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At least 307 records · Page 17Linked to original sources

PubMed2006

MMP-12, MMP-3, and TIMP-1 are markedly upregulated in chronic demyelinating theiler murine encephalomyelitis.

Theiler murine encephalomyelitis (TME) represents a highly relevant viral model for multiple sclerosis. Matrix metalloproteinases (MMPs) degrade extracellular matrix molecules and are involved in demyelination processes. To elucidate their impact on demyelination in TME, spinal cords of TME virus (TMEV)-infected SJL/J mice were taken at 9 different time points postinfection (pi) ranging from 1 hour to 196 days pi and investigated for the expression of TMEV, MMP-2, -3, -7, -9, -10, -11, -12, -13, -14, -15, -24, and TIMP-1 to -4 by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). High TMEV RNA levels were detectable throughout the observation period using RT-qPCR. In addition, TMEV RNA was visualized within demyelinated lesions by in situ hybridization. MMP-3 mRNA was significantly upregulated at 1 day pi and again in the late phase of infection. TIMP-1 mRNA was significantly elevated throughout the observation period. MMP-12 mRNA was most prominently upregulated in the late phase of infection and MMP-12 protein was localized in intralesional microglia/macrophages and astrocytes by immunohistochemistry. In summary, in early TMEV infection, MMP-3 and TIMP-1 mRNA upregulation might be directly virus-induced, whereas persistent TMEV infection directly or indirectly stimulated MMP-12 production in microglia/macrophages and astrocytes and might account for ongoing demyelination in TME.

Animals↗

PubMed1995

Cloning and expression of the VP1 major capsid protein of diabetogenic encephalomyocarditis (EMC) virus and prevention of EMC virus-induced diabetes by immunization with the recombinant VP1 protein.

The development of diabetes in mice induced by encephalomyocarditis (EMC) virus provides the best experimental evidence that viruses have an aetiological role in the pathogenesis of this disease. The major capsid protein (VP1) of EMC virus is important for both the attachment of the virus to pancreatic beta cells and for the determination of antigenicity. This experiment was initiated to clone the gene for the major capsid protein, VP1, of the diabetogenic EMC (EMC-D) virus, express the VP1 protein, and test whether the recombinant VP1 protein can prevent development of EMC-D virus-induced diabetes in mice. We successfully cloned the VP1 gene of the EMC-D virus in the expression vector pRSET and subsequently expressed the protein in Escherichia coli. The recombinant VP1 protein was then purified by affinity chromatography. Five- to six-week-old male SJL/J mice were immunized intraperitoneally with purified VP1 protein and then challenged after various intervals with highly diabetogenic EMC-D virus. None of the VP1-immunized mice developed diabetes, irrespective of the interval between immunization and virus challenge, whereas 80 to 95% of the EMC-D virus-infected control mice did develop diabetes. All of the VP1-immunized mice showed intact pancreatic islet architecture, whereas most of the infected control mice showed severe beta cell necrosis and lymphocytic infiltration of their pancreatic islets. On the basis of these observations, we conclude that the recombinant VP1 protein of EMC-D virus can completely prevent the development of EMC-D virus-induced diabetes in mice.

Amino Acid Sequence↗

PubMed1995

Cytotoxic T cell response to Mengo virus in mice: effector cell phenotype and target proteins.

The Mengo virus specific cytotoxic T lymphocyte (CTL) response was investigated after intraperitoneal infection of mice with the attenuated Mengo virus strain vMC24. A high level of CTL activity was detected in spleen cell cultures obtained from infected C3H/HeJ (H-2k) or C57BL/6 (H-2b) mice after a secondary in vitro stimulation with Mengo virus-infected cells. The CTL activity, which was MHC class I-restricted, was shown to be mediated by CD8+ T cells. Recombinant vaccinia viruses that expressed capsid proteins VP0, VP1 or VP3 were produced and used to identify the protein(s) recognized by the Mengo virus-specific CTLs. In both C3H/HeJ and C57BL/6 mice, analysis of CTL activity against target cells expressing each capsid protein showed that VP0 was the only capsid protein recognized by the CD8+ CTLs. The CTL epitope(s) could be further located in the C-terminal half of VP0, i.e. in capsid protein VP2. Moreover, using unlabelled target cells expressing VP0 as cold competitors, we were able to almost completely inhibit recognition and lysis of Mengo virus-infected cells by specific CD8+ CTLs. Thus, the CTL response directed against VP2 was immunodominant in both C3H/HeJ- and C57BL/6-infected mice.

