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PubMed2002

Enhanced detection of Theiler's virus RNA copy equivalents in the mouse central nervous system by real-time RT-PCR.

Infection of mice by low-neurovirulence Theiler's murine encephalomyelitis virus (TMEV), such as BeAn and DA viruses, provides a relevant experimental animal model for multiple sclerosis (MS). As a step toward determining the kinetics of a persistent central nervous system (CNS) infection that leads to chronic demyelination, we adapted a rapid, accurate and highly specific real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assay for detection and quantitation of BeAn virus RNA copy equivalents in mouse tissues. The assay enabled detection of as few as 20-30 copies of BeAn virus RNA per microg of total RNA from infected mouse tissues and results for spinal cord revealed the same high levels of BeAn RNA as detected by Northern hybridization during the first 4 months of the persistent infection, but also was able to detect virus RNA copies as late as 1 year post-infection. Real-time RT-PCR analysis of BeAn virus RNA copy equivalents in different parts of the CNS, analyses not possible by Northern hybridization, revealed the following cline of virus persistence: spinal cord>brainstem/cerebellum>cerebrospinal fluid (CSF)>cerebral hemispheres. Systemic organs, including heart, intestine and mesenteric lymph nodes of infected mice, showed no evidence of viral persistence at 4 months post-infection.

Animals↗

PubMed1997

Rapid diagnosis of encephalomyocarditis virus infections in pigs using a reverse transcription-polymerase chain reaction.

Encephalomyocarditis virus (EMCV) is widespread and the economic losses caused by an EMCV outbreak in pig holdings and the similarity between a foot-and-mouth disease virus (FMDV) and an EMCV infection in young piglets stress the need for a rapid, specific and broad diagnostic assay. An alternative to the time-consuming seroneutralisation assay, currently used for the characterisation of EMCV, is described. An EMCV specific reverse transcription-polymerase chain reaction (RT-PCR), using primers located in a conserved region of the 3D gene of the viral genome, was developed and tested on 114 different EMCV isolates. The identity of the respective amplicons was confirmed by sequencing. The potential of this assay for future diagnostic purposes was demonstrated by applying the RT-PCR on tissue samples collected from an experimentally infected piglet.

Animals↗

PubMed1997

Calcium channel blocker-induced protection against cardiovascular damage.

The therapeutic effects of calcium channel blockers on heart failure are controversial. However, a recent clinical trial demonstrated a favorable effect of amlodipine on survival rates in patients with heart failure resulting from nonischemic dilated cardiomyopathy. There are a number of studies showing that cytokines generated by activated immune cells cause an increase in nitric oxide (NO) via induction of NO synthase (NOS), which results in a direct negative inotropic effect and a modulation of inotropic responsiveness. Increases in inflammatory circulating cytokines have been detected in patients with heart failure and cardiomyopathy, elevated plasma levels of nitrite/nitrate in patients with heart failure have been reported, and inducible NOS (iNOS) has been found in ventricular tissue from patients with dilated cardiomyopathy. In our recent study, amlodipine improved histopathological lesions in the heart and survival rates in a murine model of nonischemic heart failure induced by encephalomyocarditis virus. Amlodipine inhibited NO production in vitro and decreased the number of iNOS positive cells in vivo. In this model, the therapeutic effect of amlodipine on myocardial injury is considered in part to result from inhibition of overproduction of NO. In this review, the possible roles of cytokines and NO in the pathophysiology of heart failure are discussed, along with the opportunities for therapeutic intervention.

Amlodipine↗

PubMed1999

Increased severity of viral myocarditis in mice lacking lymphocyte maturation.

