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At least 163 records · Page 9Linked to original sources
PubMed1997

Effects of levamisole, an immunomodulator, upon murine encephalomyocarditis virus myocarditis.

To test the therapeutic efficacy of levamisole, 5-week-old DBA/2 mice were inoculated intraperitoneally with 10 plaque-forming units of encephalo-myocarditis virus. Levamisole (2.5 mg/kg/per day) was administered intraperitoneally daily, starting simultaneously with the virus inoculation, in experiment I for 14 days, and daily on days 14 to 28 in experiment II in mice that survived to 14 days after virus inoculation. In experiment I, survival was higher, the severity of myocarditis was less, and myocardial virus titers were lower in treated than in untreated animals. In experiment II, levamisole was not effective. No significant changes in serum neutralizing antibody titers occurred in either experiment. Furthermore, levamisole prevented associated lymphoid organ atrophy induced by the virus infection. An additional in vitro study revealed the absence of anti-viral activity of the drug. Thus, levamisole may have favorable effects upon encephalomyocarditis virus myocarditis by preventing the virus-induced lymphoid organ atrophy and reducing myocardial virus replication in the acute stage.

Adjuvants, Immunologic↗
PubMed2001

The role of viruses in type I diabetes: two distinct cellular and molecular pathogenic mechanisms of virus-induced diabetes in animals.

Type I (insulin-dependent) diabetes mellitus results from the progressive loss of pancreatic beta cells. Environmental factors are believed to play an important part in the development of Type I diabetes by influencing the penetrance of diabetes susceptibility genes. As one environmental factor, the virus has long been considered to play a part in this disease. To date 13 different viruses have been reported to be associated with the development of Type I diabetes in humans and in various animal models. The most clear and unequivocal evidence that a virus induces diabetes in animals comes from studies on the D variant of the encephalomyocarditis (EMC-D) virus in mice and the Kilham rat virus (KRV) in rats. The infection of genetically susceptible strains of mice with a high titre of EMC-D virus results in the development of diabetes within 3 days. This is largely due to the rapid destruction of beta cells by the replication of the virus within the beta cells. In contrast, the infection of mice with a low titre of EMC-D virus results in a limited replication of the virus before the induction of neutralizing anti-virus antibody and the subsequent recruitment of activated macrophages. The Src kinases, particularly hck, play an important part in the activation of macrophages and the subsequent production of tumour necrosis factor (TNF)-alpha, interleukin (IL)-1 beta and nitric oxide (NO), leading to the destruction of beta cells which results in the development of diabetes. The Kilham rat virus causes autoimmune diabetes in diabetes resistant (DR)-BB rats without infection of beta cells. The infection of DR-BB rats with KRV results in the disruption of the finely tuned immune balance of Th1-like CD45RC+CD4+ and Th2-like CD45RC-CD4+ T cells, leading to the selective activation of beta-cell-cytotoxic effector T cells.

Animals↗
PubMed2003

Molecular analysis of the capsid coding region of a virulent encephalomyocarditis virus isolate after serial cell passages and assessment of its virulence.

EMCV has been recognized as a worldwide-shared pathogen in many host species with natural differences of virulence among strains. Differences of virulence were also demonstrated experimentally after serial passages of particular EMCV strains in cell culture. In order to evaluate the genetic variability of the CCR of an highly virulent Belgian EMCV isolate after 210 passages in cell culture, this region has been molecularly characterised by RT-PCR and sequencing. The analyses enlightened the stability of the isolate as only 3 mutations appeared within the CCR and this was observed between passage 200 and 210. One of the mutations is adjacent to the amino acid described as the differentiation amino acid between diabetogenic and non-diabetogenic variants of EMCV. An experimental inoculation of pigs with the passage 210 of the virus enlightened its attenuation and the challenged pigs were protected against the wild-type virus. Results confirm the ability of EMCV to become attenuated after passages in cell culture.

Animals↗
PubMed2006

Characterization of a recombinant encephalomyocarditis virus expressing the enhanced green fluorescent protein.