Animals↗

PubMed1996

Depletion of Mac1-positive macrophages protects DBA/2 mice from encephalomyocarditis virus-induced myocarditis and diabetes.

DBA/2 mice treated with anti-Mac1 monoclonal antibody (MAb) failed to develop encephalomyocarditis virus (EMCV)-induced diabetes and myocarditis. Virus concentrations and the number of viral RNA-positive cells in the pancreas and heart were significantly reduced in mice treated with anti-Mac1 MAb. Mac1-positive macrophages seem to be involved in EMCV-induced disease and to affect the replication of EMCV in target organs.

Animals↗

PubMed1999

Restricted Theiler's murine encephalomyelitis virus infection in murine macrophages induces apoptosis.

Increasing evidence suggests that macrophages (M(phi)s) are necessary for persistence of Theiler's murine encephalomyelitis virus (TMEV) in the mouse central nervous system. Analysis of BeAn virus infection in the Mphi cell lines P388D1, J774A.1 and PU5-1.8, which are intermediate in their state of differentiation and resemble multifunctional resident M(phi)s, revealed restricted TMEV growth. As a result of the restricted infection, these Mphi cell lines were induced to undergo apoptosis as demonstrated by cellular morphology, DNA fragmentation, caspase protease activity, and in individual cells, by terminal deoxytransferase dUTP nick-end labelling (TUNEL).

Animals↗

PubMed2000

Selection and characterization of a BHK-21 cell line resistant to infection by Theiler's murine encephalomyelitis virus due to a block in virus attachment and entry.

A clonal population of BHK-21 cells resistant to infection with the low-neurovirulence BeAn strain of Theiler's murine encephalomyelitis virus (TMEV) was derived after four cycles of infection and characterized. These cells were resistant to both low- and high-neurovirulence TMEV strains due to a block in virus attachment and entry and not in virus replication, since transfection of these cells with TMEV RNA to bypass the entry step(s) induced virus replication and assembly. The resistance to infection was stable for more than a year, suggesting that it is a heritable property arising from a mutation in the susceptible parent BHK-21 population. This cell line is being used to identify a receptor for TMEV.

Animals↗

PubMed2001

Roles of the H-2D(b) and H-K(b) genes in resistance to persistent Theiler's murine encephalomyelitis virus infection of the central nervous system.

Theiler's murine encephalomyelitis virus, a member of the Picornaviridae family, persists in the spinal cord of susceptible strains of mice. Resistant strains of mice, such as the H-2(b) strain, clear the virus infection after an acute encephalomyelitis. The H-2D locus, but not the H-2K locus, has a major effect on this resistance, although both loci code for MHC class I molecules with similar general properties. For the present work, we rendered susceptible H-2(q) FVB/N mice transgenic for either the H-2D(b)gene, the H-2K(b) gene or a chimeric H-2D(b)/K(b) gene in which the exons encoding the peptide-binding groove of the H-2K(b) gene have been replaced by those of the H-2D(b)gene. Mice transgenic for either the H-2D(b)gene or the chimeric H-2D(b)/K(b) gene were significantly more resistant to persistent virus infection than mice transgenic for the H-2K(b) gene, suggesting that the difference in the effects of the H-2D(b)gene and the H-2K(b) gene are due to the nature of the peptides presented by these class I molecules.

Animals↗

PubMed2003

Galactose is needed only for expression of co-receptors used by Theiler's murine encephalomyelitis virus as the virus does not directly bind galactose or use the UDP-galactose transporter as a receptor.

