virus was found in the gray matter of the brain, mostly in neurons, during the first week p.i. During the following weeks, the virus was present in the spinal cord, first in the gray and white matter, then exclusively in the white matter. Approximately 10% of infected cells were astrocytes at any time during the study. Infected oligodendrocytes were first noticed on day 14 p.i. and amounted to approximately 6% of infected cells. The number of infected macrophages increased with time and reached a plateau by day 21 p.i., when at least 45% of infected cells were macrophages. The role of blood-borne macrophages during infection was studied by depleting them with mannosylated liposomes containing dichloromethylene diphosphonate. The virus did not persist in the majority of the mice treated with liposomes. These mice showed only minimal mononuclear cell infiltration and no demyelination.

Animals↗
PubMed1997

The shiverer mutation affects the persistence of Theiler's virus in the central nervous system.

Theiler's virus persists in the white matter of the spinal cord of genetically susceptible mice and causes primary demyelination. The virus persists in macrophages/microglial cells, but also in oligodendrocytes, the myelin-forming cells. Susceptibility/resistance to this chronic infection has been mapped to several loci including one tentatively located in the telomeric region of chromosome 18, close to the myelin basic protein locus (Mbp locus). To determine if the MBP gene influences viral persistence, we inoculated C3H mice bearing the shiverer mutation, a 20-kb deletion in the gene. Whereas control C3H mice were of intermediate susceptibility, C3H mice heterozygous for the mutation were very susceptible, and those homozygous for the mutation were completely resistant. This resistance was not immune mediated. Furthermore, C3H/101H mice homozygous for a point mutation in the gene coding for the proteolipid protein of myelin, the rumpshaker mutation, were resistant. These results strongly support the view that oligodendrocytes are a necessary viral target for the establishment of a persistent infection by Theiler's virus.

Animals↗
PubMed1997

Theiler's virus and Mengo virus induce cross-reactive cytotoxic T lymphocytes restricted to the same immunodominant VP2 epitope in C57BL/6 mice.

C57BL/6 mice develop a virus-specific cytotoxic T-lymphocyte (CTL) response after intraperitoneal inoculation with either the DA strain of Theiler's virus or Mengo virus, two members of the Cardiovirus genus. These CTLs contribute to viral clearance in the case of Theiler's virus but do not protect the mice from the fatal encephalomyelitis caused by Mengo virus. In this study we show that DA and Mengo virus-induced CTLs are cross-reactive. The cross-reactivity is due to a conserved, H-2Db-restricted epitope located between amino acid residues 122 and 130 of the VP2 capsid protein (VP2(122-130)). This epitope is immunodominant in C57BL/6 mice infected with Theiler's virus. The VP2(122-130) epitope, initially identified for Mengo virus, is the first CTL epitope described for Theiler's virus.

Amino Acid Sequence↗
PubMed1996

Role of VP2 amino acid 141 in tropism of Theiler's virus within the central nervous system.

Following intracranial inoculation, Theiler's virus causes either an acute encephalitis (strain GDVII) or a chronic demyelinating disease (strain DA). The DA strain sequentially infects the grey matter of the brain, the grey matter of the spinal cord, and, finally, the white matter of the spinal cord, where it persists in glial cells and causes demyelinating lesions. Analysis of the phenotype of recombinant viruses has shown that the viral capsid contains determinants for persistence and demyelination. Our previous studies showed that a Lys at position 141 of the VP2 capsid protein (VP2-141) could render a chimeric virus persistent. We also reported that another recombinant virus, virus R5, migrated from the grey matter of the brain to that of the spinal cord inefficiently and was unable to infect the white matter of the spinal cord. In this article, we report that introducing a Lys at position VP2-141 in virus R5 increases its ability to infect the white matter of the spinal cord. Our results indicate that this amino acid is important for the spread of the virus within the central nervous system.

Animals↗
PubMed1996

Infection of class II-deficient mice by the DA strain of Theiler's virus.

The DA strain of Theiler's virus causes, in susceptible strains of mice, a persistent infection of the white matter of the spinal cord accompanied by chronic inflammation and primary demyelination. In resistant strains, including all H-2b strains, mice clear the infection after 1 to 2 weeks. We inoculated RHAbetao/o mice, an H-2b strain which does not express class II molecules. We found that they are susceptible to persistent infection and that they develop foci of chronic inflammation with demyelination. However, these foci are smaller and contain fewer demyelinated axons than those observed in susceptible SJL/J or beta2m-/- mice.

Animals↗
PubMed1996

Analysis of the expression directed by two HTLV-I promoters in transgenic mice.

