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Reovirus-Induced Apoptosis in the Intestine Limits Establishment of Enteric Infection.
Brown JJ, Short SP, Stencel-Baerenwald J, Urbanek K, Pruijssers AJ, McAllister N, Ikizler M, Taylor G, Aravamudhan P, Khomandiak S, Jabri B, Williams CS, Dermody TS
(2018) J Virol 92:
MeSH Terms: Animals, Antigens, Viral, Apoptosis, Cell Line, Cricetinae, Epithelial Cells, Intestinal Mucosa, Mammalian orthoreovirus 3, Mice, Orthoreovirus, Mammalian, Reoviridae Infections
Show Abstract · Added April 15, 2019
Several viruses induce intestinal epithelial cell death during enteric infection. However, it is unclear whether proapoptotic capacity promotes or inhibits replication in this tissue. We infected mice with two reovirus strains that infect the intestine but differ in the capacity to alter immunological tolerance to new food antigen. Infection with reovirus strain T1L, which induces an inflammatory immune response to fed antigen, is prolonged in the intestine, whereas T3D-RV, which does not induce this response, is rapidly cleared from the intestine. Compared with T1L, T3D-RV infection triggered apoptosis of intestinal epithelial cells and subsequent sloughing of dead cells into the intestinal lumen. We conclude that the infection advantage of T1L derives from its capacity to subvert host restriction by epithelial cell apoptosis, providing a possible mechanism by which T1L enhances inflammatory signals during antigen feeding. Using a panel of T1L × T3D-RV reassortant viruses, we identified the viral M1 and M2 gene segments as determinants of reovirus-induced apoptosis in the intestine. Expression of the T1L M1 and M2 genes in a T3D-RV background was sufficient to limit epithelial cell apoptosis and enhance viral infection to levels displayed by T1L. These findings define additional reovirus gene segments required for enteric infection of mice and illuminate the antiviral effect of intestinal epithelial cell apoptosis in limiting enteric viral infection. Viral strain-specific differences in the capacity to infect the intestine may be useful in identifying viruses capable of ameliorating tolerance to fed antigen in autoimmune conditions like celiac disease. Acute viral infections are thought to be cleared by the host with few lasting consequences. However, there may be much broader and long-lasting effects of viruses on immune homeostasis. Infection with reovirus, a common, nonpathogenic virus, triggers inflammation against innocuous food antigens, implicating this virus in the development of celiac disease, an autoimmune intestinal disorder triggered by exposure to dietary gluten. Using two reovirus strains that differ in the capacity to abrogate oral tolerance, we found that strain-specific differences in the capacity to replicate in the intestine inversely correlate with the capacity to induce apoptotic death of intestinal epithelial cells, providing a host-mediated process to restrict intestinal infection. This work contributes new knowledge about virus-host interactions in the intestine and establishes a foundation for future studies to define mechanisms by which viruses break oral tolerance in celiac disease.
Copyright © 2018 American Society for Microbiology.
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MeSH Terms
Comparison of three neurotropic viruses reveals differences in viral dissemination to the central nervous system.
Luethy LN, Erickson AK, Jesudhasan PR, Ikizler M, Dermody TS, Pfeiffer JK
(2016) Virology 487: 1-10
MeSH Terms: Animals, Cell Line, Central Nervous System, Cricetinae, HeLa Cells, Humans, Interferon Type I, Mice, Mice, Inbred C57BL, Mice, Knockout, Orthoreovirus, Mammalian, Peripheral Nerves, Poliomyelitis, Poliovirus, Receptor, Interferon alpha-beta, Reoviridae Infections, Sciatic Nerve, Yellow Fever, Yellow fever virus
Show Abstract · Added February 4, 2016
Neurotropic viruses initiate infection in peripheral tissues prior to entry into the central nervous system (CNS). However, mechanisms of dissemination are not completely understood. We used genetically marked viruses to compare dissemination of poliovirus, yellow fever virus 17D (YFV-17D), and reovirus type 3 Dearing in mice from a hind limb intramuscular inoculation site to the sciatic nerve, spinal cord, and brain. While YFV-17D likely entered the CNS via blood, poliovirus and reovirus likely entered the CNS by transport through the sciatic nerve to the spinal cord. We found that dissemination was inefficient in adult immune-competent mice for all three viruses, particularly reovirus. Dissemination of all viruses was more efficient in immune-deficient mice. Although poliovirus and reovirus both accessed the CNS by transit through the sciatic nerve, stimulation of neuronal transport by muscle damage enhanced dissemination only of poliovirus. Our results suggest that these viruses access the CNS using different pathways.
