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PubMed1985

A comparative study on the translation of cardiovirus RNAs in rabbit reticulocyte lysates.

In rabbit reticulocyte lysates the RNAs of encephalomyocarditis (EMC) virus, mengovirus, and Mous-Elberfeld (ME) virus directed the synthesis of similar sets of products. Moreover, the viral protease synthesized from any one of the three viral RNAs could cause cleavage of the viral capsid precursor proteins synthesized from any of the three RNAs. However, the three RNAs differed in their dependence on tRNA supplementation (to the lysates) for effective translation. In the absence of tRNA supplementation, synthesis of 5'-derived proteins of EMC viral RNA proceeded normally, but little synthesis of the proteins coded by the remaining portion of the viral genome occurred. In the case of mengoviral RNA, omission of tRNA supplementation caused mostly a generalized reduction of the synthesis of all viral proteins. In contrast, synthesis of ME viral proteins stopped almost completely in the absence of tRNA supplementation.

Animals↗
PubMed1981

Mechanism of antiviral action of quercetin against cardiovirus infection in mice.

Oral treatment with quercetin protected ABD2F1/Jena mice significantly against intraperitoneal encephalomyocarditis, Col, SK, MM, Mengo M,L and MengoM virus infections, but not against intracerebral challenge with MengoM virus. Enhanced resistance to MengoM virus were induced in the genetically different DBA 2/Jena, C57BL/Jena, C57BL/Lati and ABC2F1/Jena mice, C57BL6/Jena nu/nu mice were also protected, indicating that the thymus was non-essential to the protective effects of quercetin. In AB/Jena and Lati:CFLP mice the drug failed to be effective. Quercetin was not virucidal and did not interfere with Mengo virus replication in L cells. Interferon was not detected (less than 1 : 8) in sera of ABD2F1/Jena mice 1-48 h after oral administration of the drug. The virus spread from the site of injection to the lymph nodes and other target organs were impaired. Silica treatment, to suppress macrophage function, did not evidently increase the susceptibility of ABC2F1/Jena mice to Mengo virus. However, this treatment abolished the antiviral activity of quercetin, indicating the requirement for macrophages for quercetin to be effective. Virus replication could not be demonstrated in cultures of adherent peritoneal macrophages from either untreated or quercetin-treated ABD2F1/Jena mice.

Animals↗
PubMed1993

Conserved tertiary structural elements in the 5' nontranslated region of cardiovirus, aphthovirus and hepatitis A virus RNAs.

Statistical analyses of RNA folding in 5' nontranslated regions (5'NTR) of encephalomyocarditis virus, Theiler's murine encephalomyelitis virus, foot-and-mouth disease virus, and hepatitis A virus indicate that two highly significant folding regions occur in the 5' and 3' portions of the 5'NTR. The conserved tertiary structural elements are predicted in the unusual folding regions (UFR) for these viral RNAs. The theoretical, common structural elements predicted in the 3' parts of the 5'NTR occur in a cis-acting element that is critical for internal ribosome binding. These structural motifs are expected to be highly significant from extensive Monte Carlo simulations. Nucleotides (nt) in the conserved single-stranded polypyrimidine tract for these RNAs are involved in a distinctively tertiary interaction that is located at about 15 nt prior to the initiator AUG. Intriguingly, the proposed common tertiary structure in this study shares a similar structural feature to that proposed in human enteroviruses and rhinoviruses. Based on these common structural features, plausible base pairing models between these viral RNAs and 18 S rRNA are suggested, which are consistent with a general mechanism for regulation of internal initiation of cap-independent translation.

Aphthovirus↗
PubMed1979

Sequence and location of the poly C tract in aphtho- and cardiovirus RNA.

The poly C tract in the RNA of the aphtho- and cardio viruses has been examined in several isolates of foot-and-mouth disease virus (FMDV) and encephalomyocarditis (EMC) virus. The length of the tract is variable, containing 100 to 170 bases in the FMDV isolates and 80 to 250 bases in the EMC virus isolates. Each poly C tract contains c. 10% A and U residues, located at the 5' end, i.e. most of the tract is a continuous run of C residues. The position of the tract on the genome was the same in each of the FMDV isolates, about 400 bases from the 5' end, whereas in the EMC virus isolates it was about 150 bases from the 5' end.

Animals↗
PubMed1992

Ultrastructural study of experimental myocarditis induced by cardiovirus (EMCV-M) in swine.

