Viral Load Increases in SJL/J Mice Persistently Infected by Theiler's Virus after Inactivation of the 2m Gene (original) (raw)
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Journal of Virology, 2003
؉/؉ H-2 b mice also cleared virus from the spinal cord white matter, whereas IFN-␥ ؊/؊ H-2 b mice developed viral persistence in glial cells of the white matter and exhibited associated spinal cord demyelination. In contrast, infection of IFN-␥ ؊/؊ mice of the susceptible H-2 q haplotype resulted in frequent deaths and severe neurologic deficits within 16 days of infection compared to the results obtained for controls. Morphologic analysis demonstrated severe injury to spinal cord neurons in IFN-␥ ؊/؊ H-2 q mice during early infection. More virus RNA was detected in the brain and spinal cord of IFN-␥ ؊/؊ H-2 q mice than in those of control mice at 14 and 21 days after TMEV infection. Virus antigen was localized predominantly to anterior horn cells in infected IFN-␥ ؊/؊ H-2 q mice. IFN-␥ deletion did not affect the humoral response directed against the virus. However, the level of expression of CD4, CD8, class I MHC, or class II MHC in the central nervous system of IFN-␥ ؊/؊ H-2 q mice was lower than those in IFN-␥ ؉/؉ H-2 q mice. Finally, in vitro analysis of virus-induced death in NSC34 cells and spinal motor neurons showed that IFN-␥ exerted a neuroprotective effect in the absence of other aspects of the immune response. These data support the hypothesis that IFN-␥ plays a critical role in protecting spinal cord neurons from persistent infection and death.
Genetics, 1999
Theiler’s virus persistently infects the white matter of the spinal cord in susceptible strains of mice. This infection is associated with inflammation and primary demyelination and is studied as a model of multiple sclerosis. The H-2D gene is the major gene controlling viral persistence. However, the SJL/J strain is more susceptible than predicted by its H-2s haplotype. An (SJL/J × B10.S)F1 × B10.S backcross was analyzed, and one quantitative trait locus (QTL) was located in the telomeric region of chromosome 10 close to the Ifng locus. Another one was tentatively mapped to the telomeric region of chromosome 18, close to the Mbp locus. We now report the study of 14 congenic lines that carry different segments of these two chromosomes. Although the presence of a QTL on chromosome 18 was not confirmed, two loci controlling viral persistence were identified on chromosome 10 and named Tmevp2 and Tmevp3. Furthermore, the Ifng gene was excluded from the regions containing Tmevp2 and Tmev...
Persistence of Viral RNA in the Central Nervous System of Mice Inoculated with MHV-4
Coronaviruses, 1994
In order to study the role that viral persistence may play in chronic central nervous system (CNS) disease induced by murine coronaviruses, we have used the reverse transcriptasepolymerase chain reaction (RT-PCR) to study viral RNA in the brains of mice after intracerebral inoculation of JHM virus (JHMV or MHV-4). Quantitative RT-PCR showed that JHMV RNA decreased from approximately 2 ng/ug total brain RNA at day 6 postinoculation (PI) to 0.1 pg/ug total brain RNA at 360 days PI. Double-stranded viral RNA could be detected up to day 20 PI. By the selective use of upstream or downstream primers during the RT step, it was possible to measure negative sense and positive sense JHMV RNA respectively, and we found that there was a marked rise in the ratio of positive to negative sense JHMV RNA after day 13 PI. Analysis of amplified products by dideoxy DNA sequencing showed that the characteristic mutation of our input virus (at position 3340 of gene 3) is maintained to at least day 42 PI. Taken together, these results favor a model of JHMV persistence in vivo in which viral RNA is present as double stranded forms initially and predominantly as single stranded, positive sense forms at late timepoints. Further analysis of this model in quantitative terms may contribute to our understanding of the biological significance of coronavirus persistence in the CNS.
Infection and Immunity, 1982
The appearance of histological lesions and the localization of viral RNA in the central nervous system of mice infected with tissue culture-adapted Theiler's murine encephalomyelitis virus (WW strain) (TMEV-WW) was studied. Viral RNA was detected by autoradiography after in situ hybridization, using a 3 H-labeled DNA probe complementary to virion RNA, which was applied to deparaffinized sections of central nervous system tissues from infected mice. Subjacent histological sections of tissues were used to assess the location and extent of lesions. Lesions were first observed at 20 days post-inoculation and appeared to enlarge throughout infection. They consisted of infiltrates of mononuclear cells and lymphocytes in spinal cord white matter and leptomeninges; at 78 days post-inoculation severe necrotizing and demyelinative myelitis and gliosis were observed. In contrast to the pathogenesis of brain-derived TMEV-WW-infected mice, no lesions were found in the central nervous system ...
Immunology of theiler’s murine encephalomyelitis virus infection
Immunologic Research, 1995
Theiler's murine encephalomyelitis virus (TMEV) is a singlestranded RNA virus that belongs to the family of picornaviruses. Intracranial inoculation of susceptible mouse strains with TMEV results in biphasic disease, consisting of early acute disease that resembles poliomyelitis, followed by late chronic demyelinating disease that is characterized by the appearance of chronic inflammatory demyelinating lesions. Susceptibility to TMEV infection is genetically controlled by three loci: one that maps to the H-2D region of the major histocompatibility complex, one to the beta-chain constant region of the T-cell antigen receptor, and one located on chromosome 3. Both early acute and chronic late demyelinating diseases are immunologically mediated. T cells appear to play an important role in the pathogenesis of the disease. TMEVinduced demyelinating disease in mice has extensive similarities with multiple sclerosis, and it is considered one of the best experimental animal models for multiple sclerosis.
Identification of a Novel Neuropathogenic Theiler's Murine Encephalomyelitis Virus
Journal of Virology, 2011
Theiler's murine encephalitis viruses (TMEV) are divided into two subgroups based on their neurovirulence. Persistent strains resemble Theiler's original viruses (referred to as the TO subgroup), which largely induce a subclinical polioencephalomyelitis during the acute phase of the disease and can persist in the spinal cord of susceptible animals, inducing a chronic demyelinating disease. In contrast, members of the neurovirulent subgroup cause an acute encephalitis characterized by the rapid onset of paralysis and death within days following intracranial inoculation. We report herein the characterization of a novel neurovirulent strain of TMEV, identified using pyrosequencing technology and referred to as NIHE. Complete coverage of the NIHE viral genome was obtained, and it shares <90% nucleotide sequence identity to known TMEV strains irrespective of subgroup, with the greatest sequence variability being observed in genes encoding the leader and capsid proteins. The histopathological analysis of infected brain and spinal cord demonstrate inflammatory lesions and neuronal necrosis during acute infection with no evidence of viral persistence or chronic disease. Intriguingly, genetic analysis indicates the putative expression of the L* protein, considered a hallmark of strains within the persistent subgroup. Thus, the identification and characterization of a novel neurovirulent TMEV strain sharing features previously associated with both subgroups will lead to a deeper understanding of the evolution of TMEV strains and new insights into the determinants of neurovirulence.