Copyright © 2015 Elsevier Inc. All rights reserved.
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19 MeSH Terms
Diminished reovirus capsid stability alters disease pathogenesis and littermate transmission.
Doyle JD, Stencel-Baerenwald JE, Copeland CA, Rhoads JP, Brown JJ, Boyd KL, Atkinson JB, Dermody TS
(2015) PLoS Pathog 11: e1004693
MeSH Terms: Animals, Capsid, Capsid Proteins, Mice, Mutation, Orthoreovirus, Mammalian, Virion, Virus Assembly
Show Abstract · Added February 4, 2016
Reovirus is a nonenveloped mammalian virus that provides a useful model system for studies of viral infections in the young. Following internalization into host cells, the outermost capsid of reovirus virions is removed by endosomal cathepsin proteases. Determinants of capsid disassembly kinetics reside in the viral σ3 protein. However, the contribution of capsid stability to reovirus-induced disease is unknown. In this study, we found that mice inoculated intramuscularly with a serotype 3 reovirus containing σ3-Y354H, a mutation that reduces viral capsid stability, succumbed at a higher rate than those infected with wild-type virus. At early times after inoculation, σ3-Y354H virus reached higher titers than wild-type virus at several sites within the host. Animals inoculated perorally with a serotype 1 reassortant reovirus containing σ3-Y354H developed exaggerated myocarditis accompanied by elaboration of pro-inflammatory cytokines. Surprisingly, unchallenged littermates of mice infected with σ3-Y354H virus displayed higher titers in the intestine, heart, and brain than littermates of mice inoculated with wild-type virus. Together, these findings suggest that diminished capsid stability enhances reovirus replication, dissemination, lethality, and host-to-host spread, establishing a new virulence determinant for nonenveloped viruses.
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8 MeSH Terms
A plasmid-based reverse genetics system for mammalian orthoreoviruses driven by a plasmid-encoded T7 RNA polymerase.
Komoto S, Kawagishi T, Kobayashi T, Ikizler M, Iskarpatyoti J, Dermody TS, Taniguchi K
(2014) J Virol Methods 196: 36-9
MeSH Terms: Animals, Cell Line, DNA-Directed RNA Polymerases, Humans, Orthoreovirus, Mammalian, Reverse Genetics, Transfection, Viral Proteins, Virology
Show Abstract · Added May 20, 2014
Mammalian orthoreoviruses (reoviruses) have served as highly useful models for studies of virus replication and pathogenesis. The development of a plasmid-based reverse genetics system represented a major breakthrough in reovirus research. The current reverse genetics systems for reoviruses rely on the expression of T7 RNA polymerase within cells transfected with reovirus gene-segment cDNA plasmids. In these systems, the T7 RNA polymerase is provided by using a recombinant vaccinia virus expressing T7 RNA polymerase or a cell line constitutively expressing T7 RNA polymerase. Here, we describe an alternative plasmid-based rescue system driven by a plasmid-encoded T7 RNA polymerase, which could increase the flexibility of such reverse genetics systems. Although this approach requires transfection of an additional plasmid, virus recovery was achieved when A549, BHK-21, or L929 cells were co-transfected with a reovirus 10-plasmid set together with a plasmid encoding T7 RNA polymerase. Theoretically, this system offers the possibility to generate reoviruses in any cell line, including those amenable to propagation of viral vectors for clinical use. Thus, this approach will increase the flexibility of reverse genetics for basic studies of reovirus biology and foster development of reoviruses for clinical applications.