Eight 6-week-old piglets were inoculated with a strain of encephalomyocarditis virus (EMCV) isolated from an outbreak which occurred naturally in the Po Valley in 1988. Two non-infected animals, kept in the same cage, were used as controls. Out of the eight inoculated piglets, two died and two were suppressed on the 2nd post infection day (PID), the four remaining were killed on the 5th, 7th, 11th and 15th PIDs. Control animals were killed at the end of the experiment. The pathogenesis of myocarditis has been studied using routine methods (Alcian-PAS, Masson's trichrome, Gomori's for reticulin and Mallory's stain), histochemical techniques (ATPase and NADH-TR reactions) and ultrastructural observations (TEM). All the inoculated piglets showed macro and/or microscopic lesions of lymphocytic myocarditis, only in one case associated with fibrinous exudation. One control piglet also showed myocarditic lesions, probably due to a contact infection. An early myocardial fibrosis was already present on the 5th PID. Ultrastructurally the cardiac muscle cells showed severe myofibrillar losses and other regressive alterations. Only on the 15th PID did we observe calcification of the degenerating myocytes, while ultrastructurally we detected needle-like calcium deposits in the mitochondria from the 5th PID. From the 5th PID in the areas of myocarditis the myocytes showed a reduction and/or absence of ATPase and NADH-TR reactions. On TEM, one or more aggregates of viral particles in crystalline array were detected in the cytoplasm of many endothelial cells.

Adenine↗
PubMed2003

Genetic analysis of a Theiler-like virus isolated from rats.

Although cardioviruses related to Theiler's murine encephalomyelitis virus (TMEV) appear to be common in mice and rats, few TMEV isolates have been obtained from rat colonies. In 1991, a cardiovirus isolate designated NGS910 was obtained from sentinel rats exposed to cage bedding previously used by adult rats that were TMEV seropositive, but had never manifested clinical signs of disease. To determine to which group and subgroup of cardiovirus this virus belongs, the sequence of the viral genome was determined. The NGS910 genome consisted of 8,021 nucleotides and the 5'-nontranslated region had a predicted secondary structure that is similar to members of the TMEV group of cardioviruses. The Leader-P3D open reading frame (L ORF) of NGS910 had strong homology with L ORFs of other TMEVs (72% identity), but lower homology with EMCV cardioviruses (55 to 56%). Phylogenetic analyses on the basis of aligned nucleotide sequences of the L ORF (6,924 b) and the internal L* ORF (471 b) supported this classification of NGS910 as a TMEV strain. However, within the TMEV group, NGS910 wassufficiently divergent from other isolates that it could not be regarded as simply a mutant strain of a known TMEV. As genetic distances between NGS910 and other TMEVs were greater than those between Mengo virus of EMCV and other EMCVs, we propose to designate the NGS910 isolate as a rat Theiler-like virus.

Amino Acid Sequence↗
PubMed1996

Mengovirus leader is involved in the inhibition of host cell protein synthesis.

The presence of a leader peptide in picornaviruses is restricted to the Cardiovirus and Aphthovirus genera. However, the leader peptides of these two genera are structurally and functionally unrelated. The aphthovirus leader is a protease involved in viral polyprotein processing and host cell translation shutoff. The function of the cardiovirus leader peptide is still unknown. To gain an insight into the function of the cardiovirus leader peptide, a mengovirus leader peptide deletion mutant was constructed. The deletion mutant was able to grow at a reduced rate in baby hamster kidney cells (BHK-21). Mutant virus production in mouse fibroblasts (L929 cells), however, could be demonstrated only after inoculation of BHK-21 cells with the transfected L929 cells. Analysis of cellular and viral protein synthesis in mutant virus-infected cells showed a delayed inhibition of host cell protein synthesis and a reduced production of viral proteins. In a single-cycle infection, mutant virus produced only 1% of wild-type virus yield at 8 h postinfection. Host cell translation shutoff in L929 cells infected with mutant virus was restored by the addition of the kinase inhibitor 2-aminopurine. Mutant virus production in 2-aminopurine-treated L929 cells was increased to 60% of wild-type virus yield at 8 h postinfection. Our results suggest that the cardiovirus leader peptide is involved in the inhibition of host cell protein synthesis.

Animals↗
PubMed2005

Dipyridamole reversibly inhibits mengovirus RNA replication.