We generated several lines of mice transgenic for the lacZ reporter gene under the control of an HTLV-I LTR. Two different LTR were used; one was isolated from a case of Adult T-cell Leukemia (ATL), the other from a case of Tropical Spastic Paraparesis (TSP/HAM). These LTR differed at 18 nucleotide positions. The pattern of expression of the transgene, studied at the RNA level by RT-PCR, was the same regardless of the origin of the promoter. The beta-galactosidase activity was detected primarily in the central nervous system, in the parenchyma, the choroid plexus and the ependymal cells along the ventricles. In parenchyma, double labelling experiments showed that the cells expressing beta-galactosidase were neurons. These results show that choroid plexus cells and ependymal cells, as well as some neurons, are permissive for the activity of the HTLV-I promoter. The origin of the LTR had not influence on the pattern of expression of the reporter gene.

Animals↗
PubMed1996

[Infection of the mouse by Theiler's virus; a model for the study of demyelinating diseases of the central nervous system].

The infection of mouse by Theiler's virus is a model for the study of persistent infections of the central nervous system accompanied with primary demyelination. The pathogenesis of this disease has been studied at the molecular level. The viral capsid controls the migration of the virus from the neurons to the glial cells of the white matter. A region of the capsid, which is responsible for this control, has been identified. The susceptibility of mice to this persistent infection is determined by at least three genes, one of which, H-2D, has been identified. Two other genes have been mapped; one linked to the gene coding for gamma interferon, the other one to the gene coding for the myelin basic protein. The role of cytotoxic T lymphocytes in the resistance to persistent infection has been demonstrated. Taken together, these results illustrate how mutations in a ubiquitous virus may cause, in individuals which are genetically susceptible, a persistent infection and a chronic inflammatory disease. Similar situations could exist in man.

Animals↗
PubMed1995

Analysis of the leader and capsid coding regions of persistent and neurovirulent strains of Theiler's virus.

Most strains of Theiler's virus (TMEV) cause a persistent infection of the central nervous system of the mouse and a chronic demyelinating disease considered a model for multiple sclerosis. Two strains, on the contrary, cause an acute encephalitis and kill mice in a matter of days. We sequenced the leader and capsid coding region of three persistent (TO4, WW, and Yale) isolates and one neurovirulent (FA) isolate of TMEV. We compared these sequences and those already published for other isolates (DA, BeAn, GDVII, and Vilyuisk). The results suggest that virulent and persistent strains did not evolve as two separate groups, but rather that neurovirulent strains arose from a subgroup of persistent strains. The sequences of viruses isolated in different geographic areas and at different times were highly homologous, a surprising finding for an RNA virus. This suggests that severe constraints are imposed on the genome during the viral life cycle. The sequences of the TO4 and WW strains were identical, suggesting that the latter came from a laboratory contamination. The genomes of all the persistent strains sequenced so far contain an alternate open reading frame in the L region, which has been shown, in the case of the DA strain, to code for an 18-kDa protein called "I".

Amino Acid Sequence↗
PubMed1995

The gene coding for interferon-gamma is linked to the D12S335 and D12S313 microsatellites and to the MDM2 gene.

Interferon-gamma is a cytokine with multiple effects. It interferes with the replication of several viruses and plays a key role in the regulation of immune responses. Therefore, the gene coding for interferon-gamma could be implicated in the susceptibility of humans to several diseases. We have localized this gene close to the D12S335 and D12S313 microsatellites on both the physical and the genetic maps of the human genome. We also physically mapped this gene close to the MDM2 locus on chromosome band 12q15. Finally, we describe the organization of the Ifg, Myf-6, Mdm1, and Mdm2 loci on mouse chromosome 10, in a region syntenic to human chromosome band 12q15.

Animals↗
PubMed1995

Theiler's virus infection of 129Sv mice that lack the interferon alpha/beta or interferon gamma receptors.

The Daniels strain of Theiler's virus causes a persistent infection of the white matter of spinal cord of susceptible mice, with chronic inflammation and primary demyelination. Inbred 129Sv mice are resistant to this infection; they present with mild encephalomyelitis and clear the infection within a matter of days. A very different outcome was observed with inbred 129Sv mice whose receptors for interferon alpha/beta or interferon gamma had been inactivated by homologous recombination. The former presented severe encephalomyelitis with acute infection of neurons, particularly in brain and hippocampus, and extensive infection with necrosis of the choroid plexus. Most animals died of this acute disease. The latter, presented the same early encephalomyelitis as the control 129Sv mice. However, they remained persistently infected and developed a very severe late infection of the white matter with extensive primary demyelination. This late disease looked like an exacerbated form of the chronic demyelinating disease observed in susceptible inbred mice such as the SJL/J or FVB strains. Our results show that the two interferon systems play nonredundant roles in the resistance of the 129Sv mouse to the infection by Theiler's virus. They also lend support to the notion that the Ifg gene is involved in the resistance/susceptibility of inbred strains of mice to persistent infection by this picornavirus.

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