Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.48 (transcriptase)
9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Plants contain RNA-dependent RNA polymerase (RdRP) activities that synthesize short cRNAs by using cellular or viral RNAs as templates. During studies of salicylic acid (SA)-induced resistance to viral pathogens, we recently found that the activity of a tobacco RdRP was increased in virus-infected or SA-treated plants. Biologically active SA analogs capable of activating plant defense response also induced the RdRP activity, whereas biologically inactive analogs did not. A tobacco RdRP gene, NtRDRP1, was isolated and found to be induced both by virus infection and by treatment with SA or its biologically active analogs. Tobacco lines deficient in the inducible RDRP activity were obtained by expressing antisense RNA for the NtRDRP1 gene in transgenic plants. When infected by tobacco mosaic virus, these transgenic plants accumulated significantly higher levels of viral RNA and developed more severe disease symptoms than wild-type plants. After infection by a strain of potato virus X that does not spread in wild-type tobacco plants, the transgenic NtRDRP1 antisense plants accumulated virus and developed symptoms not only locally in inoculated leaves but also systemically in upper uninoculated leaves. These results strongly suggest that inducible RdRP activity plays an important role in plant antiviral defense.
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PMID:An important role of an inducible RNA-dependent RNA polymerase in plant antiviral defense. 1135 67

Post-transcriptional gene silencing(PTGS) is a defense mechanism of plants against foreign nucleic acids, such as virus infection. The mechanism results in sequence-specific degradation of nucleic acids, including endogenous mRNA, transgene mRNA and virus RNA. PTGS was first discovered in transgenic plants, and since then, similar mechanism has been found in fungi and animals. It appears that PTGS is initiated by aberrant RNA and double-stranded RNA in the cell. An enzyme similar to RNA-dependent RNA polymerase has been identified in various plants, which plays a key role in the PTGS process. It is hypothesized that PTGS might be the natural mechanism of plants against virus infection. To support this hypothesis, scientists from several laboratories have discovered PTGS suppressors encoded by virus genomes, and the suppressors identified so far are all viral pathogenicity determinants, such as viral movement protein.
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PMID:[Post-transcriptional gene silencing and virus resistance]. 1151 90

The mechanisms of cellular recognition for virus infection remain poorly understood despite the wealth of information regarding the signaling events and transcriptional responses that ensue. Host cells respond to viral infection through the activation of multiple signaling cascades, including the activation of NF-kappaB, c-Jun/ATF-2 (AP-1), and the interferon regulatory factors (IRFs). Although viral products such as double-stranded RNA (dsRNA) and the processes of viral binding and fusion have been implicated in the activation of NF-kappaB and AP-1, the mechanism(s) of IRF-1, IRF-3, and IRF-7 activation has yet to be fully elucidated. Using recombinant measles virus (MeV) constructs, we now demonstrate that phosphorylation-dependent IRF-3 activation represents a novel cellular detection system that recognizes the MeV nucleocapsid structure. At low multiplicities of infection, IRF-3 activation is dependent on viral transcription, since UV cross-linking and a deficient MeV containing a truncated polymerase L gene failed to induce IRF-3 phosphorylation. Expression of the MeV nucleocapsid (N) protein, without the requirement for any additional viral proteins or the generation of dsRNA, was sufficient for IRF-3 activation. In addition, the nucleocapsid protein was found to associate with both IRF-3 and the IRF-3 virus-activated kinase, suggesting that it may aid in the colocalization of the kinase and the substrate. Altogether, this study suggests that IRF-3 recognizes nucleocapsid structures during the course of an MeV infection and triggers the induction of interferon production.
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PMID:Recognition of the measles virus nucleocapsid as a mechanism of IRF-3 activation. 1190 5

Ribavirin (1-beta-D-ribofuranosyl-1,2,4-triazole) is a broad-spectrum antiviral nucleoside that is currently used in combination with interferon-alpha to treat hepatitis C virus infection and as a monotherapy to treat severe cases of respiratory syncytial virus infection and Lassa fever virus infection. The mechanism of action of ribavirin has been studied for decades. These studies have suggested that the antiviral activity of ribavirin may be related to its ability to cause a decrease in intracellular guanosine triphosphate pools, to inhibit capping of viral transcripts or to suppress humoral and cellular immune responses. Last year, another possibility was added to this list. The new proposition is that ribavirin, when converted to the triphosphate, is utilized by the viral RNA-dependent RNA polymerase and causes lethal mutagenesis of the viral genome. In this article, the data supporting this new hypothesis are reviewed. We discuss the implications of these data on alternative explanations for the apparent failure of ribavirin monotherapy in the treatment of hepatitis C virus infection, connections between developmental defects induced by ribavirin and posttranscriptional gene silencing/RNA interference, and the use of lethal mutagenesis and related concepts as strategies for antiviral therapy.
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PMID:The mechanism of action of ribavirin: lethal mutagenesis of RNA virus genomes mediated by the viral RNA-dependent RNA polymerase. 1196 96

