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NgR1 binding to reovirus reveals an unusual bivalent interaction and a new viral attachment protein.Proceedings of the National Academy of... Jun 2023Nogo-66 receptor 1 (NgR1) binds a variety of structurally dissimilar ligands in the adult central nervous system to inhibit axon extension. Disruption of ligand binding...
Nogo-66 receptor 1 (NgR1) binds a variety of structurally dissimilar ligands in the adult central nervous system to inhibit axon extension. Disruption of ligand binding to NgR1 and subsequent signaling can improve neuron outgrowth, making NgR1 an important therapeutic target for diverse neurological conditions such as spinal crush injuries and Alzheimer's disease. Human NgR1 serves as a receptor for mammalian orthoreovirus (reovirus), but the mechanism of virus-receptor engagement is unknown. To elucidate how NgR1 mediates cell binding and entry of reovirus, we defined the affinity of interaction between virus and receptor, determined the structure of the virus-receptor complex, and identified residues in the receptor required for virus binding and infection. These studies revealed that central NgR1 surfaces form a bridge between two copies of viral capsid protein σ3, establishing that σ3 serves as a receptor ligand for reovirus. This unusual binding interface produces high-avidity interactions between virus and receptor to prime early entry steps. These studies refine models of reovirus cell-attachment and highlight the evolution of viruses to engage multiple receptors using distinct capsid components.
Topics: Animals; Humans; Nogo Receptor 1; Virus Attachment; Viral Proteins; Ligands; Reoviridae; Orthoreovirus; Receptors, Virus; Mammals
PubMed: 37276413
DOI: 10.1073/pnas.2219404120 -
PLoS Pathogens Jan 2024Several egress pathways have been defined for many viruses. Among these pathways, extracellular vesicles (EVs) have been shown to function as vehicles of non-lytic viral...
Several egress pathways have been defined for many viruses. Among these pathways, extracellular vesicles (EVs) have been shown to function as vehicles of non-lytic viral egress. EVs are heterogenous populations of membrane-bound structures released from cells as a form of intercellular communication. EV-mediated viral egress may enable immune evasion and collective viral transport. Strains of nonenveloped mammalian orthoreovirus (reovirus) differ in cell lysis phenotypes, with T3D disrupting cell membranes more efficiently than T1L. However, mechanisms of reovirus egress and the influence of transport strategy on infection are only partially understood. To elucidate reovirus egress mechanisms, we infected murine fibroblasts (L cells) and non-polarized human colon epithelial (Caco-2) cells with T1L or T3D reovirus and enriched cell culture supernatants for large EVs, medium EVs, small EVs, and free reovirus. We found that both reovirus strains exit cells in association with large and medium EVs and as free virus particles, and that EV-enriched fractions are infectious. While reovirus visually associates with large and medium EVs, only medium EVs offer protection from antibody-mediated neutralization. EV-mediated protection from neutralization is virus strain- and cell type-specific, as medium EVs enriched from L cell supernatants protect T1L and T3D, while medium EVs enriched from Caco-2 cell supernatants largely fail to protect T3D and only protect T1L efficiently. Using genetically barcoded reovirus, we provide evidence that large and medium EVs can convey multiple particles to recipient cells. Finally, T1L or T3D infection increases the release of all EV sizes from L cells. Together, these findings suggest that in addition to exiting cells as free particles, reovirus promotes egress from distinct cell types in association with large and medium EVs during lytic or non-lytic infection, a mode of exit that can mediate multiparticle infection and, in some cases, protection from antibody neutralization.
Topics: Animals; Mice; Humans; Orthoreovirus, Mammalian; Caco-2 Cells; Reoviridae; Orthoreovirus; Extracellular Vesicles; Mammalian orthoreovirus 3; Mammals
PubMed: 38206991
DOI: 10.1371/journal.ppat.1011637 -
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 Jun 2022Bats have recently been identified as potential reservoir hosts for mammalian orthoreoviruses (MRVs) throughout Europe and China. Here we present the first evolutionary...
Bats have recently been identified as potential reservoir hosts for mammalian orthoreoviruses (MRVs) throughout Europe and China. Here we present the first evolutionary and biological characterization of bat-borne MRVs in North America, including phylogenomic analysis, in vitro relative infectivity in bat and other mammalian cell cultures, host cell receptor specificity, and epifluorescence microscopy of viral factory formation. Through genetic and phylogenetic comparisons, we show that two divergent MRV serotype 2 (T2) strains - isolated from a silver-haired bat (Lasionycteris noctivagans) and a big brown bat (Eptesicus fuscus) from Pennsylvania, USA - provide an evolutionary link to an MRV strain (T2W) recovered from an 8-week-old infant who died in Winnipeg, Manitoba, Canada in 1997. Although these findings suggest North American bats may represent a previously unrecognized source for the cross-species transmission of MRVs to other animals, including humans, the ecology and epidemiology of MRVs in wildlife remain enigmatic.
Topics: Animals; Animals, Wild; Chiroptera; Host Specificity; Humans; Orthoreovirus, Mammalian; Phylogeny
PubMed: 35421704
DOI: 10.1016/j.virol.2022.03.012 -
PloS One 2016Erythrocytic inclusion body syndrome (EIBS) causes mass mortality in farmed salmonid fish, including the coho salmon, Onchorhynchus kisutchi, and chinook salmon, O....