Copyright © 2013 Elsevier B.V. All rights reserved.
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9 MeSH Terms
Apoptosis induction influences reovirus replication and virulence in newborn mice.
Pruijssers AJ, Hengel H, Abel TW, Dermody TS
(2013) J Virol 87: 12980-9
MeSH Terms: Animals, Animals, Newborn, Apoptosis, Brain, Female, Humans, Male, Mammalian orthoreovirus 3, Mice, Mice, Inbred C57BL, Reoviridae Infections, Viral Proteins, Virulence, Virus Replication
Show Abstract · Added March 27, 2014
Apoptosis is a type of controlled cell death that is essential for development and tissue homeostasis. It also serves as a robust host response against infection by many viruses. The capacity of neurotropic viruses to induce apoptosis strongly correlates with virulence. However, the precise function of apoptosis in viral infection is not well understood. Reovirus is a neurotropic virus that induces apoptosis in a variety of cell types, including central nervous system neurons, leading to fatal encephalitis in newborn mice. To determine the effect of apoptosis on reovirus replication in the host, we generated two otherwise isogenic viruses that differ in a single amino acid in viral capsid protein μ1 that segregates with apoptotic capacity. Apoptosis-proficient and apoptosis-deficient viruses were compared for replication, dissemination, tropism, and tissue injury in newborn mice and for the capacity to spread to uninfected littermates. Our results indicate that apoptotic capacity enhances reovirus replication in the brain and consequent neurovirulence but reduces transmission efficiency. The replication advantage of the apoptosis-proficient strain is limited to the brain and correlates with enhanced infectivity of neurons. These studies reveal a new cell type-specific determinant of reovirus virulence.
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14 MeSH Terms
Nonstructural protein σ1s mediates reovirus-induced cell cycle arrest and apoptosis.
Boehme KW, Hammer K, Tollefson WC, Konopka-Anstadt JL, Kobayashi T, Dermody TS
(2013) J Virol 87: 12967-79
MeSH Terms: Amino Acid Motifs, Animals, Apoptosis, Cell Cycle Checkpoints, Cell Line, Humans, Mammalian orthoreovirus 3, Mice, Reoviridae Infections, Viral Nonstructural Proteins, Virus Replication
Show Abstract · Added May 20, 2014
Reovirus nonstructural protein σ1s is implicated in cell cycle arrest at the G2/M boundary and induction of apoptosis. However, the contribution of σ1s to these effects in an otherwise isogenic viral background has not been defined. To evaluate the role of σ1s in cell cycle arrest and apoptosis, we used reverse genetics to generate a σ1s-null reovirus. Following infection with wild-type virus, we observed an increase in the percentage of cells in G2/M, whereas the proportion of cells in G2/M following infection with the σ1s-null mutant was unaffected. Similarly, we found that the wild-type virus induced substantially greater levels of apoptosis than the σ1s-null mutant. These data indicate that σ1s is required for both reovirus-induced cell cycle arrest and apoptosis. To define sequences in σ1s that mediate these effects, we engineered viruses encoding C-terminal σ1s truncations by introducing stop codons in the σ1s open reading frame. We also generated viruses in which charged residues near the σ1s amino terminus were replaced individually or as a cluster with nonpolar residues. Analysis of these mutants revealed that amino acids 1 to 59 and the amino-terminal basic cluster are required for induction of both cell cycle arrest and apoptosis. Remarkably, viruses that fail to induce cell cycle arrest and apoptosis also are attenuated in vivo. Thus, identical sequences in σ1s are required for reovirus-induced cell cycle arrest, apoptosis, and pathogenesis. Collectively, these findings provide evidence that the σ1s-mediated properties are genetically linked and suggest that these effects are mechanistically related.
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11 MeSH Terms
The GM2 glycan serves as a functional coreceptor for serotype 1 reovirus.