Antigen-presenting dendritic cells (DCs), which play a major role in the triggering of primary anti viral immune reactions, may also contribute, in some viral models, to the pathogenesis of persistent viral infection. In fact, impaired immune response to hepatitis B virus (HBV)-encoded antigens is seen in patients with chronic hepatitis B (CH-B). The aim of this study was to check the function of DCs in these patients and to investigate the underlying mechanism. DCs were enriched from peripheral blood mononuclear cells by culturing with interleukin (IL)-4 and granulocyte-macrophage colony stimulating factor for 7 days. The stimulatory capacity of DCs were checked in allogenic mixed leukocyte (MLR) reaction. The levels of IL-12 in the culture supernatants were measured by an enzyme-linked immunosorbent assay. HBV DNA and HBV RNA were localized in DCs by polymerase chain reaction (PCR) in situ hybridization and reverse-transcriptase (RT)-PCR in situ hybridization. The stimulatory capacity of DCs in allogenic MLR was significantly lower in patients with CH-B (36321+/-12523 cpm, n=18) compared to that of normal controls (65678+/-11174 cpm, n=18) (p<0.0001). Significantly lower levels of IL-12 were detected in cultures containing DCs from patients with CH-B than normal controls (46.7+/-25.6 versus 122.4+/- 37.1 pg/ml, p<0.0001). In situ hybridization revealed the localization of HBV DNA and HBV RNA in DCs from patients with CH-B. These results indicate that chronic infection by HBV is associated with functional defects of DCs. Localization of HBV DNA and HBV RNA indicates that DCs may constitute an extra hepatic reservoir and possibly of replication of HBV.
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PMID:Impaired function of antigen-presenting dendritic cells in patients with chronic hepatitis B: localization of HBV DNA and HBV RNA in blood DC by in situ hybridization. 1252 72

The actual diagnosis of a tick-borne encephalitis (TBE) must be established in the laboratory because of the non-specific clinical features it presents. The method of choice is the demonstration of specific IgM- and IgG-serum antibodies by enzyme-linked immuno-sorbent assay (ELISA), since these antibodies are detectable in practically every case at the time of hospitalization. Early after onset of disease in the cerebrospinal fluid specific antibodies can only be found in 50% of the patients, but by the 10th day of illness they almost invariably become detectable. If an infection occurs after and despite the post-exposure administration of a specific immunoglobulin the seroconversion can be delayed and may cause diagnostic problems. Virusisolation from the blood, or the detection of specific nucleic acid in the blood or the cerebrospinal fluid by reverse-transcriptase polymerase chain reaction (RT-PCR) usually is only successful during the first viremic phase of the disease before seroconversion. In fatal cases, the virus can be isolated or detected by RT-PCR from the brain and other organs. For testing immunity after a TBE virus infection or after vaccination, most often the IgG ELISA is used. However, in cases of other flavivirus contacts (e.g. vaccinations against yellow fever or Japanese encephalitis; dengue virus infections), the performance of a neutralization assay is necessary for assessing immunity due to the interference of flavivirus cross-reactive antibodies in ELISA and hemagglutination inhibition (HI) test.
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PMID:Diagnosis of tick-borne encephalitis. 1262 12

Natural killer (NK) cells play an important role in the first line of defence against viral infections. We have shown earlier that exposure of human peripheral blood mononuclear cells (PBMC) to viruses results in rapid up-regulation of NK cell activity via interleukin-15 (IL-15) induction, and that this mechanism curtails viral infection in vitro. By using Candida albicans, Escherichia coli and Staphylococcus aureus, we now show here that exposure of PBMC to fungi and bacteria also results in an immediate increase of NK cytotoxicity. Reverse transcriptase-polymerase chain reaction and Western blot analyses as well as the use of antibodies against different cytokines revealed that IL-15 induction played a predominant role in this NK activation. These results indicate that IL-15 is also involved in the innate immune response against fungal and bacterial agents.
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PMID:Host's innate immune response to fungal and bacterial agents in vitro: up-regulation of interleukin-15 gene expression resulting in enhanced natural killer cell activity. 1275 22

