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Trends in Microbiology Apr 2021Cell entry and egress are essential steps in the viral life cycle that govern pathogenesis and spread. Mammalian orthoreoviruses (reoviruses) are nonenveloped viruses... (Review)
Review
Cell entry and egress are essential steps in the viral life cycle that govern pathogenesis and spread. Mammalian orthoreoviruses (reoviruses) are nonenveloped viruses implicated in human disease that serve as tractable models for studies of pathogen-host interactions. In this review we discuss the function of intracellular vesicular transport systems in reovirus entry, trafficking, and egress and comment on shared themes for diverse viruses. Designing strategic therapeutic interventions that impede these steps in viral replication requires a detailed understanding of mechanisms by which viruses coopt vesicular trafficking. We illuminate such targets, which may foster development of antiviral agents.
Topics: Animals; Biological Transport; Host-Pathogen Interactions; Humans; Mammals; Reoviridae; Virus Internalization; Virus Release
PubMed: 33008713
DOI: 10.1016/j.tim.2020.09.004 -
Journal of Microbiology (Seoul, Korea) Jun 2007REOviruses (Respiratory Enteric Orphan viruses) are ubiquitous, non-enveloped viruses containing 10 segments of double-stranded RNA (dsRNA) as their genome. They are... (Review)
Review
REOviruses (Respiratory Enteric Orphan viruses) are ubiquitous, non-enveloped viruses containing 10 segments of double-stranded RNA (dsRNA) as their genome. They are common isolates of the respiratory and gastrointestinal tract of humans but are not associated with severe disease and are therefore considered relatively benign. An intriguing characteristic of reovirus is its innate oncolytic potential, which is linked to the transformed state of the cell. When immortalized cells are transfected in vitro with activated oncogenes such as Ras, Sos, v-erbB, or c-myc, they became susceptible to reovirus infection and subsequent cellular lysis, indicating that oncogene signaling pathways are exploited by reovirus. This observation has led to the use of the virus in clinical trials as an anti-cancer agent against oncogenic tumors. In addition to the exploitation of oncogene signaling, reovirus may further utilize host immune responses to enhance its antitumor activity in vivo due to its innate interferon induction ability. Reovirus is, however, not entirely benign to immunocompromised animal models. Reovirus causes so-called "black feet syndrome" in immunodeficient mice and can also harm neonatal animals. Because cancer patients often undergo immunosuppression due to heavy chemo/radiation-treatments or advanced tumor progression, this pathogenic response may be a hurdle in virus-based anticancer therapies. However, a genetically attenuated reovirus variant derived from persistent reovirus infection of cells in vitro is able to exert potent anti-tumor activity with significantly reduced viral pathogenesis in immunocompromised animals. Importantly, in this instance the attenuated reovirus maintains its oncolytic potential while significantly reducing viral pathogenesis in vivo.
Topics: Animals; Humans; Mice; Oncolytic Virotherapy; Oncolytic Viruses; Reoviridae
PubMed: 17618222
DOI: No ID Found -
Journal of Invertebrate Pathology Jun 2021A variety of reoviruses have been described in crustacean hosts, including shrimp, crayfish, prawn, and especially in crabs. However, only one genus of crustacean...
A variety of reoviruses have been described in crustacean hosts, including shrimp, crayfish, prawn, and especially in crabs. However, only one genus of crustacean reovirus - Cardoreovirus - has been formally recognized by ICTV (International Committee on Taxonomy of Viruses) and most crustacean reoviruses remain unclassified. This arises in part from ambiguous or incomplete information on which to categorize them. In recent years, increased availability of crustacean reovirus genomic sequences is making the discovery and classification of crustacean reoviruses faster and more certain. This minireview describes the properties of the reoviruses infecting crustaceans and suggests an overall classification of brachyuran crustacean reoviruses based on a combination of morphology, host, genome organization pattern and phylogenetic sequence analysis.
Topics: Animals; Crustacea; Phylogeny; Reoviridae
PubMed: 33711318
DOI: 10.1016/j.jip.2021.107568 -
Journal of Virology Oct 2020Triple-negative breast cancer (TNBC) constitutes 10 to 15% of all breast cancer and is associated with worse prognosis than other subtypes of breast cancer. Current...