Dipyridamole is an effective inhibitor of cardiovirus growth in cell culture. The effects of dipyridamole on mengovirus replication in vivo and in vitro were examined in the hope the drug could be used as an experimental analog of the poliovirus inhibitor guanidine. Guanidine selectively inhibits poliovirus RNA synthesis but not RNA translation, and as such, has been a valuable research tool. Although guanidine does not inhibit cardiovirus infection, a compound with similar discriminatory characteristics would be experimentally useful for parallel work with these viruses. We found that mengovirus plaque formation in HeLa or L cells was inhibited nearly 100% by the presence of 80 muM dipyridamole. The inhibitory effect was reversible and targeted an early step in the replication cycle. Studies with luciferase-expressing mengovirus replicons showed that viral protein synthesis was unaffected by dipyridamole, and rather, RNA synthesis was the step targeted by the drug. This assessment was confirmed by direct analyses of viral translation and RNA synthesis activities in a Krebs-2-derived in vitro system that supported complete, infectious cardiovirus replication. In Krebs extracts, dipyridamole specifically inhibited viral RNA synthesis to more than 95%, with no concomitant effect on viral protein translation or polyprotein processing. The observed inhibition reversibly affected an early step in both minus-strand and plus-strand RNA synthesis, although inhibition of plus-strand synthesis was more profound than that of minus-strand synthesis. We conclude that dipyridamole is a potent experimental tool that readily distinguishes between cardiovirus translation and RNA replication functions.

Animals↗
PubMed2005

Theiler's murine encephalomyelitis virus in nonbarrier rat colonies.

Theiler's murine encephalomyelitis virus (TMEV), a member of the genus Cardiovirus, is an enteric pathogen of mice that causes acute encephalomyelitis followed by persistent central nervous system infection with chronic inflammation and demyelination after intracerebral inoculation. Although TMEV is a mouse pathogen, antibodies against TMEV strain GDVII have been detected in conventional rat colonies. Natural infection of rats by Cardiovirus has not yet been described. The purpose of this study was to demonstrate TMEV infection of rat colonies by using serologic assays, reverse transcription-polymerase chain reaction (RT-PCR) analysis, and clinical characterization. Indirect immunofluorescence assay of rat serum samples demonstrated antibodies against TMEV-GDVII in 86.3% of samples analyzed, and 77.2% of the antibody-positive samples had neutralizing antibodies. To determine whether rats can be infected experimentally with TMEV-GDVII, specific pathogen-free newborn mice and rats were inoculated intracerebrally with intestinal suspensions from seropositive rats. Both species showed the typical clinical signs of TMEV infection in mice, which is characterized by flaccid hindlimb paralysis and tremor. RT-PCR in brain tissue of experimentally infected animals detected RNA sequences corresponding to the 5' noncoding region of Cardiovirus known as the 'internal ribosome entry site.' These results suggest that rats can be naturally infected with TMEV and related Cardiovirus. Therefore, continued health monitoring for TMEV infection should be included in rat colonies mainly because these animals are used for various experimental purposes.

Animals↗
PubMed1994

Cardioviral poly(C) tracts and viral pathogenesis.

Mengovirus is a prototypical member of the cardiovirus genus of the family Picornaviridae. The positive-strand RNA genome is 7761 bases in length and encodes a polyprotein of 2293 amino acids. The 5' non-coding region (758 bases) contains an unusual homopolymeric poly(C) tract, which in the wild-type virus, has a sequence of C50UC10. We have discovered through genetic engineering that truncation or deletion of this poly(C) sequence yields infectious virus isolates that grow well in cell culture, but are 10(6) to 10(9) fold less pathogenic to mice than the wild type strain. Animals receiving sublethal doses of the short poly(C) strains characteristically develop high levels of neutralizing antibodies and acquire lifelong protective immunity against challenge with wild type virus. Effectively, the genetically engineered strains are superb vaccines against cardiovirus disease. Moreover, their potential is not limited to murine hosts. Pigs and sub-human primates have also been protectively vaccinated with short poly(C) tract Mengoviruses. The molecular mechanism of poly(C)-mediated pathogenesis is currently under study. Most hypotheses link the activity to induction of the antiviral cytokine, interferon.

Animals↗
PubMed1996

Protection of non-murine mammals against encephalomyocarditis virus using a genetically engineered Mengo virus.

Genetically engineered Mengo viruses with artificial deletions in the 5' noncoding poly(C) tracts are highly attenuated for pathogenicity when introduced as live vaccines into the natural murine host. Inoculation produces lifelong protective immunity without disease or viral persistence. This report extends the vaccination studies to non-murine hosts, including baboons, macaques and domestic pigs, all of which are susceptible to severe cardiovirus epizootics. All animals of these species that were inoculated with vMC24, an engineered strain of Mengo, seroconverted. When the immunized animals were challenged, they were protected against lethal doses of encephalomyocarditis virus (EMCV) derived from currently circulating epizootic strains. In baboons, the neutralizing antibody titers induced by vMC24 were significantly higher than from an inactivated EMCV vaccine. Moreover, terminal histopathology on baboons (inoculated intramuscularly), macaques (inoculated intracerebrally), and pigs (inoculated intramuscularly) showed few, if any, gross lesions characteristic of EMCV-like disease, in the vMC24 vaccinates. We suggest that genetically engineered, short poly(C) Mengo viruses may be universally potent attenuated vaccines for many types of animals and can possibly provide safe, efficacious protection against all cardioviruses of the EMCV serotype.