Compound-1453 was identified and characterized as a specific inhibitor of bovine viral diarrhea virus (BVDV). The concentration of compound-1453 which results in 50% protection from virus-induced cytopathic effect is approximately 2.2 microM, with a therapeutic index of 60, and it is not active against a panel of RNA and DNA viruses. A time-of-addition experiment suggested that compound-1453 targets a stage of the viral life cycle after viral entry. To determine the target of compound-1453, resistant virus was generated. Resistant variants grew efficiently in the presence or absence of 33 micro M compound-1453 and exhibited replication efficiency in the presence of compound-1453 approximately 1,000-fold higher than that of the wild-type (wt) virus. Functional mapping and sequence analysis of resistant cDNAs revealed a single amino acid substitution (Glu to Gly) at residue 291 in the NS5B polymerase in all eight independently generated cDNA clones. Recombinant virus containing this single mutation retained the resistance phenotype and a replication efficiency similar to that of the original isolated resistant virus. Since compound-1453 did not inhibit BVDV polymerase activity in vitro (50% inhibitory concentration > 300 microM), we developed a membrane-based assay that consisted of a BVDV RNA replicase complex isolated from virus-infected cells. Compound-1453 inhibited the activity of the wt, but not the drug-resistant, replicase in the membrane assay at concentrations similar to those observed in the viral infection assay. This work presents a novel inhibitor of a viral RNA-dependent RNA replicase.
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PMID:Specific inhibition of bovine viral diarrhea virus replicase. 1276 95

Salicylic acid (SA), a natural defensive signal chemical, and antimycin A, a cytochrome pathway inhibitor, induce resistance to Tobacco mosaic virus (TMV). Pharmacological evidence suggested signaling during resistance induction by both chemicals involved alternative oxidase (AOX), sole component of the alternative respiratory pathway (AP). Roles of the AP include regulation of intramitochondrial reactive oxygen species and maintenance of metabolic homeostasis. Transgenic tobacco (Nicotiana tabacum) with modified AP capacities (2- to 3-fold increased or decreased) showed no alteration in phenotype with respect to basal susceptibility to TMV or the ability to display SA-induced resistance to systemic viral disease. However, in directly inoculated tissue, antimycin A-induced TMV resistance was inhibited in plants with increased AP capacities, whereas SA and antimycin A-induced resistance was transiently enhanced in plant lines with decreased AP capacities. We conclude that SA-induced TMV resistance results from activation of multiple mechanisms, a subset of which are inducible by antimycin A and influenced by AOX. Other antiviral factors, potentially including the SA-inducible RNA-dependent RNA polymerase, are regulated by AOX-independent mechanisms.
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PMID:Genetic modification of alternative respiration has differential effects on antimycin A-induced versus salicylic acid-induced resistance to Tobacco mosaic virus. 1285 32

Turnip yellow mosaic virus (TYMV), a positive-strand RNA virus in the alphavirus-like superfamily, encodes two replication proteins, 140K and 66K, both being required for its RNA genome replication. The 140K protein contains domains indicative of methyltransferase, proteinase, and NTPase/helicase, and the 66K protein encompasses the RNA-dependent RNA polymerase domain. During viral infection, the 66K protein localizes to virus-induced chloroplastic membrane vesicles, which are closely associated with TYMV RNA replication. To investigate the determinants of its subcellular localization, the 66K protein was expressed in plant protoplasts from separate plasmids. Green fluorescent protein (GFP) fusion and immunofluorescence experiments demonstrated that the 66K protein displayed a cytoplasmic distribution when expressed individually but that it was relocated to the chloroplast periphery under conditions in which viral replication occurred. The 66K protein produced from an expression vector was functional in viral replication since it could transcomplement a defective replication template. Targeting of the 66K protein to the chloroplast envelope in the course of the viral infection appeared to be solely dependent on the expression of the 140K protein. Analysis of the subcellular localization of the 140K protein fused to GFP demonstrated that it is targeted to the chloroplast envelope in the absence of other viral factors and that it induces the clumping of the chloroplasts, one of the typical cytological effects of TYMV infection. These results suggests that the 140K protein is a key organizer of the assembly of the TYMV replication complexes and a major determinant for their chloroplastic localization and retention.
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PMID:Targeting of the turnip yellow mosaic virus 66K replication protein to the chloroplast envelope is mediated by the 140K protein. 1291 29


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