The role of lymphocytes in the pathogenesis of viral myocarditis is controversial. To better understand how lymphocyte maturation controls a virus-induced myocarditic process, a murine model of viral myocarditis was utilized. Encephalomyocarditis virus (EMCV) was inoculated intraperitoneally into three kinds of mice; virus-susceptible C57BL/6, virus-resistant 129/SV and recombination activity gene (RAG)-2 knockout 129/SV mice. The RAG2 participate in the maturity of T and B lymphocytes. Survival rate, heart weight (HW), HW to body weight (BW) ratio, viral genome, cardiac inflammation and myocardial necrosis were evaluated after EMCV (500 plaque forming unit/mouse) inoculation. On post-inoculation day 10, the survival rate of C57BL/6, 129/SV and RAG2 knockout mice were 42, 90 and 0%, respectively. Myocardial viral titer was significantly (P<0.05) higher in C57BL/6 and RAG2 knockout mice than in 129/SV mice. In situ hybridization demonstrated the EMCV genome in the myocardium of RAG2 knockout and C57BL/6 mice, but not in 129/SV mice. At day 8, HW and HW/BW ratios were elevated (P<0.05) in RAG2 knockout mice as well as C57BL/6 mice compared with 129/SV mice. Myocardial necroses were more severe in RAG2 knockout mice than in wild-type 129/SV mice. In conclusion, matured lymphocytes protect the development of viral myocarditis which includes viral replication and myocardial apoptosis.

Animals↗

PubMed2001

Serological evidence that Mus musculus is the natural host of Theiler's murine encephalomyelitis virus.

Theiler's murine encephalomyelitis virus (TMEV) infection is maintained in mouse colonies by fecal-oral spread (with no apparent role for persistent central nervous system infection) from an acutely infected animal to another. Therefore, serological methods offer the principal way to assess infection in mice and related rodent populations. Infection of mouse colonies with TMEV appears to be worldwide, yet no systematic serologic studies have been reported. In this study, enzyme-linked immunoassay and neutralization analysis of sera from feral Mus musculus obtained from four locations in the United States and one in Russia revealed antibodies to purified TMEV and two linear viral peptide epitopes in more than 50% of the sera derived from the five different locations. A similar analysis of sera from 26 species of related rodents trapped at multiple locations in North America and Europe indicated the presence of anti-TMEV antibodies only in a small proportion of water and bank voles that belong to a different subfamily. These results indicate that Mus musculus is the natural host of TMEV.

Amino Acid Sequence↗

PubMed2002

Nucleotide sequence and construction of an infectious cDNA clone of an EMCV strain isolated from aborted swine fetus.

A full-length cDNA clone of an Encephalomyocarditis virus (EMCV) strain (2887A) isolated from aborted swine fetus was constructed and sequenced. Sequence comparison showed more than 99% nucleotide and amino acid sequence identity with two other EMCV strains, EMCV-PV21 and -R. However, the 2887A genomic sequence showed only about 84% nucleotide identity and 96% amino acid identity with EMCV-B, -D and -PV2 variants. RNA synthesized by in vitro transcription of this cDNA clone was infectious upon transfection of BHK21 cells, as shown by cytopathic effects and identification by neutralization test, and by propagation of the virus released into the culture media. The transcript RNA led to the production of infectious particles despite the presence of two nongenomic nucleotide residues at the 5' end, the short poly(C) tract (C(10)TCTC(3)TC(10)), the short poly(A) tail (7A), and the presence of six nongenomic nucleotides at the 3' end. The rescued virus was also found to be highly pathogenic for mice by intra-peritoneal inoculation producing a fatal disease indistinguishable from that of wild-type virus. An important finding concerning the molecular basis of infectivity was that the in vitro synthesized EMCV RNA transcript is infectious, although it contains a very short poly(A). The availability of the infectious cDNA clone of the reproductive failure strain of EMCV should prove to be useful for studying the molecular basis of the pathogenicity of EMCV in pig.

Abortion, Septic↗

PubMed1998

Molecular analysis of encephalomyocarditis viruses isolated from pigs and rodents in Italy.

Partial nucleotide sequences of encephalomyocarditis (EMC) viruses isolated from five, apparently independent, outbreaks of fatal myocarditis in pigs in Italy were compared with three EMC viruses isolated from wild rodents from a different geographic region in the same country. These viruses were also compared with EMC viruses isolated from pigs in other European countries and three historical strains. All the Italian EMC viruses were closely related (> 94.6% nucleotide identity), but were distinct from viruses occurring in Belgium in 1991 (< 80.5% nucleotide identity), Greece in 1990 (< 83.3% nucleotide identity) and the three older viruses (< 82.9% nucleotide identity). An EMC virus isolated from pigs in the Netherlands in 1988, was closely related to the Italian viruses (95.3-99.3% nucleotide identity). It is suggested that pigs may play a role in the movement of EMC viruses between different geographic regions.