A recombinant encephalomyocarditis virus (rEMCV2887A-egfp) expressing the enhanced green fluorescent protein (EGFP) was produced. The EGFP gene was inserted in frame within the leader protein coding sequence of a full-length cDNA clone of EMCV. RNA transcripts derived from the recombinant full-length cDNA were synthesized in vitro and transfected into BHK-21 cells. The recombinant transcript RNA remained infectious despite the insertion of EGFP as shown by cytopathic effects on BHK-21 cells and by propagation of the rescued virus. The replication kinetics in BHK-21 cells and the pathogenicity in mice of rEMCV2887A-egfp did not differ significantly from that of the parental virus. The recombinant virus was shown to produce fluorescence in infected cells after at least five passages in BHK-21 cells. However, a decrease of EGFP expression was observed following serial passages, and this was associated with the accumulation of deletion mutations within the EGFP gene. Nevertheless, using EGFP autofluorescence, infected cells were easily detected in the brain of mice infected with the first-passage recombinant virus. These data demonstrate that rEMCV2887A-egfp could be a useful tool to study virus dissemination and pathogenicity when used at low passages.

Animals↗
PubMed2006

Synthesis of the allergen ovomucoid by a replicating Mengo virus.

Interferons induced by viral infections can have powerful immuno- modulatory effects, and several epidemiologic studies have found an association between certain viral infections and reduced prevalence of allergy. We hypothesized that allergenic proteins could be synthesized by a replicating virus, and this construct could be useful as an immunomodulator. To test this hypothesis, we cloned an allergenic protein (ovomucoid [OVM]) into a murine picornavirus (Mengo virus) vector. This plasmid has a multicloning site surrounded by auto-catalytic sequences so that a foreign protein will be cleaved from viral proteins during replication. OVM sequences were cloned in the context of full-length viral genome cDNA, T7 RNA transcripts of this plasmid were transfected into HeLa cells, and recombinant virus plaques appeared on the second passage. Sequence analysis of recombinant viruses derived from individual plaques demonstrated that three viral isolates contained up to 2/3 of the OVM coding sequence, which was retained by the viruses after 5 additional passages in HeLa cells. The experiments verify the stable expression of immunoreactive OVM subunits by replicating viruses. These virus/allergen constructs could provide a tool to evaluate whether intracellular presentation of allergenic proteins in the context of a viral infection could prevent allergic sensitization upon re-challenge.

Allergens↗
PubMed1997

Isolation of a measles virus variant: protection of newborn mice from measles encephalitis by 24 h prior intracerebral inoculation with the variant.

A small plaque mutant with reduced neurovirulence in newborn mice was obtained from Edmonston strain measles virus after propagation for 5 months in NIH3T3 cells. It retained the antigenicity of the parental virus and tended to induce higher neutralizing antibody titers in the adult BALB/c mice. The intracerebral (but not intraperitoneal) inoculation of the live mutant virus one day before prevented the newborn BALB/c mice from encephalitis caused by the intracerebral challenge with the parental strain at a dose of 10-20 LD50. The intracerebral inoculation with the mutant virus whose replication capacity was inactivated by UV-irradiation was ineffective. The protection was not attributed to interferons nor to viral interference. The mechanism remains unknown.

3T3 Cells↗
PubMed2005

Encephalomyocarditis in monkeys.

This paper presents the results of studies of a spontaneous viral infection in monkeys--encephalomyocarditis caused by encephalomyocarditis virus. The infection first detected in the Sukhumi Breeding Center in 1974 was observed in the Adler Breeding Center since 2001. The characteristics of the virus are described and principles of diagnostic by the results of pathologic studies are presented.

Animals↗
PubMed2006

Differential usage of carbohydrate co-receptors influences cellular tropism of Theiler's murine encephalomyelitis virus infection of the central nervous system.

