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Viruses Jan 2021Cells are continually exposed to stressful events, which are overcome by the activation of a number of genetic pathways. The integrated stress response (ISR) is a large... (Review)
Review
Cells are continually exposed to stressful events, which are overcome by the activation of a number of genetic pathways. The integrated stress response (ISR) is a large component of the overall cellular response to stress, which ultimately functions through the phosphorylation of the alpha subunit of eukaryotic initiation factor-2 (eIF2α) to inhibit the energy-taxing process of translation. This response is instrumental in the inhibition of viral infection and contributes to evolution in viruses. Mammalian orthoreovirus (MRV), an oncolytic virus that has shown promise in over 30 phase I-III clinical trials, has been shown to induce multiple arms within the ISR pathway, but it successfully evades, modulates, or subverts each cellular attempt to inhibit viral translation. MRV has not yet received Food and Drug Administration (FDA) approval for general use in the clinic; therefore, researchers continue to study virus interactions with host cells to identify circumstances where MRV effectiveness in tumor killing can be improved. In this review, we will discuss the ISR, MRV modulation of the ISR, and discuss ways in which MRV interaction with the ISR may increase the effectiveness of cancer therapeutics whose modes of action are altered by the ISR.
Topics: Eukaryotic Initiation Factor-2; Humans; Oncolytic Virotherapy; Oncolytic Viruses; Orthoreovirus, Mammalian; Phosphorylation; Protein Biosynthesis; RNA Caps; Reoviridae Infections; Stress, Physiological
PubMed: 33525628
DOI: 10.3390/v13020200 -
Viruses Apr 2021Oncolytic reovirus preferentially targets and kills cancer cells via the process of oncolysis, and additionally drives clinically favorable antitumor T cell responses... (Review)
Review
Oncolytic reovirus preferentially targets and kills cancer cells via the process of oncolysis, and additionally drives clinically favorable antitumor T cell responses that form protective immunological memory against cancer relapse. This two-prong attack by reovirus on cancers constitutes the foundation of its use as an anticancer oncolytic agent. Unfortunately, the efficacy of these reovirus-driven antitumor effects is influenced by the highly suppressive tumor microenvironment (TME). In particular, the myeloid cell populations (e.g., myeloid-derived suppressive cells and tumor-associated macrophages) of highly immunosuppressive capacities within the TME not only affect oncolysis but also actively impair the functioning of reovirus-driven antitumor T cell immunity. Thus, myeloid cells within the TME play a critical role during the virotherapy, which, if properly understood, can identify novel therapeutic combination strategies potentiating the therapeutic efficacy of reovirus-based cancer therapy.
Topics: Cell Line, Tumor; Clinical Trials as Topic; Humans; Myeloid Cells; Neoplasms; Oncolytic Virotherapy; Oncolytic Viruses; Orthoreovirus; Reoviridae; Tumor Microenvironment
PubMed: 33920168
DOI: 10.3390/v13040654 -
Viruses Aug 2022(MRVs) are increasingly reported to cause various diseases in humans and other animals, with many possibly originating from bats, highlighting the urgent need to...
(MRVs) are increasingly reported to cause various diseases in humans and other animals, with many possibly originating from bats, highlighting the urgent need to investigate the diversity of bat-borne MRVs (BtMRVs). Here, we report the detection and characterization of a reassortant MRV that was isolated from a bat colony in Xinjiang, China. The BtMRV showed a wide host and organ tropism and can efficiently propagate the cell lines of different animals. It caused mild damage in the lungs of the experimentally inoculated suckling mice and was able to replicate in multiple organs for up to three weeks post-inoculation. Complete genome analyses showed that the virus was closely related to MRVs in a wide range of animals. An intricate reassortment network was revealed between the BtMRV and MRVs of human, deer, cattle, civet and other bat species. Specifically, we found a bat-specific clade of segment M1 that provides a gene source for the reassortment of human MRVs. These data provide important insights to understand the diversity of MRVs and their natural circulation between bats, humans, and other animals. Further investigation and surveillance of MRV in bats and other animals are needed to control and prevent potential MRV-related diseases.
