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PubMedDate not supplied

[Interferon status and the activity of dsRNA-dependent enzymes in volunteers and influenza patients receiving human recombinant alpha 2-interferon (reaferon)].

The national recombinant preparation of alpha 2-interferon (reaferon) after intramuscular inoculation in a daily dose of 3 X 10(6) units/ml to human volunteers was found in the blood serum within 1-2 hours. In 85% of the subjects given the preparation, a 2-8-fold rise in interferon titers in the blood serum and in 64% an increase in interferon leukocyte reaction (ILR) by the 5th day after the beginning of the treatment were observed. In the examined influenza patients given the preparation, interferon circulation in the blood serum, increased ILR and 2-5A synthetase enzyme levels were demonstrated. Tests for interferon of the blood sera of patients given reaferon by inhalation revealed no significant rise in its level, in contrast to cases with reaferon intramuscular injections. It is assumed that the immunomodulating effect of the preparation given by inhalation is mediated through the hypothalamus. Thus, parameters of the interferon system may be corrected by administration of reaferon.

2',5'-Oligoadenylate Synthetase↗
PubMedDate not supplied

[Effectiveness of dsRNA as an interferon inducer in the intramuscular infection of mice with rabies street virus].

A protective effect of double-stranded RNA as interferon inducer was demonstrated in mice inoculated intramuscularly with street rabies virus. A significant degree of protection was observed when the inducer was inoculated intracerebrally and at the site of virus inoculation both 24 h before and 4 and 24 h after infection. Inoculation of the inducer into the muscle opposite to the infected leg and subcutaneously into the back proved to be ineffective. It was established that rabies infection could be arrested with the interferon inducer depending on the site of its inoculation.

Animals↗
PubMedDate not supplied

[Comparative analysis of expression of genes for 2',5'-oligoadenylate synthetase and mRNA for dsRNA-protein kinase in human fibroblasts infected with the Sindbis alphavirus and induced by alpha-interferon].

Expression of 2,5-OAS and ds-protein kinase (ds-PK) in human fibroblast culture following treatment with alpha-IF in a dose of 1000 U or challenge with Karelian fever virus (KFV) (5 PFU/cell, 4 h.p.i.) was compared. A highly sensitive and rapid method, coupled RT-PCR, was used to detect mRNA transcription levels. Alpha-IF had an expressed stimulating effect on 2,5-OAS mRNA level, whereas the virus markedly inhibited the synthesis of ds-PK mRNA.

2',5'-Oligoadenylate Synthetase↗
PubMed2000

Satellite and defective RNAs of Cryphonectria hypovirus 3-grand haven 2, a virus species in the family Hypoviridae with a single open reading frame.

Cryphonectria parasitica hypovirus 3-Grand Haven 2 (CHV3-GH2) is the most recently characterized member of the Hypoviridae family of viruses associated with hypovirulence of the chestnut blight fungus. Isolates of CHV3-GH2 contain either three or four double-stranded (ds) RNAs that are visible on ethidium bromide-stained agarose or polyacrylamide gels. Only the largest dsRNA appears to be required for virus infectivity, and was characterized previously (C. D. Smart et al., 1999, Virology 265, 66-73). In this study, we report the cloning, sequencing, and analysis of the other three dsRNAs. Sizes of the accessory dsRNAs are 3.6 kb (dsRNA 2), 1.9 kb (dsRNA 3), and 0.9 kb (dsRNA 4), compared to 9.8 kb for the genomic dsRNA segment (dsRNA 1). All three accessory dsRNA species are polyadenylated on the 3'-end of one strand, as is genomic dsRNA. DsRNA 2 represents a defective form of dsRNA 1, with the 5'-terminal 1.4 kb derived from the 5'-end of dsRNA 1 and the 3'-terminal 2.2 kb from the 3'-end of dsRNA 1. A single major open reading frame (ORF) is evident from deduced translations of dsRNA 2. The deduced translation product is a 91-kDa protein that represents a fusion consisting of the entire N-terminal protease and the entire putative helicase domain. DsRNAs 3 and 4 represent satellite RNAs that share very little sequence with dsRNA 1 and 2. DsRNA 4 is 937 nucleotides, excluding the poly(A)(+). The first AUG of the polyadenylated strand of dsRNA 4 occurs eight residues in from the 5'-terminus and would initiate the largest ORF on dsRNA 4, with the coding capacity for a 9.4-kDa protein. Within the deduced ORF and approximately 100 nucleotides from the 5'-end of dsRNA 4 is a 22-base sequence that is identical to sequences found in the nontranslated leaders of dsRNAs 1 and 2. DsRNA 3 accumulation in infected cultures varied, but it was less abundant than dsRNA 4. DsRNA 3 was found to represent a head-to-tail dimer of dsRNA 4 linked by a poly(A)/(U) stretch of 40-70 residues.

