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PubMed1981

Interaction of reovirus with cell surface receptors. III. Reovirus type 3 induces capping of viral receptors on murine lymphocytes.

We have previously shown that there are receptors for the hemagglutinin of reovirus type 3 on a subset of both murine T and B cells. Using purified reovirus type 3 particles as a ligand, followed by FITC-labeled antiviral antibody we have now been able to demonstrate viral induced capping of the reovirus receptor on both B and T cells. Kinetic studies and inhibition experiments using cytochalasin B and colchicine demonstrate that reovirus-induced capping of the viral receptor on both B and T cells has characteristics identical to the capping of immunoglobulin on B cells by anti-immunoglobulin reagents. Removal of the viral receptor and reexpression after overnight culture was demonstrated after membrane treatment by proteolytic enzymes (trypsin, pronase) or after viral induced modulation of receptor. Protein synthesis was required for reexpression since cyclohexamide prevented the reexpression of receptor in culture. Co-capping studies utilizing 2-color immunofluorescence failed to identify and association between the reovirus receptor and a variety of known surface structures on either B or T cells, but demonstrated independent modulation of the viral receptor from other surface structures. These studies suggest that the lymphocyte surface binding site for reovirus type 3 is a distinct structure that behaves identically in capping studies of both B and T cells, is protein in nature, and is intimately linked to the cell cytoskeleton.

Animals↗
PubMed1993

Biosynthesis of reovirus-specified polypeptides. Analysis of ribosome pausing during translation of reovirus S1 and S4 mRNAs in virus-infected and vector-transfected cells.

The steady-state distribution of translating ribosomes on the reovirus s1 and s4 mRNAs was determined using a sensitive primer extension inhibition assay and cDNA clones of the reovirus S1 and S4 genes. Positions of significant ribosome pausing included the sites of initiation and termination of translation, both in vivo in reovirus-infected mouse fibroblast L cells and in vitro in rabbit reticulocyte lysates. The patterns of ribosome pausing detected in vivo and in vitro were comparable. Ribosomes were far less uniformly distributed along the polycistronic s1 mRNA than they were along the monocistronic s4 mRNA. During reovirus infection, ribosome pausing was detected at the initiation codons of the s1 mRNA sigma 1 and sigma 1ns open reading frames and the s4 mRNA sigma 3 open reading frame, direct evidence that initiation is a slow step of translation in vivo. Quantitative analysis of reovirus mRNA translation in infected and transfected cells suggested that ribosomes paused longer at an AUG initiation codon present in strong context than one present in weak context. These results suggest that the dynamics of ribosome movement during translation of the reovirus s1 and s4 mRNAs are similar in vivo and in vitro and that the relative ribosome pause at an AUG initiation codon may be affected by the flanking nucleotide context of the AUG codon.

Animals↗
PubMed1996

Stable expression of the reovirus mu2 protein in mouse L cells complements the growth of a reovirus ts mutant with a defect in its M1 gene.

Reovirus mu2 protein was constitutively expressed in mammalian cells transfected with dicistronic constructs in which the reovirus M1 gene and the selectable neomycin-resistant gene (neo) were both driven by the same phosphoglycerate kinase promoter. Translation of neo was initiated with the cap-independent translation initiation element from encephalomyocarditis virus. Expression of mu2 protein was detected by mu2-specific antibody produced through immunization of rabbits with Trp-E-mu2 fusion proteins expressed in Escherichia coli. The expression levels of mu2 proteins of serotype 1 (T1) and serotype 3 (T3) were different and varied in different mouse cell lines with T1 being expressed more efficiently than T3. mu2 expressing L929 cell lines generated with the dicistronic constructs were highly stable. Inclusion of the transforming fragment of bovine papillomavirus in the dicistronic construct lead to higher levels of mu2 expression that were less stable and thus decreased on continued cell culture. The mu2 protein expressed in transfectants was authentic as shown by peptide mapping comparison with mu2 protein from reovirus-infected cells and that from in vitro transcription and translation of the M1 gene. It was further shown that the mu2 protein expressed in a stable L929 cell line complemented the growth of the reovirus tsH11.2 mutant with a defect in its M1 gene. It is concluded that the mu2 protein stably expressed by transfection is functionally equivalent to mu2 protein expressed by reovirus.