Topics: Animals; Cattle; China; Chiroptera; Deer; Humans; Mice; Orthoreovirus; Orthoreovirus, Mammalian; Phylogeny; Sequence Analysis, DNA
PubMed: 36146702
DOI: 10.3390/v14091897 -
Viruses Feb 2021De novo viral protein synthesis following entry into host cells is essential for viral replication. As a consequence, viruses have evolved mechanisms to engage the host... (Review)
Review
De novo viral protein synthesis following entry into host cells is essential for viral replication. As a consequence, viruses have evolved mechanisms to engage the host translational machinery while at the same time avoiding or counteracting host defenses that act to repress translation. Mammalian orthoreoviruses are dsRNA-containing viruses whose mRNAs were used as models for early investigations into the mechanisms that underpin the recognition and engagement of eukaryotic mRNAs by host cell ribosomes. However, there remain many unanswered questions and paradoxes regarding translation of reoviral mRNAs in the context of infection. This review summarizes the current state of knowledge about reovirus translation, identifies key unanswered questions, and proposes possible pathways toward a better understanding of reovirus translation.
Topics: Animals; Host-Pathogen Interactions; Humans; Orthoreovirus, Mammalian; Protein Biosynthesis; RNA, Viral; Reoviridae Infections; Ribosomes; Viral Proteins; Virus Replication
PubMed: 33670092
DOI: 10.3390/v13020275 -
Journal of Virology Feb 2022Segmentation of viral genomes provides the potential for genetic exchange within coinfected cells. However, for this potential to be realized, coinfecting genomes must...
Segmentation of viral genomes provides the potential for genetic exchange within coinfected cells. However, for this potential to be realized, coinfecting genomes must mix during the viral life cycle. The efficiency of reassortment, in turn, dictates its potential to drive evolution. The opportunity for mixing within coinfected cells may vary greatly across virus families, such that the evolutionary implications of genome segmentation differ as a result of core features of the viral life cycle. To investigate the relationship between viral replication compartments and genetic exchange, we quantified reassortment in mammalian orthoreovirus (reovirus). Reoviruses carry a 10-segmented, double-stranded RNA genome, which is replicated within proteinaceous structures termed inclusion bodies. We hypothesized that inclusions impose a barrier to reassortment. We quantified reassortment between wild-type () and variant () reoviruses that differ by one nucleotide per segment. Studies of systems in both T1L and T3D backgrounds revealed frequent reassortment without bias toward particular genotypes. However, reassortment was more efficient in the T3D serotype. Since T1L and T3D viruses exhibit different inclusion body morphologies, we tested the impact of this phenotype on reassortment. In both serotypes, reassortment levels did not differ by inclusion morphology. Reasoning that the merging of viral inclusions may be critical for genome mixing, we then tested the effect of blocking merging. Reassortment proceeded efficiently even under these conditions. Our findings indicate that reovirus reassortment is highly efficient despite the localization of many viral processes to inclusion bodies, and that the robustness of this genetic exchange is independent of inclusion body structure and fusion. Quantification of reassortment in diverse viral systems is critical to elucidate the implications of genome segmentation for viral evolution. In principle, genome segmentation offers a facile means of genetic exchange between coinfecting viruses. In practice, there may be physical barriers within the cell that limit the mixing of viral genomes. Here, we tested the hypothesis that localization of the various stages of the mammalian orthoreovirus life cycle within cytoplasmic inclusion bodies compartmentalizes viral replication and limits genetic exchange. Contrary to this hypothesis, our data indicate that reovirus reassortment occurs readily within coinfected cells and is not strongly affected by the structure or dynamics of viral inclusion bodies. We conclude that the potential for reassortment to contribute to reovirus evolution is high.
Topics: Animals; Cell Line; Genome, Viral; Genotype; Inclusion Bodies, Viral; Mice; Microtubules; Orthoreovirus, Mammalian; Reassortant Viruses; Serogroup; Virus Replication
PubMed: 34935439
DOI: 10.1128/JVI.01832-21 -
Pathogens (Basel, Switzerland) Nov 2021Piscine orthoreovirus (PRV) infects farmed and wild salmon and trout species in North America, South America, Europe, and East Asia. PRV groups into three distinct...