Theiler's murine encephalomyelitis virus (TMEV) infects most mammalian cells, but a TMEV receptor has not been identified. Studies have demonstrated that the UDP-galactose transporter (UGT) is critical for TMEV attachment and entry into mammalian cells (Hertzler et al., Virology 286, 336-344, 2001). It was suggested that UGT might function as a TMEV receptor. We have demonstrated that polyclonal rabbit antibodies to human UGT that cross-react with hamster UGT do not block binding to or infection of mammalian cells by either high- or low-neurovirulence TMEV. In addition, incubation of virus with galactose, or blocking galactose on the cell surface with lectins, does not inhibit TMEV binding or infection. Thus, TMEV needs UGT for its transporter activity and galactose for assembly of its co-receptors (attachment factors) but does not bind directly to galactose. Excluding direct involvement of UGT and galactose in TMEV binding and entry provides further insight into how TMEV interacts with the host cell and should facilitate ongoing studies to identify a TMEV receptor.

Animals↗

PubMed1997

Immunological defects in mice with a targeted disruption in Bcl-3.

The proto-oncogene bcl-3 is a member of the IkappaB family. The Bcl-3 protein is known to interact specifically with the p50 and p52 subunits of NFkappaB. However, the function of this interaction is not well understood. To determine the in vivo role of Bcl-3, mice were generated that lack the bcl-3 gene, Bcl 3(-/-). Here we report that Bcl 3(-/-) mice appear developmentally normal, but exhibit severe defects in humoral immune responses and protection from in vivo pathogenic challenges. Relative to wild-type mice, Bcl 3(-/-) mice are unable to clear L. monocytogenes and are more susceptible to infection with S. pneumoniae. This phenotype is similar to that observed in the p50(-/-) mice and the cross between the Bcl-3(-/-) and p50(-/-) mice generates animals with an enhanced phenotype. In accordance with the observed defects in their immune response, the Bcl 3(-/-) mice have normal immunoglobulin levels before and after immunization, but fail to produce antigen-specific antibodies. Additionally, spleens from Bcl-3(-/-) mice are abnormal and void of germinal centers. In contrast, the p50(-/-) mice have normal germinal centers. We propose that in in vivo, Bcl-3 can function independently of p50.

Animals↗

PubMed2004

Effects of tacrolimus (FK506) on encephalomyocarditic virus-induced diabetes in mice.

The effects of tacrolimus on insulin-dependent diabetes mellitus (IDDM) induced by the D-variant of encephalomyocarditis virus (D-EMCV) have been investigated. Male BALB/c mice were treated with tacrolimus before viral inoculation, and then were inoculated with 10 plaque forming units (PFU) of DEMCV. The mice continued to be treated with tacrolimus until the animals were sacrificed. D-EMCV-infected mice, which were treated with saline as controls, showed abnormal glucose tolerance test (GTT) values, whereas all infected mice with tacrolimus pretreatment were normal on 7 days-post inoculation (DPI). Histological observations revealed that non-treated tacrolimus D-EMCV-infected mice and which developed diabetes showed severe insulitis in their islets of Langerhans. On the other hand, D-EMCV-infected mice treated with tacrolimus were normal. In D-EMCV-infected mice, viruses in the pancreata were detected at the same level regardless of treatment with tacrolimus or saline. Expressions of TNF-alpha and IFN-gamma mRNA in spleens of tacrolimus-treated D-EMCV-infected mice were lower than that of non-treated tacrolimus DEMCV-infected mice on 7 DPI. The results suggest that tacrolimus suppresses expressions of TNF-alpha and IFN-gamma mRNAs to prevent the onset of D-EMCV-induced IDDM.

Animals↗

PubMed2003

Innate immune response to encephalomyocarditis virus infection mediated by CD1d.

CD1d-reactive natural killer T (NKT) cells can rapidly produce T helper type 1 (Th1) and/or Th2 cytokines, can activate antigen-presenting cell (APC) interleukin-12 (IL-12) production, and are implicated in the regulation of adaptive immune responses. The role of the CD1d system was assessed during infection with encephalomyocarditis virus (EMCV-D), a picornavirus that causes acute diabetes, paralysis and myocarditis. EMCV-D resistance depends on IL-12-mediated interferon-gamma (IFN-gamma) production. CD1d-deficient mice, which also lack CD1d-reactive NKT cells, were substantially more sensitive to infection with EMCV-D. Infected CD1d knockout mice had decreased IL-12 levels in vitro and in vivo, and indeed were protected by treatment with exogenous IL-12. IFN-gamma production in CD1d knockout mice was decreased compared with that in wild-type (WT) mice in response to EMCV-D in vitro, although differences were not detected in vivo. Treatment with anti-asialo-GM1 antibody, to deplete NK cells, caused a marked increase in susceptibility of WT mice to EMCV-D infection, whereas CD1d knockout mice were little affected, suggesting that NK-cell-mediated protection is CD1d-dependent. Therefore, these data indicate that CD1d is essential for optimal responses to acute picornaviral infection. We propose that CD1d-reactive T cells respond to early immune signals and function in the innate immune response to a physiological viral infection by rapidly augmenting APC IL-12 production and activating NK cells.