Animals↗

PubMed2001

Enhancement of VP1-specific immune responses and protection against EMCV-K challenge by co-delivery of IL-12 DNA with VP1 DNA vaccine.

It has been reported that co-delivery of IL-12 DNA with a DNA vaccine further enhances antigen (Ag)-specific protective immunity in pathogenic challenge models. However, the enhancing effects of antibody by IL-12 have been controversial. To clarify this issue, we constructed an IL-12 expression vector, co-immunized IL-12 DNA with an encephalomyocarditis virus (EMCV)-D VP1 plasmid vaccine, and then evaluated immune modulatory effects and protection against lethal EMCV-K challenge. We observed that VP1-specific IgG production, as well as seroconversion rates, were significantly enhanced by IL-12 co-injection, indicating that IL-12 can enhance antibody responses in this model system. In particular, co-injection with VP1 plus IL-12 DNA into the same leg enhanced systemic Ag-specific IgG production to a significantly greater extent than either the separate leg injection of VP1 and IL-12 DNA or VP1 DNA vaccine alone. This suggests that local co-expression of IL-12 along with antigens is more important for enhanced antibody production. Furthermore, IgG2a isotype was significantly enhanced by IL-12 DNA co-injection, indicating a Th1 bias. In addition, co-delivery of IL-12 DNA was demonstrated to enhance VP1-specific Th cell proliferative responses. When animals were challenged with a lethal dose of EMCV-K, IL-12 DNA-co-immunized animals exhibited enhanced survival, as compared to VP1 DNA vaccine alone. These studies suggest that IL-12 plays an important role in increasing Ag-specific Th1 type antibody and cellular responses, resulting in enhanced protection against lethal EMCV-K challenge.

Animals↗

PubMed1998

The efficacy of an experimental oil-adjuvanted encephalomyocarditis vaccine in elephants, mice and pigs.

An oil-adjuvanted inactivated encephalomyocarditis (EMC) vaccine was developed to protect a wild population of elephants against a natural outbreak of disease. The experimental vaccine was initially tested for efficacy by challenging mice and pigs. Mice showed protection against challenge and pigs developed high antibody levels. Since both vaccinated and control pigs failed to develop clinical disease, apparently due to the low virulence of the strain in this species, protection in pigs could not be evaluated. Vaccinated elephants developed high antibody titers which protected all vaccinates from a challenge roughly two months post-vaccination, whereas controls developed fatal or sub-clinical myocarditis. This is the first report of an inactivated EMC vaccine inducing high antibody titers in domestic and wild animal species. Due to the potency of this vaccine and the acceptability of the oil adjuvant used, it has potential for use in animals in zoological collections as well as in the pig industry.

Adjuvants, Immunologic↗

PubMed1997

Protective immunity against heterologous challenge with encephalomyocarditis virus by VP1 DNA vaccination: effect of coinjection with a granulocyte-macrophage colony stimulating factor gene.

For DNA vaccination studies, recombinant VP1 protein of encephalomyocarditis virus (EMCV) was produced from Escherichia coli, and eukaryotic VP1 expression vector, pCT-Gs-VP1, was generated and used as a DNA vaccine. Mice were immunized intramuscularly (i.m.) with pCT-Gs-VP1 in the presence or absence of plasmid DNA expressing granulocyte-macrophage colony stimulating factor (GM-CSF), and were subsequently analyzed for their anti-VP1 immune responses with recombinant VP1 in ELISA. Immunization of mice with pCT-Gs-VP1 resulted in VP1-specific immune response and 43% protection from subsequent lethal heterologous challenge of EMCV. Coinjection of mice with pCT-Gs-VP1 and plasmid DNA encoding GM-CSF was shown to increase the seroconversion rate of the immunized mice with a single DNA injection, and enhanced to a higher degree VP1-specific immunity, which appeared to result in better protection (about 80%) from lethal virus challenge. Thus, our results provide evidence for the potential use of GM-CSF to induce better immune response and resistance against viral infection in DNA vaccination.