Theiler's murine encephalomyelitis viruses (TMEV) are ubiquitous pathogens of mice, producing either rapidly fatal encephalitis (high-neurovirulence strains) or persistent central nervous system infection and inflammatory demyelination (low-neurovirulence strains). Although a protein entry receptor has not yet been identified, carbohydrate co-receptors that effect docking and concentration of the virus on the cell surface are known for both TMEV neurovirulence groups. Low-neurovirulence TMEV use alpha2,3-linked N-acetylneuramic acid (sialic acid) on an N-linked glycoprotein, whereas high-neurovirulence TMEV use the proteoglycan heparan sulfate (HS) as a co-receptor. While the binding of low-neurovirulence TMEV to sialic acid can be inhibited completely, only a third of the binding of high-neurovirulence TMEV to HS is inhibitable, suggesting that high-neurovirulence strains use another co-receptor or bind directly to the putative protein entry receptor. Four amino acids on the surface (VP2 puff B) of low-neurovirulence strains make contact with sialic acid through non-covalent hydrogen bonds. Since these virus residues are conserved in all TMEV strains, the capsid conformation of this region is probably responsible for sialic acid binding. A persistence determinant that maps within the virus coat using recombinant TMEV is also conformational in nature. Low-neurovirulence virus variants that do not bind to sialic acid fail to persist in the central nervous system of mice, indicating a role for sialic acid binding in TMEV persistence. Analysis of high-neurovirulence variants that do not bind HS demonstrates that HS co-receptor usage influences neuronal tropism in brain, whereas, the HS co-receptor use is not required for the infection of spinal cord anterior horn cells associated with poliomyelitis.

Animals↗
PubMed1993

Antiviral action of trehalose dimycolate against EMC virus: role of macrophages and interferon alpha/beta.

Preventive treatment of mice with trehalose 6,6' dimycolate (TDM), an immunomodulator of bacterial origin, enhances their resistance to encephalomyocarditis (EMC) virus infection. The protective effect of TDM is totally abolished by the injection of silica particles in mice, demonstrating the role of macrophages in the antiviral action of TDM. In vitro, peritoneal macrophages from mice treated with TDM (TDM-PM) exhibit an intrinsic antiviral activity against EMC virus, while resident peritoneal macrophages (RES-PM) are permissive to this virus. Greater amounts of interferon are detected in supernatants of cultures of TDM-PM than of RES-PM. Neutralization of interferon (IFN) by addition in vitro of anti-IFN alpha/beta serum markedly reduces the antiviral activity of TDM-PM. These results indicate that interferon alpha/beta is involved in the intrinsic anti-EMC virus activity of peritoneal macrophages from mice treated with TDM.

Animals↗
PubMed1995

Role of trehalose dimycolate-induced interferon-alpha/beta in the restriction of encephalomyocarditis virus growth in vivo and in peritoneal macrophage cultures.

Preventive intraperitoneal trehalose dimycolate (TDM) treatment of mice, inoculated with encephalomyocarditis (EMC) virus by the same route, caused restriction of virus growth in the peritoneum, which was correlated to IFN production in peritoneal fluids prior to infection. Peritoneal macrophages from TDM-treated mice (TDM-PM) spontaneously secreted IFN-alpha/beta in large amounts. By their supernatants, TDM-PM could transfer an antiviral state against EMC virus to permissive resident peritoneal macrophages from control mice. IFN-alpha/beta produced by TDM-PM was found to be involved in this transfer activity. TDM-PM also exerted a strong antiviral effect on EMC virus-infected L-929 cells, which increased with time and the macrophage-target cell ratio. This activity also occurred by an IFN-alpha/beta-dependent mechanism. These data point to the role of IFN-alpha/beta production prior to EMC virus infection in the antiviral activities of TDM-PM and, more generally, in the outcome of viral infection.

Animals↗
PubMed1996

Analysis of sequence and pathogenic properties of two variants of encephalomyocarditis virus differing in a single amino acid in VP1.

The encephalomyocarditis (EMC) virus-induced diabetes-like syndrome in mouse inbred strains was used as a model to study the insulin-dependent diabetes mellitus (IDDM). Our investigations were performed with two EMC virus variants, PV2 and PV7. After infection of SJL mice with 10(5) PFU of PV2 about 70% of the animals developed a diabetes-like syndrome, whereas the PV7 infected mice appeared healthy. Histological examination and in situ experiments revealed that the islets of Langerhans are a main target of PV2, whereas PV7 infection leads to only modest changes of the islets. Sequence analysis of both variants revealed one amino acid exchange within the capsid protein VP1. Hence, we describe the first diabetogenic and non-diabetogenic EMCV variants differing in only one single amino acid.