Animals↗
PubMed2001

Leader protein of encephalomyocarditis virus binds zinc, is phosphorylated during viral infection, and affects the efficiency of genome translation.

Encephalomyocarditis virus (EMCV) is the prototype member of the cardiovirus genus of picornaviruses. For cardioviruses and the related aphthoviruses, the first protein segment translated from the plus-strand RNA genome is the Leader protein. The aphthovirus Leader (173-201 amino acids) is an autocatalytic papain-like protease that cleaves translation factor eIF-4G to shut off cap-dependent host protein synthesis during infection. The less characterized cardioviral Leader is a shorter protein (67-76 amino acids) and does not contain recognizable proteolytic motifs. Instead, these Leaders have sequences consistent with N-terminal zinc-binding motifs, centrally located tyrosine kinase phosphorylation sites, and C-terminal, acid-rich domains. Deletion mutations, removing the zinc motif, the acid domain, or both domains, were engineered into EMCV cDNAs. In all cases, the mutations gave rise to viable viruses, but the plaque phenotypes in HeLa cells were significantly smaller than for wild-type virus. RNA transcripts containing the Leader deletions had reduced capacity to direct protein synthesis in cell-free extracts and the products with deletions in the acid-rich domains were less effective substrates at the L/P1 site, for viral proteinase 3Cpro. Recombinant EMCV Leader (rL) was expressed in bacteria and purified to homogeneity. This protein bound zinc stoichiometrically, whereas protein with a deletion in the zinc motif was inactive. Polyclonal mouse sera, raised against rL, immunoprecipitated Leader-containing precursors from infected HeLa cell extracts, but did not detect significant pools of the mature Leader. However, additional reactions with antiphosphotyrosine antibodies show that the mature Leader, but not its precursors, is phosphorylated during viral infection. The data suggest the natural Leader may play a role in regulation of viral genome translation, perhaps through a triggering phosphorylation event.

Amino Acid Motifs↗
PubMed1996

A common structural core in the internal ribosome entry sites of picornavirus, hepatitis C virus, and pestivirus.

Cap-independent translations of viral RNAs of enteroviruses and rhinoviruses, cardioviruses and aphthoviruses, hepatitis A and C viruses (HAV and HCV), and pestivirus are initiated by the direct binding of 40S ribosomal subunits to a cis-acting genetic element termed the internal ribosome entry site (IRES) or ribosome landing pad (RLP) in the 5' noncoding region (5'NCR). RNA higher ordered structure models for these IRES elements were derived by a combined approach using thermodynamic RNA folding, Monte Carlo simulation, and phylogenetic comparative analysis. The structural differences among the three groups of picornaviruses arise not only from point mutations, but also from the addition or deletion of structural domains. However, a common core can be identified in the proposed structural models of these IRES elements from enteroviruses and rhinoviruses, cardioviruses and aphthoviruses, and HAV. The common structural core identified within the picornavirus IRES is also conserved in the 5'NCR of the divergent viruses, HCV, and pestiviruses. Furthermore, the proposed structural motif shares a structural feature similar to that observed in the catalytic core of the group 1 intron. The conserved structural motif from these divergent sequences that looks like the common core region of group 1 introns is probably a crucial element involved in the IRES-dependent translation.

Animals↗
PubMed1992

Proteolytic processing of the cardioviral P2 region: primary 2A/2B cleavage in clone-derived precursors.

The primary 2A/2B cleavage within cardiovirus polyprotein was examined by construction of cDNA plasmids which linked fragments from the P2 region of encephalomyocarditis virus (EMCV) and Mengovirus genomes to the EMCV 5' nontranslated region. When RNA transcripts from these clones were tested in reticulocyte extracts, the synthesized proteins were cotranslationally processed at the 2A/2B site. No viral segments outside of the P2 region were required for this activity. Engineered deletions which removed the amino-terminal two-thirds of protein 2A or the carboxyl half of protein 2B had no effect on this scission, nor did insertions into a Ser-Ala-Phe sequence (SAF) within 2B, which is conserved in most cardio- and aphthoviruses. In contrast, mutations which disrupted a conserved Asn-Pro-Gly-Pro (NPGP) sequence abolished primary scission. Precursors thus inactivated were unable to serve as substrate when simultaneously expressed with active (wild-type) 2AB sequences. Microsequencing placed the EMCV primary cleavage site between the Gly/Pro pair within the NPGP sequence. It was also determined that endogenous viral protease 3C is the previously unidentified agent responsible for cardiovirus 1D/2A scission, a cleavage that is part of the primary processing reaction in poliovirus.