Animals↗

PubMed2002

Distinct cell death mechanisms by Theiler's murine encephalomyelitis virus (TMEV) infection in microglia and macrophage.

DA strain of Theiler's murine encephalomyelitis virus (TMEV) persists in the mouse central nervous system (CNS) and induces demyelination while GDVII strain fails to persist or demyelinate. L* protein, which is synthesized only in DA but not GDVII, is believed important in virus persistence and demyelination. Because a major reservoir for DA persistence is infiltrated macrophages or microglia, a resident macrophage of the CNS, we investigated TMEV infection of Ra2 cells, a murine microglial cell line. We found that DA strain grew well in Ra2 cells, but not GDVII strain or DAL*-1 virus (which fails to synthesize L* protein), suggesting that L* protein plays an important role in virus growth in microglia. Interestingly, in contrast to virus growth, most Ra2 cells infected with DA strain survived with no evidence of virus-induced apoptosis. These results may be important in clarifying the pathogenesis of DA-induced demyelinating disease.

Animals↗

PubMed2002

Transmission of encephalomyocarditis virus (EMCV) among pigs experimentally quantified.

Two types of transmission experiments were performed to estimate the basic reproduction ratio R(0), indicating the level of encephalomyocarditis virus (EMCV) transmission among pigs. In a first experimental set-up with nine separate pairs, one randomly chosen piglet per pair was inoculated with a Belgian (myocardial) EMCV strain (B279/95, 10(3)TCID(50)/ml oronasally) and placed back into the pen. In the second experiment with two separate groups of five piglets, two piglets in each group were inoculated at the start. During the experiments, viraemia in blood and excretions was measured as well as the serological response against EMCV antigen. After death or euthanasia, the piglets were checked for heart lesions and virus isolation was done on various tissues. In both the experiments, the majority of the inoculated piglets either died with typical heart lesions (five out of nine and three out of four resp.), or produced high levels of neutralising antibody. EMC virus was isolated from the hearts of all piglets that died during either one of the experiments. The pairwise experiment revealed a point estimate for R(0) of 2.0 (95% confidence interval (CI)=0.37-10.74), while the group experiment resulted in a R(0)-value of 0.71 (95% CI=0.08-4.93). Combining the information from both experiments results in an estimate for R(0) of 1.24 (95% CI=0.39-4.35). Since R(0) has values around the threshold value of 1, the spread of EMCV due to contacts between pigs will in most cases be limited, but due to chance processes may lead to large outbreaks as well.

Animals↗

PubMed1999

Persistence of encephalomyocarditis virus (EMCV) infection in piglets.

Six piglets that had survived experimental infection with encephalomyocarditis virus (EMCV) were treated with dexamethasone for a period of 5 days. The virus had not been detected in excretions of putative carriers for a period of 13-20 days before the treatment. All piglets showed a rise in cardiac isoenzyme (CK-MB) activity, from the first day of treatment, suggesting myocardial damage. Antibody titres against EMCV remained stable or slightly decreased during treatment. EMCV was isolated from blood, nasal and faecal samples from all piglets on days 2 and 3 after initiation of treatment and from various tissues of three piglets. Four contact piglets, that were housed together with the dexamethasone-treated piglets, became infected, indicating that EMCV was shed by treated piglets. It is suggested that recovered pigs may play an important role in the dissemination of EMCV.

Animals↗

PubMed1999

A comparative study of the pathogenic properties and transmissibility of a Greek and a Belgian encephalomyocarditis virus (EMCV) for piglets.