Amino Acid Sequence↗
PubMed1996

Enhancement by muramyl peptides of the protective response of interferon-alpha/beta against encephalomyocarditis virus infection.

The use of interferon-alpha (IFN-alpha) in the treatment of infectious diseases has shown limited efficacy and dose-limiting toxicity. We have selected safe immunomodulators of the muramyl peptide family with the potential of enhancing the efficacy of IFN-alpha without resulting in increased toxicity. One of these synthetic muramyl dipeptide (MDP) derivatives, namely murabutide which is in a clinical stage of development, has been recently found to synergize with IFN-alpha 2a in the selective induction of anti-inflammatory mediators and to enhance the biological activities of the therapeutic cytokine. The present study was performed to assess the antiviral activity of such muramyl peptides and a possible potentiation of the antiviral activity of IFN-alpha/beta by associated therapy using the classical assay of Encephalomyocarditis virus (EMCV) infection. In vitro, pretreatment of Moloney Sarcoma virus (MSV)-transformed cell line with MDP derivatives followed by treatment with IFN-alpha/beta showed a synergistic protection against the cytopathogenic effect of a subsequent EMCV infection. None of the MSV cultures could be protected by stimulation with muramyl peptides alone. In vivo, all of the muramyl peptide derivatives tested were found to be more potent than the parent molecule MDP in inducing protection against death or in the prolongation of the mean survival time of infected mice. Sequential administration of suboptimal doses of exogenous IFN-alpha/beta and muramyl peptides established a strong antiviral state and considerably improved the protective effect of the cytokine, frequently leading to an abortive infection. Our findings suggest that combination therapy with safe muramyl peptides and IFN-alpha/beta could constitute a highly effective and new regimen for the treatment of viral infections in humans.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1994

Reproductive failure in sows following experimental infection with a Belgian EMCV isolate.

In this study, a transplacental infection with fetal death was demonstrated following inoculation of pregnant sows with a Belgian encephalomyocarditis virus (EMCV) isolate. Eight multiparus sows were inoculated between 60 and 92 days of gestation with this EMCV-isolate to investigate its ability to cause reproductive failure in sows. Virus persistence and antibody titre in their offspring were also studied. Only the two sows inoculated at 60 days of gestation showed premature farrowing, but all sows seroconverted to EMCV. Virus was recovered from the offspring of all sows at the time of farrowing, but not from every piglet born. One month after birth EMCV could be isolated from all the piglets examined. These results can help in a better understanding of the spread of the disease in piggeries.

Animals↗
PubMedDate not supplied

Relevance of inflammatory cell infiltrates for complete atrioventricular block in experimental murine myocarditis.

BACKGROUND: There are few systemic pathologic studies on myocarditis. This study aimed to clarify the pathologic characteristics of murine myocarditis. METHODS: We recorded serial electrocardiograms in experimental viral myocarditis in mice and then examined their cardiac pathology. After taking baseline electrocardiograms, we inoculated the mice intraperitoneally with the encephalomyocarditis virus. Electrocardiograms were serially recorded until 220 days after the virus inoculation. RESULTS: Serial electrocardiograms revealed ectopic beats, low voltage of the QRS complex, and the appearance of complete atrioventricular (AV) block. Corresponding myocardial lesions were found in the hearts of mice with these ectopic beats. Mononuclear cell infiltrations into the His bundle were most frequently found in mice with complete AV block. CONCLUSIONS: Inflammatory change with cellular infiltrations was the most common pathologic finding in mice with complete AV block. In clinical settings, anti-inflammatory therapy might be recommended for patients with myocarditis complicated with conduction disturbances.

Animals↗
PubMed2006

Theiler's virus induces the MIP-2 chemokine (CXCL2) in astrocytes from genetically susceptible but not from resistant mouse strains.