Animals↗

PubMed1993

Experimental encephalomyocarditis virus infection in pigs.

A field isolate of Encephalomyocarditis (EMC) virus was inoculated intravenously into 8 pigs. Four animals died at post inoculation day (PID) 2, the remaining being sacrificed at PID 5, 7, 11 and 15. Two control, in-contact pigs were sacrificed at PID 19. Virus was isolated from leucocytes and nasal swabs until PID 4, from rectal swabs until PID 2 and, in the pigs found dead at PID 2, from several organs. EMC virus was further isolated from brain and spleen of the pig sacrificed at PID 7. One of the 2 control pigs became infected: virus was isolated from nasal swabs at days 6 and 7 and from leucocytes at day 4 of the experiment. Serum-neutralizing (SN) antibody was detected in the injected pigs starting from PID 4; two days later, it was also revealed in the infected, in-contact control. To our knowledge, this is the first report of an experimental transmission of EMC virus infection in pigs by contact exposure.

Animals↗

PubMed1997

Comparative study of the pathogenic properties of a Belgian and a Greek encephalomyocarditis virus (EMCV) isolate for sows in gestation.

Thirteen conventional sows were inoculated between 61 and 92 days of gestation with a Belgium or a Greek EMCV isolate to investigate the difference in pathogenicity of both strains for sows in gestation. The Belgian EMCV strain was isolated from the offspring of a sow with productive failure and without myocardial lesions. The Greek strain was isolated from a 3-month-old pig with prominent myocardial lesions. The present study demonstrates a transplacental virus transmission with fetal death following an infection of the sows in gestation with both isolates. The fetal pathogenicity was more severe with the Greek strain than with the Belgian isolate. No myocardial lesions were noticed.

Animals↗

PubMed2005

Pharmacological modulation of the endocannabinoid system in a viral model of multiple sclerosis.

Theiler's virus infection of the central nervous system (CNS) induces an immune-mediated demyelinating disease in susceptible mouse strains and serves as a relevant infection model for human multiple sclerosis (MS). Cannabinoids have been shown to exert beneficial effects on animal models of MS and evidence suggests that the endocannabinoid system plays a role in the tonic control of spasticity. In this study we show that OMDM1 [(R)-N-oleoyl-(1'-hydroxybenzyl)-2'-ethanolamine] and OMDM2 [(S)-N-oleoyl-(1'-hydroxybenzyl)-2'-ethanolamine], two selective inhibitors of the putative endocannabinoid transporter and hence of endocannabinoid inactivation, provide an effective therapy for Theiler murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD). Treatment of TMEV-infected mice with OMDM1 and OMDM2 enhanced anandamide levels in the spinal cord and ameliorated motor symptoms. This was associated with a down-regulation of inflammatory responses in the spinal cord. In addition we show that OMDM1 and OMDM2 down-regulate macrophage function by (i) decreasing the surface expression of major histocompatibility complex (MHC) class II molecules, (ii) inhibiting nitric oxide synthase-2 (NOS-2) expression and (iii) reducing the production of the pro-inflammatory cytokines interleukin-1beta (IL-1beta) and interleukin-12 (IL-12p40). Taken together, these results point to the manipulation of the endocannabinoid system as a possible strategy to develop future MS therapeutic drugs.

Animals↗

PubMed1998

The functional significance of epitope spreading and its regulation by co-stimulatory molecules.