Reiss K, Stencel JE, Liu Y, Blaum BS, Reiter DM, Feizi T, Dermody TS, Stehle T
(2012) PLoS Pathog 8: e1003078
MeSH Terms: Animals, Cricetinae, Embryo, Mammalian, Fibroblasts, Gangliosidoses, GM2, L Cells (Cell Line), Mice, Mutation, Orthoreovirus, Mammalian, Protein Structure, Tertiary, Receptors, Virus, Reoviridae Infections, Viral Proteins
Show Abstract · Added May 20, 2014
Viral attachment to target cells is the first step in infection and also serves as a determinant of tropism. Like many viruses, mammalian reoviruses bind with low affinity to cell-surface carbohydrate receptors to initiate the infectious process. Reoviruses disseminate with serotype-specific tropism in the host, which may be explained by differential glycan utilization. Although α2,3-linked sialylated oligosaccharides serve as carbohydrate receptors for type 3 reoviruses, neither a specific glycan bound by any reovirus serotype nor the function of glycan binding in type 1 reovirus infection was known. We have identified the oligosaccharide portion of ganglioside GM2 (the GM2 glycan) as a receptor for the attachment protein σ1 of reovirus strain type 1 Lang (T1L) using glycan array screening. The interaction of T1L σ1 with GM2 in solution was confirmed using NMR spectroscopy. We established that GM2 glycan engagement is required for optimal infection of mouse embryonic fibroblasts (MEFs) by T1L. Preincubation with GM2 specifically inhibited type 1 but not type 3 reovirus infection of MEFs. To provide a structural basis for these observations, we defined the mode of receptor recognition by determining the crystal structure of T1L σ1 in complex with the GM2 glycan. GM2 binds in a shallow groove in the globular head domain of T1L σ1. Both terminal sugar moieties of the GM2 glycan, N-acetylneuraminic acid and N-acetylgalactosamine, form contacts with the protein, providing an explanation for the observed specificity for GM2. Viruses with mutations in the glycan-binding domain display diminished hemagglutination capacity, a property dependent on glycan binding, and reduced capacity to infect MEFs. Our results define a novel mode of virus-glycan engagement and provide a mechanistic explanation for the serotype-dependent differences in glycan utilization by reovirus.
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13 MeSH Terms
Utilization of sialylated glycans as coreceptors enhances the neurovirulence of serotype 3 reovirus.
Frierson JM, Pruijssers AJ, Konopka JL, Reiter DM, Abel TW, Stehle T, Dermody TS
(2012) J Virol 86: 13164-73
MeSH Terms: Animals, Base Sequence, Cell Line, Central Nervous System, DNA Primers, Immunohistochemistry, Mammalian orthoreovirus 3, Mice, Mice, Inbred C57BL, N-Acetylneuraminic Acid, Polymerase Chain Reaction, Polysaccharides, Receptors, Virus, Viral Load, Virulence, Virus Replication
Show Abstract · Added December 10, 2013
Mammalian reoviruses display serotype-specific patterns of tropism and disease in the murine central nervous system (CNS) attributable to polymorphisms in viral attachment protein σ1. While all reovirus serotypes use junctional adhesion molecule-A as a cellular receptor, they differ in their utilization of carbohydrate coreceptors. This observation raises the possibility that carbohydrate binding by σ1 influences reovirus pathology in the CNS. In this study, we sought to define the function of carbohydrate binding in reovirus neuropathogenesis. Newborn mice were inoculated intramuscularly with wild-type strain type 3 Dearing (T3D) and T3D-σ1R202W, a point mutant T3D derivative that does not bind sialic acid (SA). Infected mice were monitored for survival, and viral loads at the sites of primary and secondary replication were quantified. Fewer mice inoculated with the wild-type virus survived in comparison to those inoculated with the mutant virus. The wild-type virus also produced higher titers in the spinal cord and brain at late times postinoculation but lower titers in the liver in comparison to those produced by the mutant virus. In addition, the wild-type virus was more virulent and produced higher titers in the brain than the mutant following intracranial inoculation. These animal infectivity studies suggest that T3D-σ1R202W harbors a defect in neural growth. Concordantly, compared with the wild-type virus, the mutant virus displayed a decreased capacity to infect and replicate in primary cultures of cortical neurons, a property dependent on cell surface SA. These results suggest that SA binding enhances the kinetics of reovirus replication in neural tissues and highlight a functional role for sialylated glycans as reovirus coreceptors in the CNS.
