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Rotavirus and reovirus interaction with mouse peritoneal resident phagocytic cells

Guimarães,M.A.A.M.; Nozawa,C.M.; Guimarães,A.C.C.; Ramos,S.
Fonte: Associação Brasileira de Divulgação Científica Publicador: Associação Brasileira de Divulgação Científica
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/10/1997 Português
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Rotaviruses and reoviruses are involved in human and animal diseases. It is known that both viruses penetrate the gastrointestinal tract but their interaction with phagocytic cells is unknown. To study this interaction, peritoneal resident phagocytic cells were used and rotavirus and reovirus replication in peritoneal phagocytic cells was observed. However, rotavirus replication in these cells led to the production of defective particles since MA-104 cells inoculated with rotavirus phagocytic cell lysate did not show any evidence of virus replication. On the basis of these results, we suggest that, although reovirus dissemination may be helped by these phagocytic cells, these cells may control rotavirus infection and probably contribute to the prevention of its dissemination.

Reovirus-Induced Apoptosis Requires Activation of Transcription Factor NF-κB

Connolly, Jodi L.; Rodgers, Steven E.; Clarke, Penny; Ballard, Dean W.; Kerr, Lawrence D.; Tyler, Kenneth L.; Dermody, Terence S.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /04/2000 Português
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Reovirus infection induces apoptosis in cultured cells and in vivo. To identify host cell factors that mediate this response, we investigated whether reovirus infection alters the activation state of the transcription factor nuclear factor kappa B (NF-κB). As determined in electrophoretic mobility shift assays, reovirus infection of HeLa cells leads to nuclear translocation of NF-κB complexes containing Rel family members p50 and p65. Reovirus-induced activation of NF-κB DNA-binding activity correlated with the onset of NF-κB-directed transcription in reporter gene assays. Three independent lines of evidence indicate that this functional form of NF-κB is required for reovirus-induced apoptosis. First, treatment of reovirus-infected HeLa cells with a proteasome inhibitor prevents NF-κB activation following infection and substantially diminishes reovirus-induced apoptosis. Second, transient expression of a dominant-negative form of IκB that constitutively represses NF-κB activation significantly reduces levels of apoptosis triggered by reovirus infection. Third, mutant cell lines deficient for either the p50 or p65 subunits of NF-κB are resistant to reovirus-induced apoptosis compared with cells expressing an intact NF-κB signaling pathway. These findings indicate that NF-κB plays a significant role in the mechanism by which reovirus induces apoptosis in susceptible host cells.

Virion Disassembly Is Required for Apoptosis Induced by Reovirus

Connolly, Jodi L.; Dermody, Terence S.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /02/2002 Português
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Reovirus infection leads to apoptosis in cultured cells and in vivo. Binding of viral attachment protein ς1 to both sialic acid and junction adhesion molecule is required for induction of apoptosis. However, it is not known whether viral engagement of receptors is sufficient to elicit this cellular response. To determine whether steps in reovirus replication subsequent to viral attachment are required for reovirus-induced apoptosis, we used inhibitors of viral disassembly and RNA synthesis, viral disassembly intermediates, temperature-sensitive (ts) reovirus mutants, and reovirus particles deficient in genomic double-stranded RNA (dsRNA). We found that reovirus-induced apoptosis is abolished in the presence of the viral disassembly inhibitors ammonium chloride and E64. Infectious subvirion particles (ISVPs), which are intermediates in reovirus disassembly that can be generated in vitro by protease treatment, are capable of inducing apoptosis in the presence or absence of these inhibitors. Treatment of cells with the viral RNA synthesis inhibitor ribavirin does not diminish the capacity of reovirus to induce apoptosis, and reovirus ts mutants arrested at defined steps in viral replication produce apoptosis with efficiency similar to that of wild-type virus. Furthermore...

Circulating immunoglobulin G can play a critical role in clearance of intestinal reovirus infection.