Thirteen susceptible piglets, aged 40 days, were divided into two groups and were experimentally infected either with a Greek (myocardial) or a Belgian (reproductive) encephalomyocarditis virus (EMCV) strain (total dose 5 x 10(6) TCID50, intramuscularly and intranasally). Six piglets were placed in the same rooms, 24 h later, as contact controls. The following criteria were studied: ante mortem: clinical signs, serum cardiac isoenzyme activities (CK-MB and LD-1), viraemia, nasal and faecal virus excretion and serological response. Post mortem (after death or euthanasia): gross lesions, virus isolation from tissues, RT-PCR, as well as histopathological and immunohistochemical findings. The Greek strain was more pathogenic, producing mortality, with high cardiac isoenzyme activities and pronounced macroscopic myocardium lesions. The Belgian strain was able to induce mild heart lesions, as detected only by cardiac isoenzyme activity and histopathologically. All contact pigs were infected, within the first 1-2 days of their introduction, that coincided with the period of viral excretion by the experimentally infected pigs (up to the 3rd day post infection). Disease was mild, with no mortality.

Animals↗

PubMed2000

Immunoglobulin treatment ameliorates murine myocarditis associated with reduction of neurohumoral activity and improvement of extracellular matrix change.

OBJECTIVES: We examined effects of immunoglobulin on murine myocarditis induced by encephalomyocarditis virus, not pathogenic to humans, and analyzed the plasma cytokine and catecholamine levels and the changes of the extracellular matrix with or without the treatment. BACKGROUND: We have previously shown that immunoglobulin therapy suppressed murine coxsackievirus B3 myocarditis by an antiviral effect. However, it is not yet determined whether beneficial effects of immunoglobulin for myocarditis are due to antiviral effects or to other unknown effects. METHODS: Antiviral activity of human immunoglobulin (Polyglobin-N) against encephalomyocarditis virus was determined in vitro. Immunoglobulin (1 g/kg/day) was administered intraperitoneally to the virus-infected mice daily for two weeks, beginning simultaneously with virus inoculation in experiment I and on day 14 after virus inoculation in experiment II. RESULTS: Antiviral activity of immunoglobulin could not be detected in the assay of a plaque-reduction method in vitro. The in vivo study showed that immunoglobulin administration ameliorated both myocardial necrosis with interstitial fibrin deposition in experiment I and interstitial fibrosis with the improvement of ventricular remodeling in experiment II by the reduction of plasma catecholamines, interferon-alpha, and soluble intercellular adhesion molecule-1. CONCLUSIONS: Immunoglobulin therapy could suppress myocarditis associated with the improvement of extracellular matrix changes by the reduction of neurohumoral activity.

Animals↗

PubMed2001

Therapeutic effects of FTY720, a new immunosuppressive agent, in a murine model of acute viral myocarditis.

OBJECTIVES: This study examines the efficacy of FTY720 (FTY), a new immunosuppressor, in the treatment of acute viral myocarditis in a murine model. BACKGROUND: Immunosuppressive agents have no proven therapeutic efficacy in experimental or clinical myocarditis. METHODS: Encephalomyocarditis virus was inoculated i.p. in DBA/2 mice on day 0. Postinoculation treatment consisted of FTY 10 mg/kg/day p.o. (FTY group), or cyclosporine A (CsA) 40 mg/kg/day p.o. (CsA group) or distilled water p.o. only (control group). Survival until day 14, as well as cardiac histopathology, virus concentrations, cytokines (interleukin [IL]-2, IL-12, interferon [IFN]-gamma and tumor necrosis factor [TNF]-alpha) and nitric oxide (NO) on day 5 were examined. RESULTS: In the control and CsA groups, all mice died within 10 and 7 days, respectively. However, in the FTY group, 27% of the animals survived up to day 14. Compared with the control group, 1) histological scores were significantly lower in the FTY group but unchanged in the CsA group; 2) virus concentration was significantly higher in the CsA group but not in the FTY group; 3) expressions of IL-2, IL-12 and IFN-gamma in the heart were suppressed in both the FTY and CsA groups, though suppression was weaker in the FTY group; 4) TNF-alpha and NO were significantly increased in the CsA group but not in the FTY group. CONCLUSIONS: FTY720 had a significant therapeutic effect in acute experimental myocarditis without inducing excessive virus replication. This report is the first to describe a beneficial effect by an immunosuppressive agent in the treatment of acute viral myocarditis.

