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A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Animal Viruses".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 40284

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Special Issue Editors

Dr. Pranav Danthi

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Guest Editor

Department of Biology, Indiana University, Bloomington, IN, USA
Interests: reovirus entry; host responses and cell death

Dr. Maya Shmulevitz

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Guest Editor

Department of Medical Microbiology and Immunology, Li Ka Shing Institute for Virology, University of Alberta, Edmonton, AB, Canada
Interests: reoviridae; virus-host interactions; oncolytic viruses
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Special Issue Information

Dear Colleagues,

Since the fortuitous discovery of reoviruses in the 1950s, these dsRNA icosahedral members of the Reoviridae family have served to understand countless concepts in cell biology, virology, and virus–host interactions in vitro, cell cultures, and animal models. Among the many molecular contributions, research on reoviruses facilitated the discovery of mRNA capping, and the realization that non-enveloped viruses can also encode membrane fusogenic proteins, thus understanding the virus structure, mechanisms of cell attachment, and virus entry. Recent advances in high resolution virus structure determination show remarkable routes of capsid evolution among members of the Reoviridae. In vivo, reoviruses serve as powerful model systems for a better understanding antiviral signaling and virus-induced disease pathogenesis. Most recently, reoviruses provide insight into gut microbe interactions between viruses and bacteria. Reoviruses, as well as reovirus-derived fusogenic proteins, are also being developed into cancer therapies.

Reoviridae diverged into the sedoreovirinae (nonturreted) and spinareovirinae (turreted) subfamilies; each subfamily containing virus members that are pathogenic, or potential tools for beneficial application. Although the reovirus designation generally refers to the orthoreovirus genus, this Special Issue is designed to provide an up-to-date view of the spinareovirinae subfamily in general. With shared evolution, each genus of spinareovirinae offers a strategy to better understand, control, or exploit this subfamily of viruses. This Special Issue invites both general updating reviews on aquareoviruses, coltiviruses, cypoviruses, fijiviruses, orthoreoviruses, idnoreoviruses, dinovernaviruses, oryzaviruses, and mycoreoviruses, as well as reviews and original research articles on specific topics such as evolution, structure–function of specific spinareovirinae proteins, or host–pathogen interactions.

Dr. Pranav Danthi
Dr. Maya Shmulevitz
Guest Editors

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Keywords

Aquareoviruses
Coltiviruses
Cypoviruses
Fijiviruses
Orthoreoviruses
Idnoreoviruses
Dinovernaviruses
Oryzaviruses
mycoreoviruses
virus attachment
virus entry
replication mechanisms
pathogenesis
innate immune responses
oncolytics
reverse genetics
virus structure
evolution

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Published Papers (12 papers)

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Research

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15 pages, 28158 KiB

Open AccessArticle

Targeting JAK/STAT Signaling Antagonizes Resistance to Oncolytic Reovirus Therapy Driven by Prior Infection with HTLV-1 in Models of T-Cell Lymphoma

by Shariful Islam, Claudia M. Espitia, Daniel O. Persky, Jennifer S. Carew and Steffan T. Nawrocki

Viruses 2021, 13(7), 1406; https://doi.org/10.3390/v13071406 - 20 Jul 2021

Cited by 5 | Viewed by 2818

Abstract

Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus that infects at least 10 million people worldwide and is associated with the development of T-cell lymphoma (TCL). The treatment of TCL remains challenging and new treatment options are urgently needed. With the goal of developing a novel therapeutic approach for TCL, we investigated the activity of the clinical formulation of oncolytic reovirus (Reolysin, Pelareorep) in TCL models. Our studies revealed that HTLV-1-negative TCL cells were highly sensitive to Reolysin-induced cell death, but HTLV-1-positive TCL cells were resistant. Consistent with these data, reovirus displayed significant viral accumulation in HTLV-1-negative cells, but failed to efficiently replicate in HTLV-1-positive cells. Transcriptome analyses of HTLV-1-positive vs. negative cells revealed a significant increase in genes associated with retroviral infection including interleukin-13 and signal transducer and activator of transcription 5 (STAT5). To investigate the relationship between HTLV-1 status and sensitivity to Reolysin, we infected HTLV-1-negative cells with HTLV-1. The presence of HTLV-1 resulted in significantly decreased sensitivity to Reolysin. Treatment with the JAK inhibitor ruxolitinib suppressed STAT5 phosphorylation and expression of the key anti-viral response protein MX1 and enhanced the anti-TCL activity of Reolysin in both HTLV-1-positive and negative cells. Our data demonstrate that the inhibition of the JAK/STAT pathway can be used as a novel approach to antagonize the resistance of HTLV-1-positive cells to oncolytic virus therapy. Full article