Barkon, M L; Haller, B L; Virgin, H W
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /02/1996 Português
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Reoviruses are encapsidated double-stranded RNA viruses that cause systemic disease in mice after peroral (p.o.) inoculation and primary replication in the intestine. In this study, we define components of the immune system involved in the clearing of reovirus from the proximal small intestine. The intestines of immunocompetent adult CB17, 129, and C57BL/6 mice were cleared of reovirus serotype 3 clone 9 (T3C9) within 7 days of p.o. inoculation. Antigen-specific lymphocytes were important for the clearance of intestinal infection, since severe combined immunodeficient (SCID) mice failed to clear T3C9 infection. To define specific immune components required for intestinal clearance, reovirus infection of mice with null mutations in the immunoglobulin M (IgM) transmembrane exon (MuMT; B cell and antibody deficient) or beta 2 microglobulin gene (beta 2-/-; CD8 deficient) was evaluated. beta 2-/- mice cleared reovirus infection with normal kinetics, while MuMT mice showed delayed clearance of T3C9 7 to 11 days after p.o. inoculation. Adoptive transfer of splenic lymphocytes from reovirus-immune CB17 mice inhibited growth of T3C9 in CB17 SCID mouse intestine 11 days after p.o. inoculation. The efficiency of viral clearance by adoptively transferred cells was significantly diminished by depletion of B cells prior to adoptive transfer. Results in SCID and MuMT mice demonstrate an important role for B cells or IgG in clearance of reovirus from the intestines. Polyclonal reovirus-immune rabbit serum...

Reovirus serotypes 1 and 3 differ in their in vitro association with microtubules.

Babiss, L E; Luftig, R B; Weatherbee, J A; Weihing, R R; Ray, U R; Fields, B N
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /06/1979 Português
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Utilizing negative-stain electron microscopy in which similar concentrations of reovirus types 1 and 3 are incubated with a carbon support film containing chick brain, rabbit brain, or HeLa cell microtubules, 81% of the type 1 and 56% of type 3 exhibited an association with the apparent "edge" of the microtubule. This implies that there is a high level of specific affinity for type 1 but not for type 3 to microtubules, since it has previously been determined that only 50% of randomly associated particles would be associated with the edge. The high edge binding of reovirus type 1 is virtually independent of the origin of microtubule, or of whether microtubules or virus has been initially adhered to the support film. On the other hand, reovirus type 1-specific antiserum reduced the edge binding or reovirus type 1 to 45%, whereas type 3 specific antiserum caused no less (within the variability of the assay) of the edge binding of reovirus type 1 to microtubules (76% edge bound). High edge binding of reovirus type 1 to microtubules is correlated with the presence of type 1 or sigma 1 polypeptide. This minor outer capsid polypeptide is encoded in the S1 double-stranded RNA segment and is the viral hemagglutinin and neutralization antigen. Recombinant reovirus clones containing the S1 double-stranded RNA segment of type 1 (80 and 802) show about 85% edge binding...

Involvement of the Interferon-Regulated Antiviral Proteins PKR and RNase L in Reovirus-Induced Shutoff of Cellular Translation

Smith, Jennifer A.; Schmechel, Stephen C.; Williams, Bryan R. G.; Silverman, Robert H.; Schiff, Leslie A.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /02/2005 Português
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Cellular translation is inhibited following infection with most strains of reovirus, but the mechanisms responsible for this phenomenon remain to be elucidated. The extent of host shutoff varies in a strain-dependent manner; infection with the majority of strains leads to strong host shutoff, while infection with strain Dearing results in minimal inhibition of cellular translation. A genetic study with reassortant viruses and subsequent biochemical analyses led to the hypothesis that the interferon-induced, double-stranded RNA-activated protein kinase, PKR, is responsible for reovirus-induced host shutoff. To directly determine whether PKR is responsible for reovirus-induced host shutoff, we used a panel of reovirus strains and mouse embryo fibroblasts derived from knockout mice. This approach revealed that PKR contributes to but is not wholly responsible for reovirus-induced host shutoff. Studies with cells lacking RNase L, the endoribonuclease component of the interferon-regulated 2′,5′-oligoadenylate synthetase-RNase L system, demonstrated that RNase L also down-regulates cellular protein synthesis in reovirus-infected cells. In many viral systems, PKR and RNase L have well-characterized antiviral functions. An analysis of reovirus replication in cells lacking these molecules indicated that...