Acute Disease↗

PubMed2003

Carvedilol increases the production of interleukin-12 and interferon-gamma and improves the survival of mice infected with the encephalomyocarditis virus.

OBJECTIVES: This study was designed to examine the effects of carvedilol in a murine model of viral myocarditis induced by encephalomyocarditis virus (EMCV) infection. BACKGROUND: Cytokines play an important role in the pathophysiology of viral myocarditis. Catecholamines influence the production of cytokines via beta-adrenergic receptors, suggesting that beta-adrenergic blockers could modulate the production of cytokines and exert a therapeutic effect in viral myocarditis by blocking the beta-stimulating action of endogenous catecholamines. In clinical trials, the third-generation, nonselective beta-blocker carvedilol was the first among several beta-blockers to reduce mortality in heart failure. However, the effects of carvedilol in acute viral myocarditis and on cytokine production are unknown. METHODS: This study compared the effects of carvedilol, the selective beta(1)-blocker metoprolol, and the nonselective beta-blocker propranolol in a murine model of viral myocarditis induced by EMCV. RESULTS: Carvedilol improved the 14-day survival of the animals, attenuated myocardial lesions on day 7, and increased myocardial levels of interleukin (IL)-12 and interferon (IFN)-gamma, whereas reducing myocardial virus replication. Propranolol also attenuated myocardial lesions, but to a lesser extent, and increased IL-12 and IFN-gamma levels. Metoprolol had no effect in this model. Encephalomyocarditis virus infection increased plasma catecholamine levels. CONCLUSIONS: These results suggest that by blocking the beta(2)-stimulating effects of catecholamines, carvedilol exerts some of its beneficial effects by increasing the production of IL-12 and IFN-gamma. Carvedilol may be effective in patients with viral myocarditis by boosting IL-12 and IFN-gamma production.

Adrenergic beta-Antagonists↗

PubMed1998

Denopamine, a beta1-adrenergic agonist, prolongs survival in a murine model of congestive heart failure induced by viral myocarditis: suppression of tumor necrosis factor-alpha production in the heart.

OBJECTIVES: This study was designed to examine the effects of denopamine, a selective beta1-adrenergic agonist, in a murine model of congestive heart failure (CHF) due to viral myocarditis. BACKGROUND: Positive inotropic agents are used to treat severe heart failure due to myocarditis. However, sympathomimetic agents have not been found beneficial in animal models of myocarditis. METHODS: In vitro: The effects of denopamine on lipopolysaccharide-induced tumor necrosis factor-alpha (TNF-alpha) production was studied in murine spleen cells. In vivo: Four-week-old DBA/2 mice were inoculated with the encephalomyocarditis virus (day 0). Denopamine (14 micromol/kg), denopamine (14 micromol/kg) with a selective beta1-blocker metoprolol (42 micromol/kg), or denopamine (14 micromol/kg) with metoprolol (84 micromol/kg) was given daily, and control mice received the vehicle only. Survival and myocardial histology on day 14 and TNF-alpha levels in the heart on day 6 were examined. RESULTS: In the in vitro study, TNF-alpha levels in treated cells were significantly lower than in controls (p < 0.05). In the in vivo study treatment with denopamine significantly improved the survival of the animals (14 of 25 (56%) treated, vs 5 of 25 (20%) control mice), attenuated myocardial lesions, and suppressed TNF-alpha production (66.5+/-7.5 pg/mg of heart in treated mice vs 113.5+/-15.1 pg/mg of heart in control mice, mean+/-SE). There was a strong linear relationship between mortality and TNF-alpha levels (r=0.98, n=4, p < 0.05). These in vitro and in vivo effects of denopamine were significantly inhibited by metoprolol. CONCLUSIONS: These results suggest that denopamine may exert its beneficial effects, in part, by suppressing the production of TNF-alpha via beta1-adrenoceptors.

Adrenergic beta-Agonists↗