Animals↗
PubMed2001

Mammalian reovirus L2 gene and lambda2 core spike protein sequences and whole-genome comparisons of reoviruses type 1 Lang, type 2 Jones, and type 3 Dearing.

The reovirus L2 genome segment encodes the core spike protein lambda2, which mediates enzymatic reactions in 5' capping of the viral plus-strand transcripts. Complete nucleotide-sequence determinations were made for the L2 genome segments of eight mammalian reoviruses, including the prototype isolates of serotypes 1 and 2: Lang (T1L) and Jones (T2J), respectively. Each L2 segment was found to be 3912 or 3915 bases in length. Partial nucleotide-sequence determinations were also made for the 3916-base L2 segment of reovirus type 3 Dearing (T3D), the prototype isolate of serotype 3. The whole-genome sequence of reovirus T3D was reported previously. The T1L L2 analysis represents completion of the whole-genome sequence of that isolate as well. The T2J L2 analysis leaves only the sequence of the M1 segment yet to be reported from the genome of that isolate. The T2J M1 sequence made available from analysis in another lab was used for initiating whole-genome comparisons of reoviruses T1L, T2J, and T3D in this report. The nine L2 gene sequences and deduced lambda2 protein sequences were used to gain further insights into the biological variability, structure, and functions of lambda2 through comparisons of the sequences and reference to the crystal structure of core-bound lambda2. Phylogenetic comparisons suggest the presence of three evolutionary lines of divergent L2 alleles among the nine isolates. Localized regions of conserved amino acids in the lambda2 crystal structure include active-site clefts of the RNA capping enzyme domains, sites of interactions between lambda2 domains within the pentameric spike structure, and sites of interaction between lambda2 subunits and other proteins in viral particles.

Amino Acid Sequence↗
PubMed1991

Biosynthesis of reovirus-specified polypeptides: expression of reovirus S1-encoded sigma 1NS protein in transfected and infected cells as measured with serotype specific polyclonal antibody.

Polyclonal monospecific antibody was prepared against the reovirus serotype 1 Lang strain nonstructural sigma 1NS protein encoded by the S1 gene. The antibody was serotype-specific. The sigma 1NS protein of reovirus serotype 1, but not reovirus serotype 3, was recognized by the polyclonal antibody in both immunoprecipitation and Western immunoblot assays. The sigma 1NS protein expressed in vector-transfected COS cells was indistinguishable by immunoprecipitation and immunoblot analyses from the authentic sigma 1NS protein synthesized in virus-infected mouse L or monkey COS cells. The temporal appearance of sigma 1NS protein in virus-infected cells was similar to that of the other reovirus proteins. Both sigma 1NS and sigma 1, the two S1 gene products, were observed in the cytoplasm of COS cells by immunofluorescent microscopy, although their staining patterns were distinct from each other. However, sigma 1NS, but not sigma 1 or the other reovirion structural proteins, was also detected in the nucleoli of COS cells. These results suggest that sigma 1NS, like sigma 1, is a serotype-specific reovirus protein, but unlike sigma 1 is localized in part to the cell nucleus.

Animals↗
PubMed1993

Ecological studies on reovirus pollution of rivers in Toyama Prefecture. II. Molecular epidemiological study of reoviruses isolated from river water.

In order to clarify the source of reovirus pollution in river water, comparative surveys have been carried out between reovirus isolates from river water and those from sewage, human or animal, by making use of the analysis of genomic RNA-migration pattern of reovirus in polyacrylamide gel electrophoresis (electropherotype). The strains of reovirus serotype 1 and 2 isolated from river water were classified into 3 and 9 electropherotypes, respectively, and 8 out of these 12 types were also found among strains isolated from sewage or human. When the monthly distribution of the river isolates classified by electropherotypes was compared with that of the sewage isolates, there were cases in which strains of the same electropherotype were simultaneously isolated from both sources. The electropherotypes of 3 isolates from pig and field rodents were different from those of the other isolates. The electropherotype of an oyster isolate coincided with that of some of the isolates from humans and river water. These results indicate that the major source of reoviruses polluting river water may be the human excretion.

Child↗
PubMed2002

Mammalian reovirus nonstructural protein microNS forms large inclusions and colocalizes with reovirus microtubule-associated protein micro2 in transfected cells.