(This article belongs to the Special Issue Reoviruses)

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23 pages, 12145 KiB

Open AccessArticle

Reovirus Low-Density Particles Package Cellular RNA

by Timothy W. Thoner, Jr., Xiang Ye, John Karijolich and Kristen M. Ogden

Viruses 2021, 13(6), 1096; https://doi.org/10.3390/v13061096 - 8 Jun 2021

Cited by 2 | Viewed by 2851

Abstract

Packaging of segmented, double-stranded RNA viral genomes requires coordination of viral proteins and RNA segments. For mammalian orthoreovirus (reovirus), evidence suggests either all ten or zero viral RNA segments are simultaneously packaged in a highly coordinated process hypothesized to exclude host RNA. Accordingly, reovirus generates genome-containing virions and “genomeless” top component particles. Whether reovirus virions or top component particles package host RNA is unknown. To gain insight into reovirus packaging potential and mechanisms, we employed next-generation RNA-sequencing to define the RNA content of enriched reovirus particles. Reovirus virions exclusively packaged viral double-stranded RNA. In contrast, reovirus top component particles contained similar proportions but reduced amounts of viral double-stranded RNA and were selectively enriched for numerous host RNA species, especially short, non-polyadenylated transcripts. Host RNA selection was not dependent on RNA abundance in the cell, and specifically enriched host RNAs varied for two reovirus strains and were not selected solely by the viral RNA polymerase. Collectively, these findings indicate that genome packaging into reovirus virions is exquisitely selective, while incorporation of host RNAs into top component particles is differentially selective and may contribute to or result from inefficient viral RNA packaging. Full article

(This article belongs to the Special Issue Reoviruses)

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13 pages, 3063 KiB

Open AccessArticle

A Single Point Mutation, Asn₁₆→Lys, Dictates the Temperature-Sensitivity of the Reovirus tsG453 Mutant

by Kathleen K. M. Glover, Danica M. Sutherland, Terence S. Dermody and Kevin M. Coombs

Viruses 2021, 13(2), 289; https://doi.org/10.3390/v13020289 - 12 Feb 2021

Cited by 2 | Viewed by 2271

Abstract

Studies of conditionally lethal mutants can help delineate the structure-function relationships of biomolecules. Temperature-sensitive (ts) mammalian reovirus (MRV) mutants were isolated and characterized many years ago. Two of the most well-defined MRV ts mutants are tsC447, which contains mutations in the S2 gene encoding viral core protein σ2, and tsG453, which contains mutations in the S4 gene encoding major outer-capsid protein σ3. Because many MRV ts mutants, including both tsC447 and tsG453, encode multiple amino acid substitutions, the specific amino acid substitutions responsible for the ts phenotype are unknown. We used reverse genetics to recover recombinant reoviruses containing the single amino acid polymorphisms present in ts mutants tsC447 and tsG453 and assessed the recombinant viruses for temperature-sensitivity by efficiency-of-plating assays. Of the three amino acid substitutions in the tsG453 S4 gene, Asn₁₆-Lys was solely responsible for the tsG453ts phenotype. Additionally, the mutant tsC447 Ala₁₈₈-Val mutation did not induce a temperature-sensitive phenotype. This study is the first to employ reverse genetics to identify the dominant amino acid substitutions responsible for the tsC447 and tsG453 mutations and relate these substitutions to respective phenotypes. Further studies of other MRV ts mutants are warranted to define the sequence polymorphisms responsible for temperature sensitivity. Full article

(This article belongs to the Special Issue Reoviruses)

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11 pages, 271 KiB

Open AccessArticle

Mammalian Orthoreovirus (MRV) Is Widespread in Wild Ungulates of Northern Italy

by Sara Arnaboldi, Francesco Righi, Virginia Filipello, Tiziana Trogu, Davide Lelli, Alessandro Bianchi, Silvia Bonardi, Enrico Pavoni, Barbara Bertasi and Antonio Lavazza