Piscine orthoreovirus (PRV) infects farmed and wild salmon and trout species in North America, South America, Europe, and East Asia. PRV groups into three distinct genotypes (PRV-1, PRV-2, and PRV-3) that can vary in distribution, host specificity, and/or disease potential. Detection of the virus is currently restricted to genotype specific assays such that surveillance programs require the use of three assays to ensure universal detection of PRV. Consequently, herein, we developed, optimized, and validated a real-time reverse transcription quantitative PCR assay (RT-qPCR) that can detect all known PRV genotypes with high sensitivity and specificity. Targeting a conserved region at the 5' terminus of the M2 segment, the pan-PRV assay reliably detected all PRV genotypes with as few as five copies of RNA. The assay exclusively amplifies PRV and does not cross-react with other salmonid viruses or salmonid host genomes and can be performed as either a one- or two-step RT-qPCR. The assay is highly reproducible and robust, showing 100% agreement in test results from an inter-laboratory comparison between two laboratories in two countries. Overall, as the assay provides a single test to achieve highly sensitive pan-specific PRV detection, it is suitable for research, diagnostic, and surveillance purposes.
PubMed: 34959503
DOI: 10.3390/pathogens10121548 -
Journal of Virology Mar 2021For viruses with segmented genomes, genetic diversity is generated by genetic drift, reassortment, and recombination. Recombination produces RNA populations distinct...
For viruses with segmented genomes, genetic diversity is generated by genetic drift, reassortment, and recombination. Recombination produces RNA populations distinct from full-length gene segments and can influence viral population dynamics, persistence, and host immune responses. Viruses in the family, including rotavirus and mammalian orthoreovirus (reovirus), have been reported to package segments containing rearrangements or internal deletions. Rotaviruses with RNA segments containing rearrangements have been isolated from immunocompromised and immunocompetent children and following serial passage at relatively high multiplicity. Reoviruses that package small, defective RNA segments have established chronic infections in cells and in mice. However, the mechanism and extent of RNA recombination are undefined. Towards filling this gap in knowledge, we determined the titers and RNA segment profiles for reovirus and rotavirus following serial passage in cultured cells. The viruses exhibited occasional titer reductions characteristic of interference. Reovirus strains frequently accumulated segments that retained 5' and 3' terminal sequences and featured large internal deletions, while similarly fragmented segments were rarely detected in rotavirus populations. Using next-generation RNA-sequencing to analyze RNA molecules packaged in purified reovirus particles, we identified distinct recombination sites within individual viral genome segments. Recombination junctions were frequently but not always characterized by short direct sequence repeats upstream and downstream that spanned junction sites. Taken together, these findings suggest that reovirus accumulates defective gene segments featuring internal deletions during passage and undergoes sequence-directed recombination at distinct sites. Viruses in the family include important pathogens of humans and other animals and have segmented RNA genomes. Recombination in RNA virus populations can facilitate novel host exploration and increased disease severity. The extent, patterns, and mechanisms of recombination and the functions and effects of recombined RNA products are poorly understood. Here, we provide evidence that mammalian orthoreovirus regularly synthesizes RNA recombination products that retain terminal sequences but contain internal deletions, while rotavirus rarely synthesizes such products. Recombination occurs more frequently at specific sites in the mammalian orthoreovirus genome, and short regions of identical sequence are often detected at junction sites. These findings suggest that mammalian orthoreovirus recombination events are directed in part by RNA sequences. An improved understanding of recombined viral RNA synthesis may enhance our capacity to engineer improved vaccines and virotherapies in the future.
PubMed: 33472930
DOI: 10.1128/JVI.02181-20 -
Poultry Science Oct 2023Since 2005, novel duck reoviruses have been outbreaks in duck breeding areas such as central China and South China. In recent years, the incidence rate of this disease...
Since 2005, novel duck reoviruses have been outbreaks in duck breeding areas such as central China and South China. In recent years, the incidence rate of this disease is still increasing, bringing serious economic losses to waterfowl breeding industry. This study isolated 3 novel duck reoviruses (NDRV-SDLS, NDRV-SDWF, and NDRV-SDYC) from sick ducks in 3 local duck farms in Shandong Province. The study aimed to investigate the characteristics of these viruses. The virus is inoculated into duck embryo fibroblasts, where the virus replicates to produce syncytium and dies within 3 to 5 d. The viruses were also isolated from infected ducks, and RT-PCR amplified the whole genomes after passage purification in duck embryos. The resulting whole genome was analyzed for genetic evolution. The total length of the gene sequencing was 23,418 bp, divided into 10 fragments. Gene sequence comparison showed that the 3 strains had high similarity with novel duck reoviruses (NDRV) but low similarity with chicken-origin reovirus (chicken ARV) and Muscovy duck reovirus (MDRV), especially in the σC segment. Phylogenetic analysis of the 10 fragments showed that the 3 isolates constituted the same evolutionary clade as other DRV reference strains and were far related to ARV and MDRV in different evolutionary clades. The results of all 10 segments indicate that the isolates are in the evolutionary branch of NDRV, suggesting that the novel waterfowl reovirus is the dominant circulating strain in Shandong. This study complements the gene bank information of NDRV and provides references for vaccine research and disease prediction of NDRV in Shandong.