Cells infected with mammalian orthoreoviruses contain large cytoplasmic phase-dense inclusions believed to be the sites of viral replication and assembly, but the morphogenesis, structure, and specific functions of these "viral factories" are poorly understood. Using immunofluorescence microscopy, we found that reovirus nonstructural protein microNS expressed in transfected cells forms inclusions that resemble the globular viral factories formed in cells infected with reovirus strain type 3 Dearing from our laboratory (T3D(N)). In the transfected cells, the formation of microNS large globular perinuclear inclusions was dependent on the microtubule network, as demonstrated by the appearance of many smaller microNS globular inclusions dispersed throughout the cytoplasm after treatment with the microtubule-depolymerizing drug nocodazole. Coexpression of microNS and reovirus protein micro2 from a different strain, type 1 Lang (T1L), which forms filamentous viral factories, altered the distributions of both proteins. In cotransfected cells, the two proteins colocalized in thick filamentous structures. After nocodazole treatment, many small dispersed globular inclusions containing microNS and micro2 were seen, demonstrating that the microtubule network is required for the formation of the filamentous structures. When coexpressed, the micro2 protein from T3D(N) also colocalized with microNS, but in globular inclusions rather than filamentous structures. The morphology difference between the globular inclusions containing microNS and micro2 protein from T3D(N) and the filamentous structures containing microNS and micro2 protein from T1L in cotransfected cells mimicked the morphology difference between globular and filamentous factories in reovirus-infected cells, which is determined by the micro2-encoding M1 genome segment. We found that the first 40 amino acids of microNS are required for colocalization with micro2 but not for inclusion formation. Similarly, a fusion of microNS amino acids 1 to 41 to green fluorescent protein was sufficient for colocalization with the micro2 protein from T1L but not for inclusion formation. These observations suggest a functional difference between microNS and microNSC, a smaller form of the protein that is present in infected cells and that is missing amino acids from the amino terminus of microNS. The capacity of microNS to form inclusions and to colocalize with micro2 in transfected cells suggests a key role for microNS in forming viral factories in reovirus-infected cells.

Animals↗
PubMed1989

The function of reovirus proteins during the reovirus multiplication cycle: analysis using monoreassortants.

When cultured cells are injected with mixtures of cores of two reovirus strains, a high proportion of reassortants are monoreassortants, that is, virus particles that contain one genome segment of 1 parent and 9 genome segments of the other. We have isolated two complete sets of monoreassortants, those that contain a single serotype 2 genome segment and 9 serotype 3 genome segments, and those that contain 1 serotype 3 genome segment and 9 serotype 1 genome segments. We have used the former set of monoreassortants (because reovirus serotypes 2 and 3 are less closely related than serotypes 1 and 3) to assess the effect of all 10 genome segments, or rather of the proteins that they encode, in controlling parameters of the reovirus multiplication cycle such as yield size, extent of viral ssRNA, dsRNA and protein synthesis, plaque size, and cytopathogenicity. Among the major findings are: proteins lambda 2, mu 1/mu 1C, and sigma 3 control yield size and extent of RNA and protein synthesis; proteins mu 2 and sigma 1 control severity of cytopathic effects; and proteins sigma 1, mu 1/mu 1C, and mu 2 control plaque size. Identification of monoreassortant phenotypes is useful for identifying which viral proteins are functionally involved at the various stages of the reovirus multiplication cycle.

Animals↗
PubMed1990

Biosynthesis of reovirus-specified polypeptides. 2-aminopurine increases the efficiency of translation of reovirus s1 mRNA but not s4 mRNA in transfected cells.

The effect of 2-aminopurine (2AP), an inhibitor of the RNA-dependent P1/eIF-2 protein kinase, on the expression of the reovirus serotype 1 Lang strain S1 and S4 genes in transfected simian COS cells was examined. In the absence of 2AP, the s4-encoded sigma 3 gene product was expressed about five times more efficiently than the s1-encoded sigma 1 gene product. When COS cells were treated with 2AP, the synthesis of the sigma 1 polypeptide was increased about fivefold compared to that in untreated cells even though s1 mRNA levels were not detectably altered. In contrast to the increased translational efficiency of the s1 mRNA observed in 2AP-treated cells, the translational efficiency of the s4 mRNA was not affected by 2AP treatment. However, the cytoplasmic accumulation of s4 mRNA was transiently decreased by 2AP treatment. These results demonstrate that the expression of the reovirus S1 and S4 genes in transient transfection assays is differentially affected by 2AP. Furthermore, when considered together with the prior observation that the reovirus s1 mRNA is a potent activator of the RNA-dependent protein kinase relative to the s4 mRNA which is a very poor activator, the results are consistent with the suggestion that the differential translational efficiency of the reovirus s1 and s4 mRNAs in vivo may be attributed in part to their differential ability to activate the P1/eIF-2 protein kinase.