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16 MeSH Terms
Serotype-specific differences in inhibition of reovirus infectivity by human-milk glycans are determined by viral attachment protein σ1.
Iskarpatyoti JA, Morse EA, McClung RP, Ikizler M, Wetzel JD, Contractor N, Dermody TS
(2012) Virology 433: 489-97
MeSH Terms: Animals, Capsid Proteins, Cattle, Female, G(M3) Ganglioside, Gangliosides, Genes, Viral, HeLa Cells, Hemagglutination Inhibition Tests, Host-Pathogen Interactions, Humans, L Cells (Cell Line), Mammalian orthoreovirus 3, Mice, Milk, Human, Oligosaccharides, Orthoreovirus, Mammalian, Polysaccharides, Reoviridae Infections, Serotyping, Species Specificity, Virus Attachment
Show Abstract · Added December 10, 2013
Human milk contains many bioactive components, including secretory IgA, oligosaccharides, and milk-associated proteins. We assessed the antiviral effects of several components of milk against mammalian reoviruses. We found that glucocerebroside (GCB) inhibited the infectivity of reovirus strain type 1 Lang (T1L), whereas gangliosides GD3 and GM3 and 3'-sialyllactose (3SL) inhibited the infectivity of reovirus strain type 3 Dearing (T3D). Agglutination of erythrocytes mediated by T1L and T3D was inhibited by GD3, GM3, and bovine lactoferrin. Additionally, α-sialic acid, 3SL, 6'-sialyllactose, sialic acid, human lactoferrin, osteopontin, and α-lactalbumin inhibited hemagglutination mediated by T3D. Using single-gene reassortant viruses, we found that serotype-specific differences segregate with the gene encoding the viral attachment protein. Furthermore, GD3, GM3, and 3SL inhibit T3D infectivity by blocking binding to host cells, whereas GCB inhibits T1L infectivity post-attachment. These results enhance an understanding of reovirus cell attachment and define a mechanism for the antimicrobial activity of human milk.
Copyright © 2012 Elsevier Inc. All rights reserved.
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22 MeSH Terms
Mutational analysis of residues involved in nucleotide and divalent cation stabilization in the rotavirus RNA-dependent RNA polymerase catalytic pocket.
Ogden KM, Ramanathan HN, Patton JT
(2012) Virology 431: 12-20
MeSH Terms: Amino Acid Sequence, Cations, Divalent, Mammalian orthoreovirus 3, Models, Molecular, Molecular Sequence Data, Mutagenesis, Site-Directed, Nucleotides, Protein Conformation, RNA, RNA Replicase, Rotavirus, Sequence Alignment, Viral Core Proteins
Show Abstract · Added April 26, 2017
The rotavirus RNA-dependent RNA polymerase (RdRp), VP1, contains canonical RdRp motifs and a priming loop that is hypothesized to undergo conformational rearrangements during RNA synthesis. In the absence of viral core shell protein VP2, VP1 fails to interact stably with divalent cations or nucleotides and has a retracted priming loop. To identify residues of potential import to nucleotide and divalent cation stabilization, we aligned VP1 of divergent rotaviruses and the structural homolog reovirus λ3. VP1 mutants were engineered and characterized for RNA synthetic capacity in vitro. Conserved aspartic acids in RdRp motifs A and C and arginines in motif F that likely stabilize divalent cations and nucleotides were required for efficient RNA synthesis. Mutation of individual priming loop residues diminished or enhanced RNA synthesis efficiency without obviating the need for VP2, which suggests that this structure serves as a dynamic regulatory element that links RdRp activity to particle assembly.
Published by Elsevier Inc.
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13 MeSH Terms