Triple-negative breast cancer (TNBC) constitutes 10 to 15% of all breast cancer and is associated with worse prognosis than other subtypes of breast cancer. Current therapies are limited to cytotoxic chemotherapy, radiation, and surgery, leaving a need for targeted therapeutics to improve outcomes for TNBC patients. Mammalian orthoreovirus (reovirus) is a nonenveloped, segmented, double-stranded RNA virus in the family. Reovirus preferentially kills transformed cells and is in clinical trials to assess its efficacy against several types of cancer. We previously engineered a reassortant reovirus, r2Reovirus, that infects TNBC cells more efficiently and induces cell death with faster kinetics than parental reoviruses. In this study, we sought to understand the mechanisms by which r2Reovirus induces cell death in TNBC cells. We show that r2Reovirus infection of TNBC cells of a mesenchymal stem-like (MSL) lineage downregulates the mitogen-activated protein kinase/extracellular signal-related kinase pathway and induces nonconventional cell death that is caspase-dependent but caspase 3-independent. Infection of different MSL lineage TNBC cells with r2Reovirus results in caspase 3-dependent cell death. We map the enhanced oncolytic properties of r2Reovirus in TNBC to epistatic interactions between the type 3 Dearing M2 gene segment and type 1 Lang genes. These findings suggest that the genetic composition of the host cell impacts the mechanism of reovirus-induced cell death in TNBC. Together, our data show that understanding host and virus determinants of cell death can identify novel properties and interactions between host and viral gene products that can be exploited for the development of improved viral oncolytics. TNBC is unresponsive to hormone therapies, leaving patients afflicted with this disease with limited treatment options. We previously engineered an oncolytic reovirus (r2Reovirus) with enhanced infective and cytotoxic properties in TNBC cells. However, how r2Reovirus promotes TNBC cell death is not known. In this study, we show that reassortant r2Reovirus can promote nonconventional caspase-dependent but caspase 3-independent cell death and that the mechanism of cell death depends on the genetic composition of the host cell. We also map the enhanced oncolytic properties of r2Reovirus in TNBC to interactions between a type 3 M2 gene segment and type 1 genes. Our data show that understanding the interplay between the host cell environment and the genetic composition of oncolytic viruses is crucial for the development of efficacious viral oncolytics.
Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Caspase 3; Cell Death; Cell Line; Cell Survival; Humans; Mitochondria; Oncolytic Virotherapy; Oncolytic Viruses; Orthoreovirus, Mammalian; Reoviridae; Viral Proteins
PubMed: 32847857
DOI: 10.1128/JVI.01613-20 -
PLoS Pathogens Sep 2022Reoviridae virus family members, such as mammalian orthoreovirus (reovirus), encounter a unique challenge during replication. To hide the dsRNA from host recognition,...
Reoviridae virus family members, such as mammalian orthoreovirus (reovirus), encounter a unique challenge during replication. To hide the dsRNA from host recognition, the genome remains encapsidated in transcriptionally active proteinaceous core capsids that transcribe and release +RNA. De novo +RNAs and core proteins must repeatedly assemble into new progeny cores in order to logarithmically amplify replication. Reoviruses also produce outercapsid (OC) proteins μ1, σ3 and σ1 that assemble onto cores to create highly stable infectious full virions. Current models of reovirus replication position amplification of transcriptionally-active cores and assembly of infectious virions in shared factories, but we hypothesized that since assembly of OC proteins would halt core amplification, OC assembly is somehow regulated. Kinetic analysis of virus +RNA production, core versus OC protein expression, and core particles versus whole virus particle accumulation, indicated that assembly of OC proteins onto core particles was temporally delayed. All viral RNAs and proteins were made simultaneously, eliminating the possibility that delayed OC RNAs or proteins account for delayed OC assembly. High resolution fluorescence and electron microscopy revealed that core amplification occurred early during infection at peripheral core-only factories, while all OC proteins associated with lipid droplets (LDs) that coalesced near the nucleus in a μ1-dependent manner. Core-only factories transitioned towards the nucleus despite cycloheximide-mediated halting of new protein expression, while new core-only factories developed in the periphery. As infection progressed, OC assembly occurred at LD-and nuclear-proximal factories. Silencing of OC μ1 expression with siRNAs led to large factories that remained further from the nucleus, implicating μ1 in the transition to perinuclear factories. Moreover, late during infection, +RNA pools largely contributed to the production of de-novo viral proteins and fully-assembled infectious viruses. Altogether the results suggest an advanced model of reovirus replication with spatiotemporal segregation of core amplification, OC complexes and fully assembled virions.
Topics: Animals; Capsid Proteins; Cell Line; Cycloheximide; Kinetics; Mammals; RNA, Viral; Reoviridae; Viral Proteins; Virus Assembly
PubMed: 36099325
DOI: 10.1371/journal.ppat.1010641 -
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 Jun 2023Oncolytic viruses (OVs) are an emerging cancer therapeutic that are intended to act by selectively targeting and lysing cancerous cells and by stimulating anti-tumour...