2-Aminopurine↗
PubMed2001

Reovirus reverse genetics: Incorporation of the CAT gene into the reovirus genome.

We have modified the infectious reovirus RNA system so as to generate a reovirus reverse genetics system. The system consists of (i) the plus strands of nine wild-type reovirus genome segments; (ii) transcripts of the genetically modified cDNA form of the tenth genome segment; and (iii) a cell line transformed so as to express the protein normally encoded by the tenth genome segment. In the work described here, we have generated a serotype 3 reovirus into the S2 double-stranded RNA genome segment of which the CAT gene has been cloned. The virus is stable, replicates in cells that have been transformed (so as to express the S2 gene product, protein final sigma 2), and expresses high levels of CAT activity. This technology can be extended to members of the orbivirus and rotavirus genera. This technology provides a powerful system for basic studies of double-stranded RNA virus replication; a nonpathogenic viral vector that replicates to high titers and could be used for clinical applications; and a system for providing nonselectable viral variants (the result of mutations, insertions, and deletions) that could be valuable for the construction of viral vaccine strains against human and animal pathogens.

Chloramphenicol O-Acetyltransferase↗
PubMed1982

Binding to selected regions of reovirus mRNAs by a nonstructural reovirus protein.

When assembled into 13--19S particles, the reovirus nonstructural protein sigma-NS selectively binds single-stranded RNAs. Sedimentation analyses combined with binding to nitrocellulose membrane filters showed that 1--2 pmol of reovirus mRNAs from the large, medium, or small size classes saturated in vitro the binding site(s) on 13--19S particles containing 100 pmol of sigma-NS. All mRNA segments in each size class bound to particles, and no mRNAs in one size class excluded the binding of mRNAs in any other class. In competition experiments, the maximal binding of all reovirus mRNAs to particles of sigma-NS was achieved when medium and small mRNAs were bound before the large mRNAs. This preferred order of addition of mRNAs to sigma-NS resulted in a marked increase in the size of some of the complexes. This finding suggests that the addition of large mRNAs last to particles promoted the formation of complexes with more than one RNA segment bound per particle. The 13--19S particles of sigma-NS protected 20- to 40-nucleotide RNA fragments from nuclease digestion. At least one of the protected fragments from mRNAs of each size class included the 3' terminus; the remaining were from internal regions of the mRNAs. The protected RNA fragments rebound to particles during a second or third cycle of binding in a configuration in which they were fully protected from nuclease digestion. We conclude that binding of particles of sigma-NS to reovirus mRNAs was not at random sites but was to specific regions unique for members of each size class.

Binding Sites↗
PubMed2005

The goose reovirus genome segment encoding the minor outer capsid protein, sigma1/sigmaC, is bicistronic and shares structural similarities with its counterpart in Muscovy duck reovirus.

Reoviruses have recently been shown to be associated with disease in young geese and to be involved in epizooties of severe outcome in Hungary. To assess the genetic variability among these pathogenic goose reoviruses (GRVs), we sequenced the S4 genome segment of five GRV strains isolated from different diseased flocks. We found that the GRV S4 genome segment, consisting of two partially overlapping open reading frames (ORFs), shares substantial structural similarity with its counterpart in muscovy duck reoviruses (DRVs). ORF1 is predicted to encode a polypeptide highly similar to the p10 polypeptide of DRV, and ORF2 supposedly encodes the minor outer capsid protein, sigma1/sigmaC. In one of the five GRV strains examined, we identified a single uracil base insertion close to the middle of ORF2. This insertion resulted in a frameshift and in concomitant acquisition of a termination codon (UAA) a few codons downstream, apparently causing truncation of the C-terminal part of the protein. The functional consequences of this assumed mutation, which would result in loss of more than a half of the protein, have yet to be determined. Nonetheless, the sequence and structural similarities between the genome segment encoding sigmal/sigmaC in GRVs and DRVs suggest that these viruses belong to a species distinct from other established species within subgroup 2 of orthoreoviruses.