Amino Acid Sequence↗
PubMed1993

Development of a recombinant RNA technique for the construction of chimeric RNA with a long poly(C) tract.

The murine cardioviruses and bovine aphthoviruses are distinguished from other (+) strand RNA viruses by their long poly(C) tract in the 5'-noncoding region. The presence of this poly(C) tract has long hampered the construction of full-length cDNA with the complete poly(C) tract, because long poly(dC-dG) homopolymer-containing plasmids are difficult to amplify in bacterial systems. To overcome this problem, we constructed a chimeric RNA by joining the poly(C) region of the viral RNA to the 5'-truncated RNA transcript of the encephalomyocarditis (EMC) virus cDNA. The non-chimeric, recombinant EMC virus with a short poly(C) tract produces recombinant progeny virus, but this is not pathogenic in vivo. On the other hand, the EMC viral RNA chimera with the complete poly(C) tract produces recombinant progeny virus that is pathogenic in vivo. This method of viral RNA construction will be invaluable for functional studies of other cardioviruses and aphthoviruses, as well as for recombinant RNA manipulations.

Animals↗
PubMed1982

Neuraminidase-sensitive erythrocyte receptor for enterovirus type 70.

Enterovirus type 70 (EV70) agglutinated human 'O' erythrocytes at 4 degrees C as well as 22 degrees C, but visible agglutination was lost when warmed at 37 degrees C although the virus remained attached to the surface of the erythrocyte. The receptor sites for the virus were neuraminidase-sensitive. A direct involvement of sialic acid on the cell surface in virus-cell interaction was confirmed by the fact that the presence of fetuin or free N-acetylneuraminic acid inhibited the haemagglutinating activity of EV70. Similar numbers of virus particles were required for 1 haemagglutinating unit (HAU) of EV70 and 1 HAU of mengovirus, whereas 2.6-fold or more of virus particles of echovirus type 7 and type 11 gave the same activity. On the other hand, the number of receptor sites on the cell surface for EV70 was found to be sevenfold more than for mengovirus. Therefore, the erythrocyte receptor for EV70 is different from that for common enteroviruses and similar, though not identical, to the cardiovirus receptor. However, serological tests such as neutralization, complement fixation or haemagglutination inhibition did not reveal any common antigen between EV70 and cardiovirus.

Adsorption↗
PubMed1988

Relationship of p220 cleavage during picornavirus infection to 2A proteinase sequencing.

Infection of HeLa cells by poliovirus results in an abrupt inhibition of host cell protein synthesis. It is thought that the mechanism of this inhibition involves proteolytic cleavage of the p220 component of the cap-binding protein complex, thereby causing functional inactivation of the cap-binding protein complex and preventing capped (cellular) mRNAs from binding ribosomes. Current data suggest that the viral proteinase 2A indirectly induces p220 cleavage via alteration or activation of a second proteinase of cellular origin. We present evidence that translation of poliovirus proteinase 2A sequences in vitro activates p220 cleavage. We have also aligned published picornavirus 2A amino acid sequences for maximum homology, and we show that the picornaviruses can be divided into two classes based on the presence or absence of a highly conserved 18-amino acid sequence in the carboxy-terminal portion of 2A. This conserved 2A sequence is homologous with the active site of the cysteine proteinase 3C common to all picornaviruses. We show that picornaviruses which contain the putative 2A active site sequence (e.g., enteroviruses and rhinoviruses) will induce cleavage of p220 in vivo. Conversely, we show that two cardioviruses (encephalomyocarditis virus and Theiler's encephalomyelitis virus) do not encode this putative proteinase sequence in the 2A region and do not induce cleavage of p220 in vivo. The foot-and-mouth disease virus (FMDV) 2A sequence represents an apparent deletion and consists of only 16 amino acids, most homologous with the carboxy terminus of the cardiovirus 2A sequence. It does not contain the putative cysteine proteinase active site. However, FMDV infection induces complete cleavage of BK cell p220, and translation of FMDV RNA in vitro induces an activity that cleaves HeLa cell p220. The data predict that an alternate FMDV viral protease is responsible for the induction of p220 cleavage.

Amino Acid Sequence↗