The murine encephalomyelitis virus of Theiler (TMEV) induces demyelination in susceptible strains of mice by a CD4(+) Th1 T cell mediated immunopathologic process. We focused on the production of one chemokine, the macrophage inflammatory protein-2 (MIP-2 or CXCL2), by cultured mouse astrocytes infected with the BeAn strain of TMEV. Analysis of a murine genome DNA hybridized with cRNA from mock- and TMEV-infected astrocytes, revealed up-regulation of three sequences encoding MIP-2. Northern blot analysis indicated increased MIP-2 mRNA expression. Levels of MIP-2 in the supernatants of infected cells as detected by ELISA, varied directly with the multiplicity of infection used. This secreted CXCL2 was biologically active inducing chemoattraction of neutrophils but not of lymphocytes. CXCL2 was specifically induced by TMEV infection, since induction was inhibited by anti TMEV antibodies. The inflammatory cytokines, IL-1alpha and TNF-alpha, which are also induced in astrocytes by TMEV, were very potent inducers of CXCL2. Nevertheless, both mechanisms of induction follows different pathways as antibodies to both cytokines fails to inhibit TMEV-induced CXCL2 up-regulation. Sera from TMEV-infected SJL/J mice with chronic demyelination, but not from BALB/c TMEV-resistant mice, revealed CXCL2 at the peak of clinical disease. Our main novel finding is the strain-dependent differences in CXCL2 expression both in vitro and in vivo. This suggest an role for this chemokine in attracting immune cells within the CNS, which in turn, might trigger demyelination in this experimental model of MS.

Animals↗
PubMed2004

Suppression of cytokines and nitric oxide production, and protection against lethal endotoxemia and viral myocarditis by a new NF-kappaB inhibitor.

BACKGROUND: Nuclear factor kappa B (NF-kappaB) is activated by several factors, which increase the inflammatory response, and this activation, in turn, leads to the expression of several genes such as cytokines, and may play an important role in cardiovascular diseases. AIMS: The aim of the study is to examine the effect of SUN C8079, a newly synthesized NF-kappaB inhibitor in vitro and in vivo. METHODS: We examined the effects of SUN C8079 on the transcriptional responses of NF-kappaB, on activation of NF-kappaB in electrophoretic mobility shift assay, and on the gene expressions of tumor necrosis factor (TNF)-alpha and iNOS. We also studied effects of SUN C8079 on lethal endotoxemia and viral myocarditis in mice. RESULTS: SUN C8079 inhibited the lipopolysaccharide (LPS)-induced expression of the genes of TNF-alpha and iNOS by inhibiting the activation of NF-kappaB in vitro. SUN C8079 inhibited the systemic release of TNF-alpha and improved mortality in LPS-treated mice. In addition to protecting mice against lethal endotoxemia, SUN C8079 prevented the development of myocarditis due to the encephalomyocarditis virus (EMCV), and inhibited the expressions of proinflammatory cytokines and the iNOS gene in cardiac tissues. CONCLUSION: These findings suggest that the activation of NF-kappaB plays an important role in the pathogenesis of endotoxemia and viral myocarditis, and that the NF-kappaB inhibitor, SUN C8079, may be therapeutic in these disorders.

Animals↗
PubMed2005

ERK-MAP-kinases differentially regulate expression of IL-23 p19 compared with p40 and IFN-beta in Theiler's virus-infected RAW264.7 cells.

Theiler's murine encephalomyelitis virus (TMEV) infection of macrophages induces a demyelinating disease (DD) in certain strains of mice that is similar to human multiple sclerosis. In contrast to IFN-beta, expression of IL-23 p19 and p40 subunits by macrophages in response to TMEV may contribute to DD. TMEV infection of macrophages likely induces IL-23 and IFN-beta by activating p38 or ERK MAP-kinases (MAPK) and the p38 substrate ATF-2 within 30 min. To determine the role of MAPKs in TMEV-induced IL-23 and IFN-beta expression, RAW264.7 cells were pretreated with SB203580 or U0126, inhibitors of p38 and ERK MAPKs, respectively. SB203580 significantly increased TMEV-induced p19 but decreased p40 expression. In contrast, U0126 decreased p19 and increased TMEV-induced p40 and IFN-beta expression. Interestingly, U0126 prolonged TMEV-induced ATF-2 activation to at least 3h. Thus ERK MAPKs regulate expression of TMEV-induced p19 differently than p40 and IFN-beta suggesting the benefits of U0126 in treatment of DD.

Activating Transcription Factor 2↗