Epitope spreading is a process whereby epitopes distinct from and non-cross-reactive with an inducing epitope become major targets of an ongoing immune response. This phenomenon has been defined in experimental and natural situations as a consequence of acute or persistent infection and secondary to chronic tissue destruction that occurs during progressive autoimmune disease. We have investigated the functional significance of this process in the chronic stages of both autoimmune and virus-induced central nervous system (CNS) demyelinating disease models in the SJL/J mouse. During the relapsing-remitting course of experimental autoimmune encephalomyelitis (R-EAE) induced with defined encephalitogenic myelin peptides, CD4+ T cells specific for endogenous epitopes on both the initiating myelin protein (intramolecular epitope spreading) and distinct myelin proteins (intermolecular epitope spreading) are primed secondary to myelin destruction during acute disease and play a major functional role in mediating disease relapses. Similarly, epitope spreading to endogenous myelin epitopes appears to play a major functional role in the chronic-progressive course of Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), a virus-induced CD4+ T-cell-mediated immunopathology. In TMEV-IDD, myelin destruction is initiated by virus-specific CD4+ T cells which target virus epitopes persisting in CNS-derived antigen-presenting cells. However, the chronic stage of this progressive disease is associated with the activation of CD4+ T cells specific for multiple myelin epitopes. In both models, the temporal course of T-cell activation occurs in a hierarchical order of epitope dominance, spreading first to the most immunodominant epitope and progressing to lesser immunodominant epitopes. In addition, epitope spreading in R-EAE is regulated predominantly by CD28/B7-1 co-stimulatory interactions, as antagonism of B7-1-mediated co-stimulation using anti-B7-1 F(ab) fragments is an effective ameliorative therapy for ongoing disease. The process of epitope spreading has obvious important implications for the design of antigen-specific therapies for the treatment of autoimmune disease since these therapies will have to identify and target endogenous self epitopes associated with chronic tissue destruction.

Animals↗

PubMed1996

Antibody responses to two encephalomyocarditis virus vaccines in rhesus macaques (Macaca mulatta).

Two groups of rhesus macaques (Macaca mulatta) housed in rodent-controlled outdoor corrals were inoculated with two different encephalomyocarditis virus (EMCV) vaccines. One group (n = 45) received a vaccine made from an inactivated field isolate of virus cultured during an outbreak at a zoo in Florida. This vaccine produced fourfold increases in the titers of 28 animals (62%); the increases persisted for at least 18 months (last test) after a single injection of the vaccine. The other group (n = 51) received a vaccine made from an inactivated porcine field strain of the virus. This vaccine did not produce titers in any of the vaccinees.

Animals↗

PubMed2005

Fatal inflammatory heart disease in a bonobo (Pan paniscus).

We report the first probable identification of encephalomyocarditis virus (EMCV) in a bonobo (Pan paniscus) that had been part of a forest re-introduction programme. Clinical presentation was of episodic acute on chronic heart failure and cerebral infarction with end-stage renal failure rather than sudden death which is more commonly associated with EMCV infection. A postmortem diagnosis of probable EMCV was made using gross pathological and histopathological examination. Findings included acute on chronic heart failure combined with the unusual but characteristic histopathological features of non-suppurative necrotizing myocarditis with mononuclear, inflammatory infiltration of the brain.

Animals↗

PubMed1999

CNS cell populations are protected from virus-induced pathology by distinct arms of the immune system.

The basis for the distinct patterns of brain pathology in individuals experiencing virus-induced encephalitis may be related to either the tropism of the virus or the host's response to virus infection of the central nervous system (CNS). In these studies we used Theiler's murine encephalomyelitis virus (TMEV) and a series of mice deficient in various immune system components (alpha/beta T cells, antibody, Class I MHC, and Class II MHC) to examine the hypothesis that discrete populations of CNS cells are protected differentially from virus infection by distinct arms of the immune response. Here we demonstrate that the Class I-mediated immune response provided more protection from areas of the brain (brainstem, corpus callosum and cerebellum) with abundant white matter as there was significantly more disease in these areas in beta2m -/- (Class I-deficient) mice as compared to A beta(0) (Class II-deficient) mice. In contrast, the striatum, with an abundance of neurons, was protected from virus-induced pathology primarily by antibody. In addition, we determined that antibody and alpha/beta T cells provided protection from severe deficits and death during the acute phase of the disease. The data presented here support the hypothesis that distinct immune system components function to protect discrete areas of the CNS from virus-induced pathology.

Animals↗