Amino Acid Sequence↗
PubMed1984

The nature of the interaction of eukaryotic initiation factor 2 with double-stranded RNA.

In addition to binding messenger RNA molecules at specific sequences, eukaryotic initiation factor 2 (eIF-2) also binds to double-stranded RNA (dsRNA). The dsRNA is a powerful inhibitor of initiation of eukaryotic translation, causing the inactivation of eIF-2, but in the presence of certain mRNA templates, dsRNA fails to establish inhibition. Such mRNA templates bind to eIF-2 with higher affinity than does dsRNA, while globin mRNA, a template sensitive to inhibition, binds with lower affinity. Here, the nature of the interaction between dsRNA and eIF-2 was studied by examining both the binding of eIF-2 to Penicillium chrysogenum dsRNA molecules carrying 32P label at their 5' ends, and the ability of eIF-2 to protect such label against pancreatic ribonuclease digestion. The results reveal binding sites for eIF-2 at the 5' ends, as well as throughout internal regions of the dsRNA molecule. At least 15 molecules of eIF-2 can be accommodated on a 3000-base molecule of P. chrysogenum dsRNA. eIF-2 protects a 105-base-pair 5'-terminal fragment in dsRNA against digestion, but exhibits no noticeable preference for the 5' ends. By contrast, eIF-2 fails to protect label at the 5' ends of denatured dsRNA molecules, even though it binds to them at internal sites more avidly than to native dsRNA. Binding of eIF-2 to dsRNA is not restricted to specific sequences: eIF-2 binds with equal affinity to the synthetic dsRNA sequence, poly(rI . rC). The data support the interpretation that eIF-2 recognizes the A conformation in dsRNA rather than sequence. Apparently binding of eIF-2 at sites spaced 200 base pairs apart prevents relaxation of the intervening length of the double helix, thereby stabilizing the dsRNA molecule against ribonuclease attack. These results show that, even though dsRNA and mRNA compete in their binding to eIF-2, the structural features recognized by eIF-2 in these RNA species are distinct.

Animals↗
PubMed1999

Molecular characterization of two endogenous double-stranded RNAs in rice and their inheritance by interspecific hybrids.

We completely sequenced 13,936 nucleotides (nt) of a double-stranded RNA (dsRNA) of wild rice (W-dsRNA). A single long open reading frame (13,719 nt) containing the conserved motifs of RNA-dependent RNA polymerase and RNA helicase was located in the coding strand. The identity between entire nucleotide sequence of W-dsRNA and that of the dsRNA of temperate japonica rice (J-dsRNA, 13,952 nt) was 75.5%. A site-specific discontinuity (nick) was identified at nt 1,197 from the 5' end of the coding strand of W-dsRNA. This nick is also located at nt 1,211 from the 5' end in the coding strand of J-dsRNA. The dsRNA copy number was increased more than 10-fold in pollen grains of both rice plants. This remarkable increase may be responsible for the highly efficient transmission of J-dsRNA via pollen that we already reported. J-dsRNA and W-dsRNA were also efficiently transmitted to interspecific F1 hybrids. Seed-mediated dsRNA transmission to F2 plants was also highly efficient when the maternal parent was wild rice. The efficiency of dsRNA transmission to F2 plants was reduced when the maternal parent was temperate japonica rice; however, the reduced rates in F2 plants were returned to high levels in F3 plants.

Base Sequence↗
PubMed1991

Regulation of a double-stranded RNA modification activity in human cells.