Viruses 2021, 13(2), 238; https://doi.org/10.3390/v13020238 - 3 Feb 2021

Cited by 4 | Viewed by 2333

Abstract

Mammalian orthoreoviruses (MRVs) are emerging infectious agents that may affect wild animals. MRVs are usually associated with asymptomatic or mild respiratory and enteric infections. However, severe clinical manifestations have been occasionally reported in human and animal hosts. An insight into their circulation is essential to minimize the risk of diffusion to farmed animals and possibly to humans. The aim of this study was to investigate the presence of likely zoonotic MRVs in wild ungulates. Liver samples were collected from wild boar, red deer, roe deer, and chamois. Samples originated from two areas (Sondrio and Parma provinces) in Northern Italy with different environmental characteristics. MRV detection was carried out by PCR; confirmation by sequencing and typing for MRV type 3, which has been frequently associated with disease in pigs, were carried out for positive samples. MRV prevalence was as high as 45.3% in wild boars and 40.6% in red deer in the Sondrio area, with lower prevalence in the Parma area (15.4% in wild boars). Our findings shed light on MRV occurrence and distribution in some wild species and posed the issue of their possible role as reservoir. Full article

(This article belongs to the Special Issue Reoviruses)

20 pages, 2082 KiB

Open AccessArticle

Polycistronic Genome Segment Evolution and Gain and Loss of FAST Protein Function during Fusogenic Orthoreovirus Speciation

by Yiming Yang, Gerard Gaspard, Nichole McMullen and Roy Duncan

Viruses 2020, 12(7), 702; https://doi.org/10.3390/v12070702 - 29 Jun 2020

Cited by 9 | Viewed by 3195

Abstract

The Reoviridae family is the only non-enveloped virus family with members that use syncytium formation to promote cell–cell virus transmission. Syncytiogenesis is mediated by a fusion-associated small transmembrane (FAST) protein, a novel family of viral membrane fusion proteins. Previous evidence suggested the fusogenic reoviruses arose from an ancestral non-fusogenic virus, with the preponderance of fusogenic species suggesting positive evolutionary pressure to acquire and maintain the fusion phenotype. New phylogenetic analyses that included the atypical waterfowl subgroup of avian reoviruses and recently identified new orthoreovirus species indicate a more complex relationship between reovirus speciation and fusogenic capacity, with numerous predicted internal indels and 5’-terminal extensions driving the evolution of the orthoreovirus’ polycistronic genome segments and their encoded FAST and fiber proteins. These inferred recombination events generated bi- and tricistronic genome segments with diverse gene constellations, they occurred pre- and post-orthoreovirus speciation, and they directly contributed to the evolution of the four extant orthoreovirus FAST proteins by driving both the gain and loss of fusion capability. We further show that two distinct post-speciation genetic events led to the loss of fusion in the waterfowl isolates of avian reovirus, a recombination event that replaced the p10 FAST protein with a heterologous, non-fusogenic protein and point substitutions in a conserved motif that destroyed the p10 assembly into multimeric fusion platforms. Full article

(This article belongs to the Special Issue Reoviruses)

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21 pages, 3901 KiB

Open AccessArticle

Unexpected Genetic Diversity of Two Novel Swine MRVs in Italy

by Lara Cavicchio, Luca Tassoni, Gianpiero Zamperin, Mery Campalto, Marilena Carrino, Stefania Leopardi, Paola De Benedictis and Maria Serena Beato

Viruses 2020, 12(5), 574; https://doi.org/10.3390/v12050574 - 22 May 2020

Cited by 6 | Viewed by 3381

Abstract

Mammalian Orthoreoviruses (MRV) are segmented dsRNA viruses in the family Reoviridae. MRVs infect mammals and cause asymptomatic respiratory, gastro-enteric and, rarely, encephalic infections. MRVs are divided into at least three serotypes: MRV1, MRV2 and MRV3. In Europe, swine MRV (swMRV) was first isolated in Austria in 1998 and subsequently reported more than fifteen years later in Italy. In the present study, we characterized two novel reassortant swMRVs identified in one same Italian farm over two years. The two viruses shared the same genetic backbone but showed evidence of reassortment in the S1, S4, M2 segments and were therefore classified into two serotypes: MRV3 in 2016 and MRV2 in 2018. A genetic relation to pig, bat and human MRVs and other unknown sources was identified. A considerable genetic diversity was observed in the Italian MRV3 and MRV2 compared to other available swMRVs. The S1 protein presented unique amino acid signatures in both swMRVs, with unexpected frequencies for MRV2. The remaining genes formed distinct and novel genetic groups that revealed a geographically related evolution of swMRVs in Italy. This is the first report of the complete molecular characterization of novel reassortant swMRVs in Italy and Europe, which suggests a greater genetic diversity of swMRVs never identified before. Full article

(This article belongs to the Special Issue Reoviruses)