Amino Acid Sequence↗
PubMed1988

Biosynthesis of reovirus-specified polypeptides: effect of point mutation of the sequences flanking the 5'-proximal AUG initiator codons of the reovirus S1 and S4 genes on the efficiency of mRNA translation.

The effect on translation of site-directed nucleotide substitutions around the 5'-proximal AUG initiation codon of the reovirus s1 mRNA specifying polypeptide sigma 1 and the reovirus s4 mRNA specifying polypeptide sigma 3 was examined. The efficiency of synthesis of the S1-encoded sigma 1 polypeptide and the S4-encoded sigma 3 polypeptide was analyzed in transfected simian COS cells. Mutant s1 mRNAs possessing either GCU AUG G or GCA AUG G sequences surrounding the 5'-proximal sigma 1 AUG were translated with an efficiency comparable to that of the wild-type s1 mRNA which possesses the flanking sequence CCU AUG G. Mutant s4 mRNAs possessing either CCU AUG G or CCA AUG G sequences surrounding the 5'-proximal sigma 3 AUG were translated with an efficiency comparable to that of wild-type s4 mRNA which possesses the flanking sequence GCA AUG G. The s4 mRNAs, both wild-type and mutant, were translated in vivo about five times more efficiently than the s1 mRNAs, both wild-type and mutant. These results suggest that nucleotide positions other than the -3, -2, -1, and +4 positions relative to the 5'-proximal initiator AUG, where the A is +1, play a dominant role in determining the efficiency of translation of these two reovirus mRNAs in vivo.

Codon↗
PubMed1989

The sequences of the reovirus serotype 1, 2, and 3 L1 genome segments and analysis of the mode of divergence of the reovirus serotypes.

We report the sequence of the L1 genome segment of reovirus serotype 3 strain Dearing, which encodes the minor core component protein lambda 3. It is 3854 bp long, with a long open reading frame starting at position 19 that is 1267 codons long. Protein lambda 3 is not detectably related to any other protein, nor does it appear to possess motifs indicative of recognized specialized functions. We have also sequenced the L1 genome segments of reovirus serotypes 1 and 2. The serotype 1 and 3 L1 genome segments are extremely closely related; there are only 154 mismatches (4.1%), 80% of which are in third base codon positions, so that these two lambda 3 proteins are 98.3% related (only 22 mismatches out of 1267). The serotype 2 L1 genome segment is only 75% related to the serotype 1 and 3 genome segments, and the serotype 2 lambda 3 protein is 92% related to the serotype 1 and 3 lambda 3 proteins. We have also analyzed the divergence patterns by which the various reovirus genome segments evolved into the three serotype forms. It appears that serotype 2 separated from the serotype 1/3 precursor long before serotypes 1 and 3 themselves diverged. In all cases the third base codon positions in the various genome segments have diverged about 80% toward randomness. The first and second base codon positions have diverged much less and to varying degree, depending, presumably, on each protein's ability to accept changes without significant loss of function. For the separation into the serotype 1 and 3 forms, the extent of divergence of the various genome varies over a very wide range. The S1 genome segments have again diverged most extensively, the extent of divergence in the first, second, and third base codon positions being about 50, 35 and 75%, respectively. For seven other genome segments that we examined the extent of third base codon position divergence is 56, 53, 48, 29, 22, 13, and 6%, whereas first and second base codon position divergence ranges from no more than 6 to 2 and 3 to less than 1%, respectively. The most likely explanation of these patterns is that the separation of the various genome segments into the present-day serotype 1 and 3 associated forms occurred at different times during evolution, from progenitors that were genome segment reassortants with survival rates as high as or higher than those of homologous genome segment sets.

Amino Acid Sequence↗
PubMed2006

Characterization of the sigmaB-encoding genes of muscovy duck reovirus: sigmaC-sigmaB-ELISA for antibodies against duck reovirus in ducks.