A double-stranded RNA (dsRNA)-specific modification activity from Xenopus oocytes and human cells dsRNA modifier) converts adenosine residues present in dsRNA to inosines. The function of the dsRNA modifier is unknown, although it has been suggested that it may be part of the cellular antiviral response. We investigated the relationship between the activity of the dsRNA modifier, viral infection, and the antiviral response in human cells induced by poly(rI)-poly(rC) [poly(I.C)] treatment. We found, unexpectedly, that treatment of HeLa cells with poly(I.C) or other dsRNA molecules resulted in the dramatic inhibition of the dsRNA modifier. Mixing experiments, reconstruction experiments, and pretreatment of extracts with RNases indicated that inhibition of the dsRNA modifier did not result from the continued presence of a soluble inhibitor such as dsRNA) in the in vitro modification reactions. Treatment of cells with cyclohexamide or dactinomycin simultaneously with the poly(I.C) demonstrated that in vivo inhibition of the dsRNA modifier did not require new transcription or translation. The dsRNA modification activity was also substantially inhibited in cells infected with poliovirus and was slightly inhibited in cells infected with adenovirus. The inhibition of the dsRNA modifier during the antiviral state is thus not consistent with an antiviral function, and instead suggests another cellular function for dsRNA modification.

Adenoviruses, Human↗
PubMed1975

The characteristics of inhibition of protein synthesis by double-stranded ribonucleic acid in reticulocyte lysates.

All types of double-stranded RNA (DSRNA) tested inhibit protein synthesis in rabbit reticulocyte lysates. The inhibition is characterized by its strongly biphasic kinetics, and can be enhanced by preincubation of the lysate with dsRNA in the absence of protein synthesis. Only properly and extensively matched dsRNA (greater than about 50 base pairs) has this property; no form of DNA, single-stranded RNA or even RNA-DNA hybrids act as inhibitors in this way. The cause of the inhibition appears to be a failure of initiator tRNA to associate with native ribosomal subunits in the initiation process (Darnbrough, C., Hunt, T., and Jackson, R. J. (1973) Biochem. Biophys. Res. Commun. 48, 1556-1564). We have shown that this block is not accompanied by stable association of dsRNA with the ribosomes. There are several reasons to believe that the mechanism of action of dsRNA may be complex with the possible involvement of at least one catalytic step. First, the lysate is inhibited by levels of dsRNA at which ribosomes are present in 100-fold excess over base pairs of dsRNA present. Second, high concentrations of dsRNA (greater than 10 mug per ml) are not inhibitory, but can in some, but not all experiments, reverse the inhibition caused by lower levels of dsRNA. Third, a lysate which has been inhibited by dsRNA, when mixed with a fresh lysate will inhibit synthesis in the mixture much more severely than would be expected from the concentration of dsRNA now present. These results indicate that low levels of dsRNA promote the formation of an inhibitor which may exist in two forms: one that is reversible by high levels of dsRNA and one that is irreversible.

Animals↗
PubMed1995

Identification of a satellite double-stranded RNA in the parasitic protozoan Trichomonas vaginalis infected with T. vaginalis virus T1.

Co-infection by a 0.5-kb small double-stranded (ds) RNA together with Trichomonas vaginalis virus (TVV) genomic 4.6-kb dsRNA is commonly observed in a number of T. vaginalis isolates. By molecular cloning and primer extension experiments, the 497-bp cDNA sequence of a 0.5-kb dsRNA co-infecting with TVV-T1 in T vagina/is T1 isolate was elucidated. Consistent with the replication cycle of a typical dsRNA virus, a plus-strand viral RNA beginning at +1 of the 0.5-kb dsRNA was identified in infected T. vaginalis T1 cells by primer extension and Northern hybridization studies. The 0.5-kb dsRNA was separately encased in TVV capsids from the viral genomic dsRNA, as shown by protein analysis and electron microscopic examination of viral particles purified by multiple rounds of CsCl gradient centrifugation. The riboprobes transcribed from a cloned cDNA of the 0.5-kb dsRNA exhibited strong hybridization to a small dsRNA in a T vaginalis T9 isolate, which harbors a TVV-T9 distantly related to TVV-T1, but the same probes showed very little hybridization to the viral genomic dsRNA of both TVV-T1 and TVV-T9. Very little sequence homology between the 0.5-kb dsRNA and the 4.6-kb dsRNA in TVV-T1 was found by computer-assisted analysis, suggesting that the small dsRNA in T. vaginalis T1 is not derived from the genome of TVV-T1 or other distantly related T. vaginalis viruses. These results suggest that the small dsRNAs in T vaginalis are satellite RNAs of T. vaginalis virus.