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Review

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18 pages, 1729 KiB

Open AccessReview

Role of Myeloid Cells in Oncolytic Reovirus-Based Cancer Therapy

by Vishnupriyan Kumar, Michael A. Giacomantonio and Shashi Gujar

Viruses 2021, 13(4), 654; https://doi.org/10.3390/v13040654 - 10 Apr 2021

Cited by 10 | Viewed by 4174

Abstract

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. Full article

(This article belongs to the Special Issue Reoviruses)

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27 pages, 6311 KiB

Open AccessReview

Captivating Perplexities of Spinareovirinae 5′ RNA Caps

by Justine Kniert, Qi Feng Lin and Maya Shmulevitz

Viruses 2021, 13(2), 294; https://doi.org/10.3390/v13020294 - 13 Feb 2021

Cited by 3 | Viewed by 2952

Abstract

RNAs with methylated cap structures are present throughout multiple domains of life. Given that cap structures play a myriad of important roles beyond translation, such as stability and immune recognition, it is not surprising that viruses have adopted RNA capping processes for their own benefit throughout co-evolution with their hosts. In fact, that RNAs are capped was first discovered in a member of the Spinareovirinae family, Cypovirus, before these findings were translated to other domains of life. This review revisits long-past knowledge and recent studies on RNA capping among members of Spinareovirinae to help elucidate the perplex processes of RNA capping and functions of RNA cap structures during Spinareovirinae infection. The review brings to light the many uncertainties that remain about the precise capping status, enzymes that facilitate specific steps of capping, and the functions of RNA caps during Spinareovirinae replication. Full article

(This article belongs to the Special Issue Reoviruses)

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17 pages, 916 KiB

Open AccessReview

The Paradoxes of Viral mRNA Translation during Mammalian Orthoreovirus Infection

by Yingying Guo and John S. L. Parker

Viruses 2021, 13(2), 275; https://doi.org/10.3390/v13020275 - 11 Feb 2021

Cited by 6 | Viewed by 3579

Abstract

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. Full article

(This article belongs to the Special Issue Reoviruses)

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18 pages, 1359 KiB

Open AccessReview

Reovirus and the Host Integrated Stress Response: On the Frontlines of the Battle to Survive

by Luke D. Bussiere and Cathy L. Miller

Viruses 2021, 13(2), 200; https://doi.org/10.3390/v13020200 - 28 Jan 2021

Cited by 5 | Viewed by 3251

Abstract

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. Full article

(This article belongs to the Special Issue Reoviruses)

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9 pages, 8237 KiB

Open AccessReview

Control of Capsid Transformations during Reovirus Entry

by Stephanie L. Gummersheimer, Anthony J. Snyder and Pranav Danthi

Viruses 2021, 13(2), 153; https://doi.org/10.3390/v13020153 - 21 Jan 2021

Cited by 10 | Viewed by 3352

Abstract

Mammalian orthoreovirus (reovirus), a dsRNA virus with a multilayered capsid, serves as a model system for studying the entry of similar viruses. The outermost layer of this capsid undergoes processing to generate a metastable intermediate. The metastable particle undergoes further remodeling to generate an entry-capable form that delivers the genome-containing inner capsid, or core, into the cytoplasm. In this review, we highlight capsid proteins and the intricacies of their interactions that control the stability of the capsid and consequently impact capsid structural changes that are prerequisites for entry. We also discuss a novel proviral role of host membranes in promoting capsid conformational transitions. Current knowledge gaps in the field that are ripe for future investigation are also outlined. Full article

(This article belongs to the Special Issue Reoviruses)

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10 pages, 609 KiB

Open AccessReview

Recognition of Reovirus RNAs by the Innate Immune System

by Andrew T. Abad and Pranav Danthi

Viruses 2020, 12(6), 667; https://doi.org/10.3390/v12060667 - 20 Jun 2020

Cited by 21 | Viewed by 4561

Abstract

Mammalian orthoreovirus (reovirus) is a dsRNA virus, which has long been used as a model system to study host–virus interactions. One of the earliest interactions during virus infection is the detection of the viral genomic material, and the consequent induction of an interferon (IFN) based antiviral response. Similar to the replication of related dsRNA viruses, the genomic material of reovirus is thought to remain protected by viral structural proteins throughout infection. Thus, how innate immune sensor proteins gain access to the viral genomic material, is incompletely understood. This review summarizes currently known information about the innate immune recognition of the reovirus genomic material. Using this information, we propose hypotheses about host detection of reovirus. Full article

(This article belongs to the Special Issue Reoviruses)

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