The sigmaB/sigmaC-encoding genes of muscovy duck reovirus (DRV) S12 strain were cloned, sequenced, and expressed in Escherichia coli. The sigmaC-encoding gene of DRV showed only 21-22% identity to that of avian reovirus (ARV) at both nucleotide and amino acid level. The sigmaB-encoding gene of DRV comprised 1163bp with one open reading frame (ORF). The ORF comprised 1104bp and encoded 367 amino acids with a predicted molecular mass of 40.44 kDa. A zinc-binding motif and a basic amino acid motif were found within the predicted amino acid sequence of sigmaB. The identities between the S12 and ARV were 59.3-64.0% and 60.9-62.5%, respectively, at the nucleotide and deduced amino acid levels. Phylogenetic analysis of the sigmaB-encoding gene sequence indicated that S12 separated as a distinct virus relative to other avian strains. The expressed sigmaB/sigmaC fusion proteins in E. coli could be detected, approximately 45 and 50kDa, respectively, by duck anti-reovirus polyclonal serum. In addition, an ELISA (sigmaB-sigmaC-ELISA) using the expressed sigmaB-sigmaC proteins as coating antigen for detection of antibodies to DRV in ducks was developed. In comparison with the virus neutralization test and agar gel immuno-diffusion test (AGID), the sigmaB-sigmaC-ELISA showed perfect specificity and sensitivity. The sigmaB-sigmaC-ELISA did not react with the antisera to other duck pathogens, implying that these two proteins were specific in recognition of DRV antibodies. Taken together, the results demonstrated that sigmaB-sigmaC-ELISA was a sensitive and accurate method for detecting antibodies to DRV.

Amino Acid Sequence↗
PubMed1972

Translation of reovirus messenger RNAs synthetesized in vitro into reovirus polypeptides by several mammalian cell-free extracts.

Single-stranded reovirus RNA, synthesized in vitro by reovirus cores, functioned as messenger RNA in cell-free extracts prepared from several mammalian cells: Krebs II mouse ascites cells, mouse L cells, Chinese hamster ovary cells, HeLa cells, and rabbit reticulocytes. As shown by acrylamide gel electrophoresis, all eight polypeptides known to be specified by reovirus were synthesized in the reticulocyte system. In the other extracts, from 5 to 7 complete virus proteins were made.

Animals↗
PubMed1987

Transport of infectious reovirus into bile: class II major histocompatibility antigen-bearing cells determine reovirus transport.

We have previously demonstrated that mammalian reovirus type 1 enters the bile and gut lumen after systemic administration. In the present study, we showed that Kupffer cell uptake is essential for the transport of reovirus into the bile. Furthermore, class II major histocompatibility antigen (I-A)-bearing cells are a major determinant for the transit of reovirus from the hepatic environment, as well as from the intestine, during the course of systemic infection. These findings may provide an approach to the control of viral pathogens that cause systemic disease by selective utilization or modification of I-A-bearing cells.

Animals↗
PubMed1989

The reovirus M1 gene, encoding a viral core protein, is associated with the myocarditic phenotype of a reovirus variant.

Reoviruses contain a genome composed of 10 double-stranded RNA gene segments. A reovirus reassortant, 8B, derived from type 1 Lang (T1L) and type 3 Dearing (T3D), displayed a phenotype unlike that of either of its parents in that it efficiently induced numerous macroscopic external cardiac lesions in neonatal mice (B. Sherry, F. J. Schoen, E. Wenske, and B. N. Fields, J. Virol. 63:4840-4849, 1989). A panel of T1L/T3D reassortants and a panel of reassortants derived from 8B were used to determine whether novel T1L/T3D gene associations in 8B were responsible for its myocarditic phenotype. The results eliminated the possibility that any T1L/T3D gene combination found in 8B, from 2 genes to all 10 genes, was the explanation for its induction of cardiac lesions. This suggested that a mutation(s) in an 8B gene(s) might be responsible for induction of the myocarditis. Statistical analysis of experiments with 31 reassortants derived from 8B revealed a highly significant association (P = 0.002) of the 8B M1 gene with induction of cardiac lesions. The reovirus M1 gene encodes a viral core protein of unknown function, although evidence suggests a potential role in core structure and/or viral RNA synthesis. This represents the first report of the association of a viral gene with induction of myocarditis.

Animals↗