Topics: Animals; Orthoreovirus, Avian; Reoviridae Infections; Phylogeny; Chickens; China; Poultry Diseases
PubMed: 37566967
DOI: 10.1016/j.psj.2023.102969 -
The Onderstepoort Journal of Veterinary... Nov 2022Infectious bronchitis virus (IBV) and avian reovirus (ARV) cause significant losses in the poultry industry throughout the world. A cross-sectional study was conducted...
Infectious bronchitis virus (IBV) and avian reovirus (ARV) cause significant losses in the poultry industry throughout the world. A cross-sectional study was conducted in four villages in Manjacaze district, Southern Mozambique, to determine the seroprevalence of IBV and ARV. A total of 467 serum samples from adult unvaccinated backyard chickens were screened using commercial and competitive enzyme-linked immunoabsorbent assay kits. Our results showed anti-IBV and anti-ARV antibodies in all surveyed households and villages. The overall seroprevalence was 89.5% (95% confidence interval [CI]: 77.2-97.4) and 95.7% (95% CI: 88.0-99.2) for IBV and ARV, respectively. The risk of becoming exposed to IBV was lower in Chidenguele village compared with the other three villages (p 0.05). However, no statistically significant differences were observed for becoming exposed to ARV between villages (p 0.05). The backyard chickens tested in this study had no previous history of vaccination, outbreaks or typical clinical signs of IB and AR diseases. Therefore, the presence of antibodies to IBV and ARV was considered clear evidence that the birds have been naturally exposed to those two infectious agents, and the infection was of subclinical type. It is concluded that IBV and ARV are widespread in backyard chickens in the studied area. These obtained data are essential for design and implementation of chicken health development programmes.Contribution: The epidemiology of IBV and ARV of backyard chicken in Mozambique is unknown. This study determined the seroprevalence of IBV and ARV in backyard chicken health. The obtained data are essential for design and implementation of chicken health development programmes.
Topics: Animals; Infectious bronchitis virus; Orthoreovirus, Avian; Chickens; Seroepidemiologic Studies; Cross-Sectional Studies
PubMed: 36453824
DOI: 10.4102/ojvr.v89i1.2042 -
Virology Dec 2020Mammalian orthoreovirus (MRV) infections are ubiquitous in mammals. Increasing evidence suggests that some MRVs can cause severe respiratory disease and encephalitis in...
Mammalian orthoreovirus (MRV) infections are ubiquitous in mammals. Increasing evidence suggests that some MRVs can cause severe respiratory disease and encephalitis in humans and other animals. Previously, we isolated six bat MRV strains. However, the pathogenicity of these bat viruses remains unclear. In this study, we investigated the host range and pathogenicity of 3 bat MRV strains (WIV2, 3 and 7) which represent three serotypes. Our results showed that all of them can infect cell lines from different mammalian species and displayed different replication efficiency. The BALB/c mice infected by bat MRVs showed clinical symptoms with systematic infection especially in lung and intestines. Obvious tissue damage were found in all infected lungs. One of the strains, WIV7, showed higher replication efficiency in vitro and vivo and more severe pathogenesis in mice. Our results provide new evidence showing potential pathogenicity of bat MRVs in animals and probable risk in humans.
Topics: Animals; Cell Line; Chiroptera; Female; Host Specificity; Humans; Intestines; Lung; Mice; Mice, Inbred BALB C; Orthoreovirus, Mammalian; Pneumonia, Viral; Reoviridae Infections; Serogroup
PubMed: 32859395
DOI: 10.1016/j.virol.2020.05.014