Erythrocytic inclusion body syndrome (EIBS) causes mass mortality in farmed salmonid fish, including the coho salmon, Onchorhynchus kisutchi, and chinook salmon, O. tshawytscha. The causative agent of the disease is a virus with an icosahedral virion structure, but this virus has not been characterized at the molecular level. In this study, we sequenced the genome of a virus purified from EIBS-affected coho salmon. The virus has 10 dsRNA genomic segments (L1, L2, L3, M1, M2, M3, S1, S2, S3, and S4), which closely resembles the genomic organization of piscine orthoreovirus (PRV), the causative agent of heart and skeletal inflammation (HSMI) in Atlantic salmon and HSMI-like disease in coho salmon. The genomic segments of the novel virus contain at least 10 open reading frames (ORFs): lambda 1 (λ1), λ2, λ3, mu 1 (μ1), μ2, μNS, sigma 1 (σ1), σ2, σ3, and σNS. An additional ORF encoding a 12.6-kDa protein (homologue of PRV p13) occurs in the same genomic segment as σ3. Phylogenetic analyses based on S1 and λ3 suggest that this novel virus is closely related to PRV, but distinctly different. Therefore, we designated the new virus 'piscine orthoreovirus 2' (PRV-2). Reverse transcription-quantitative real-time PCR revealed a significant increase in PRV-2 RNA in fish blood after the artificial infection of EIBS-naïve fish but not in that of fish that had recovered from EIBS. The degree of anemia in each fish increased as the PRV-2 RNA increased during an epizootic season of EIBS on an inland coho salmon farm. These results indicate that PRV-2 is the probable causative agent of EIBS in coho salmon, and that the host acquires immunity to reinfection with this virus. Further research is required to determine the host range of PRV species and the relationship between EIBS and HSMI in salmonid fish.
Topics: Animals; Fish Diseases; Genomics; Oncorhynchus; Orthoreovirus; RNA, Viral
PubMed: 27788206
DOI: 10.1371/journal.pone.0165424 -
Viruses Dec 2022Grasshoppers can swarm in the millions and destroy crops over wide areas, posing a major economic threat to agriculture. A wide range of insect-related viruses has...
Grasshoppers can swarm in the millions and destroy crops over wide areas, posing a major economic threat to agriculture. A wide range of insect-related viruses has recently been reported in the metagenomics of grasshoppers. Here, we identified and isolated a novel reovirus from grasshoppers, named Acrididae reovirus (ARV). The complete genome of ARV was composed of nine dsRNA segments. Phylogenetic analysis revealed that ARV formed a monophyletic lineage with unclassified insect-associated reoviruses and was sufficiently distinct from known genera of . ARV could replicate in its host and result in host death. Lower-dose ARV infection affected ovary development and resulted in a significant reduction in fecundity. The identification and characterization of a novel pathogenic reovirus could potentially promote the development of new biological control agents.
Topics: Animals; Grasshoppers; Phylogeny; Reoviridae; Orthoreovirus; Reoviridae Infections
PubMed: 36560814
DOI: 10.3390/v14122810 -
Current Topics in Microbiology and... 2005Reovirus infection has proven to be an excellent experimental system for studying mechanisms of virus-induced pathogenesis. Reoviruses induce apoptosis in a wide variety... (Review)
Review
Reovirus infection has proven to be an excellent experimental system for studying mechanisms of virus-induced pathogenesis. Reoviruses induce apoptosis in a wide variety of cultured cells in vitro and in target tissues in vivo, including the heart and central nervous system. In vivo, viral infection, tissue injury, and apoptosis colocalize, suggesting that apoptosis is a critical mechanism by which disease is triggered in the host. This review examines the mechanisms of reovirus-induced apoptosis and investigates the possibility that inhibition of apoptosis may provide a novel strategy for limiting virus-induced tissue damage following infection.
Topics: Animals; Apoptosis; Central Nervous System Diseases; Humans; Myocarditis; Orthoreovirus, Mammalian; Reoviridae Infections
PubMed: 15791949
DOI: 10.1007/3-540-27320-4_1 -
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 -
Emerging Microbes & Infections Dec 2021Mammalian orthoreovirus (MRV) infects multiple mammalian species including humans. A United States Midwest swine farm with approximately one thousand 3-month-old pigs...
Mammalian orthoreovirus (MRV) infects multiple mammalian species including humans. A United States Midwest swine farm with approximately one thousand 3-month-old pigs experienced an event, in which more than 300 pigs showed neurological signs, like "down and peddling", with approximately 40% mortality. A novel MRV was isolated from the diseased pigs. Sequence and phylogenetic analysis revealed that the isolate was a reassortant virus containing viral gene segments from three MRV serotypes that infect human, bovine and swine. The M2 and S1 segment of the isolate showed 94% and 92% nucleotide similarity to the M2 of the MRV2 D5/Jones and the S1 of the MRV1 C/bovine/Indiana/MRV00304/2014, respectively; the remaining eight segments displayed 93%-95% nucleotide similarity to those of the MRV3 FS-03/Porcine/USA/2014. Pig studies showed that both MRV-infected and native contact pigs displayed fever, diarrhoea and nasal discharge. MRV RNA was detected in different intestinal locations of both infected and contact pigs, indicating that the MRV isolate is pathogenic and transmissible in pigs. Seroconversion was also observed in experimentally infected pigs. A prevalence study on more than 180 swine serum samples collected from two states without disease revealed 40%-52% positive to MRV. All results warrant the necessity to monitor MRV epidemiology and reassortment as the MRV could be an important pathogen for the swine industry and a novel MRV might emerge to threaten animal and public health.
Topics: Animals; Cattle; Dogs; High-Throughput Nucleotide Sequencing; Humans; Madin Darby Canine Kidney Cells; Orthoreovirus, Mammalian; Phylogeny; RNA, Viral; Reassortant Viruses; Reoviridae Infections; Sequence Analysis, RNA; Swine; United States
PubMed: 34018466
DOI: 10.1080/22221751.2021.1933608 -
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