Oncolytic viruses (OVs) are an emerging cancer therapeutic that are intended to act by selectively targeting and lysing cancerous cells and by stimulating anti-tumour immune responses, while leaving normal cells mainly unaffected. Reovirus is a well-studied OV that is undergoing advanced clinical trials and has received FDA approval in selected circumstances. However, the mechanisms governing reoviral selectivity are not well characterised despite many years of effort, including those in our accompanying paper where we characterize pathways that do not consistently modulate reoviral cytolysis. We have earlier shown that reovirus is capable of infecting and lysing both certain types of cancer cells and also cancer stem cells, and here we demonstrate its ability to also infect and kill healthy pluripotent stem cells (PSCs). This led us to hypothesize that pathways responsible for stemness may constitute a novel route for the modulation of reoviral tropism. We find that reovirus is capable of killing both murine and human embryonic and induced pluripotent stem cells. Differentiation of PSCs alters the cells' reoviral-permissive state to a resistant one. In a breast cancer cell line that was resistant to reoviral oncolysis, induction of pluripotency programming rendered the cells permissive to cytolysis. Bioinformatic analysis indicates that expression of the Yamanaka pluripotency factors may be associated with regulating reoviral selectivity. Mechanistic insights from these studies will be useful for the advancement of reoviral oncolytic therapy.
Topics: Humans; Animals; Mice; Reoviridae; Neoplasms; Orthoreovirus; Oncolytic Viruses; Cell Line, Tumor; Cell Death; Oncolytic Virotherapy
PubMed: 37515162
DOI: 10.3390/v15071473 -
Viruses Jun 2023Patients with stage IV gastric cancer suffer from dismal outcomes, a challenge especially in many Asian populations and for which new therapeutic options are needed. To...
Patients with stage IV gastric cancer suffer from dismal outcomes, a challenge especially in many Asian populations and for which new therapeutic options are needed. To explore this issue, we used oncolytic reovirus in combination with currently used chemotherapeutic drugs (irinotecan, paclitaxel, and docetaxel) for the treatment of gastric and other gastrointestinal cancer cells in vitro and in a mouse model. Cell viability in vitro was quantified by WST-1 assays in human cancer cell lines treated with reovirus and/or chemotherapeutic agents. The expression of reovirus protein and caspase activity was determined by flow cytometry. For in vivo studies, athymic mice received intratumoral injections of reovirus in combination with irinotecan or paclitaxel, after which tumor size was monitored. In contrast to expectations, we found that reoviral oncolysis was only poorly correlated with Ras pathway activation. Even so, the combination of reovirus with chemotherapeutic agents showed synergistic cytopathic effects in vitro, plus enhanced reovirus replication and apoptosis. In vivo experiments showed that reovirus alone can reduce tumor size and that the combination of reovirus with chemotherapeutic agents enhances this effect. Thus, we find that oncolytic reovirus therapy is effective against gastric cancer. Moreover, the combination of reovirus and chemotherapeutic agents synergistically enhanced cytotoxicity in human gastric cancer cell lines in vitro and in vivo. Our data support the use of reovirus in combination with chemotherapy in further clinical trials, and highlight the need for better biomarkers for reoviral oncolytic responsiveness.
Topics: Mice; Animals; Humans; Irinotecan; Stomach Neoplasms; Oncolytic Virotherapy; Cell Line, Tumor; Orthoreovirus; Reoviridae; Paclitaxel; Oncolytic Viruses
PubMed: 37515160
DOI: 10.3390/v15071472 -
Emerging Infectious Diseases Nov 2005Coltiviruses are tickborne viruses of the genus Coltivirus. The type species, Colorado tick fever virus (from North America), has been isolated from patients with... (Review)
Review
Coltiviruses are tickborne viruses of the genus Coltivirus. The type species, Colorado tick fever virus (from North America), has been isolated from patients with flulike syndromes, meningitis, encephalitis, and other severe complications. Another coltivirus, Eyach virus, has been isolated from ticks in France and Germany and incriminated in febrile illnesses and neurologic syndromes. Seadornaviruses are endemic in Southeast Asia, particularly Indonesia and China. The prototype virus of the genus, Banna virus (BAV), has been isolated from many mosquito species, humans with encephalitis, pigs, and cattle. Two other seadornaviruses, Kadipiro and Liao Ning, were isolated only from mosquitoes. The epidemiology of seadornaviruses remains poorly documented. Evidence suggests that BAV is responsible for encephalitis in humans. Infection with BAV may be underreported because it circulates in regions with a high incidence of Japanese encephalitis and could be misdiagnosed as this disease.
Topics: Animals; Asia; Cats; Coltivirus; Europe; Humans; Mice; North America; Rabbits; Reoviridae; Reoviridae Infections
PubMed: 16318717
DOI: 10.3201/eid1111.050868 -
Journal of Virology Sep 2003
Review
Topics: Animals; Apoptosis; Capsid Proteins; Carbohydrate Metabolism; Cell Adhesion Molecules; Humans; Junctional Adhesion Molecules; Mice; Models, Biological; Models, Molecular; N-Acetylneuraminic Acid; Receptors, Virus; Reoviridae
PubMed: 12915527
DOI: 10.1128/jvi.77.17.9109-9115.2003