Animals↗
PubMed2006

Diversity, complexity and transmission of double-stranded RNA elements in Chalara elegans (synanam. Thielaviopsis basicola).

Double-stranded (ds) RNA banding patterns were determined in 21 wild-type strains of the soilborne plant pathogen Chalara elegans originating from different geographic regions worldwide. Five strains, each with a unique dsRNA pattern, were selected for cDNA cloning, northern blot analysis and dsRNA transmission experiments. Four strains contained multiple (up to 6) dsRNA elements (2.0kbp to 12kbp in size) and one strain contained a single 2.8kbp fragment. These five strains were distinguished from one another by their unique RAPD-PCR patterns. Seven partial cDNA clones were derived from the predominant 2.8, 5.3, and 12kbp dsRNA elements. Nucleotide sequence analysis and northern blot hybridizations revealed a high degree of genetic dissimilarity among the different molecular-size dsRNA elements, even those found within a single strain. Four clones from the 5.3kbp dsRNA fragment showed a 23-43 % amino acid identity to either the coat protein or RNA-dependent RNA polymerase regions of viruses in the Totiviridae. One clone from the 2.8kbp dsRNA fragment had a 55-57 % amino acid identity to the RdRp region of viruses in the Narnaviridae. Two clones from the 12kbp dsRNA fragment showed no significant homology to any known virus group. Colonies derived from 100 single-conidia isolates of C. elegans strains with the 2.8, 5.3 and 12kbp elements all contained the corresponding dsRNA element, indicating that dsRNA transmission through conidia was highly efficient, regardless of molecular size. However, transmission of dsRNA between the mycelium of strains of C. elegans could not be achieved in this study. Genetically unique strains carrying diverse dsRNA elements appear to have evolved within populations of C. elegans. Based on our findings, there are at least 3 groups of viruses present in C. elegans.

Ascomycota↗
PubMed2000

Activation of p38 mitogen-activated protein kinase and c-Jun NH(2)-terminal kinase by double-stranded RNA and encephalomyocarditis virus: involvement of RNase L, protein kinase R, and alternative pathways.

Double-stranded RNA (dsRNA) accumulates in virus-infected mammalian cells and signals the activation of host defense pathways of the interferon system. We describe here a novel form of dsRNA-triggered signaling that leads to the stimulation of the p38 mitogen-activated protein kinase (p38 MAPK) and the c-Jun NH(2)-terminal kinase (JNK) and of their respective activators MKK3/6 and SEK1/MKK4. The dsRNA-dependent signaling to p38 MAPK was largely intact in cells lacking both RNase L and the dsRNA-activated protein kinase (PKR), i. e., the two best-characterized mediators of dsRNA-triggered antiviral responses. In contrast, activation of both MKK4 and JNK by dsRNA was greatly reduced in cells lacking RNase L (or lacking both RNase L and PKR) but was restored in these cells when introduction of dsRNA was followed by inhibition of ongoing protein synthesis or transcription. These results are consistent with the notion that the role of RNase L and PKR in the activation of MKK4 and JNK is the elimination, via inhibition of protein synthesis, of a labile negative regulator(s) of the signaling to JNK acting upstream of SEK1/MKK4. In the course of these studies, we identified a long-sought site of RNase L-mediated cleavage in the 28S rRNA, which could cause inhibition of translation, thus allowing the activation of JNK by dsRNA. We propose that p38 MAPK is a general participant in dsRNA-triggered cellular responses, whereas the activation of JNK might be restricted to cells with reduced rates of protein synthesis. Our studies demonstrate the existence of alternative (RNase L- and PKR-independent) dsRNA-triggered signaling pathways that lead to the stimulation of stress-activated MAPKs. Activation of p38 MAPK (but not of JNK) was demonstrated in mouse fibroblasts in response to infection with encephalomyocarditis virus (ECMV), a picornavirus that replicates through a dsRNA intermediate. Fibroblasts infected with EMCV (or treated with dsRNA) produced interleukin-6, an inflammatory and pyrogenic cytokine, in a p38 MAPK-dependent fashion. These findings suggest that stress-activated MAPKs participate in mediating inflammatory and febrile responses to viral infections.

Animals↗