Organ-specific roles for transcription factor NF-κB in reovirus-induced apoptosis and disease

O’Donnell, Sean M.; Hansberger, Mark W.; Connolly, Jodi L.; Chappell, James D.; Watson, Melissa J.; Pierce, Janene M.; Wetzel, J. Denise; Han, Wei; Barton, Erik S.; Forrest, J. Craig; Valyi-Nagy, Tibor; Yull, Fiona E.; Blackwell, Timothy S.; Rottman, Je
Fonte: American Society for Clinical Investigation Publicador: American Society for Clinical Investigation
Tipo: Artigo de Revista Científica
Português
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Reovirus induces apoptosis in cultured cells and in vivo. In cell culture models, apoptosis is contingent upon a mechanism involving reovirus-induced activation of transcription factor NF-κB complexes containing p50 and p65/RelA subunits. To explore the in vivo role of NF-κB in this process, we tested the capacity of reovirus to induce apoptosis in mice lacking a functional nfkb1/p50 gene. The genetic defect had no apparent effect on reovirus replication in the intestine or dissemination to secondary sites of infection. In comparison to what was observed in wild-type controls, apoptosis was significantly diminished in the CNS of p50-null mice following reovirus infection. In sharp contrast, the loss of p50 was associated with massive reovirus-induced apoptosis and uncontrolled reovirus replication in the heart. Levels of IFN-β mRNA were markedly increased in the hearts of wild-type animals but not p50-null animals infected with reovirus. Treatment of p50-null mice with IFN-β substantially diminished reovirus replication and apoptosis, which suggests that IFN-β induction by NF-κB protects against reovirus-induced myocarditis. These findings reveal an organ-specific role for NF-κB in the regulation of reovirus-induced apoptosis...

β1 Integrin Mediates Internalization of Mammalian Reovirus

Maginnis, Melissa S.; Forrest, J. Craig; Kopecky-Bromberg, Sarah A.; Dickeson, S. Kent; Santoro, Samuel A.; Zutter, Mary M.; Nemerow, Glen R.; Bergelson, Jeffrey M.; Dermody, Terence S.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /03/2006 Português
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Reovirus infection is initiated by interactions between the attachment protein σ1 and cell surface carbohydrate and junctional adhesion molecule A (JAM-A). Expression of a JAM-A mutant lacking a cytoplasmic tail in nonpermissive cells conferred full susceptibility to reovirus infection, suggesting that cell surface molecules other than JAM-A mediate viral internalization following attachment. The presence of integrin-binding sequences in reovirus outer capsid protein λ2, which serves as the structural base for σ1, suggests that integrins mediate reovirus endocytosis. A β1 integrin-specific antibody, but not antibodies specific for other integrin subunits, inhibited reovirus infection of HeLa cells. Expression of a β1 integrin cDNA, along with a cDNA encoding JAM-A, in nonpermissive chicken embryo fibroblasts conferred susceptibility to reovirus infection. Infectivity of reovirus was significantly reduced in β1-deficient mouse embryonic stem cells in comparison to isogenic cells expressing β1. However, reovirus bound equivalently to cells that differed in levels of β1 expression, suggesting that β1 integrins are involved in a postattachment entry step. Concordantly, uptake of reovirus virions into β1-deficient cells was substantially diminished in comparison to viral uptake into β1-expressing cells. These data provide evidence that β1 integrin facilitates reovirus internalization and suggest that viral entry occurs by interactions of reovirus virions with independent attachment and entry receptors on the cell surface.

Activation of p53 by Chemotherapeutic Agents Enhances Reovirus Oncolysis

Pan, Da; Marcato, Paola; Ahn, Dae-Gyun; Gujar, Shashi; Pan, Lu-Zhe; Shmulevitz, Maya; Lee, Patrick W. K.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 16/01/2013 Português
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Mammalian reovirus is a benign virus that possesses the natural ability to preferentially infect and kill cancer cells (reovirus oncolysis). Reovirus exploits aberrant Ras signalling in many human cancers to promote its own replication and spread. In vitro and in vivo studies using reovirus either singly or in combination with anti-cancer drugs have shown very encouraging results. Presently, a number of reovirus combination therapies are undergoing clinical trials for a variety of cancers. Previously we showed that accumulation of the tumor suppressor protein p53 by Nutlin-3a (a specific p53 stabilizer) enhanced reovirus-induced apoptosis, and resulted in significantly higher levels of reovirus dissemination. In this study, we examined the role of p53 in combination therapies involving reovirus and chemotherapeutic drugs. We showed that sub-lethal concentrations of traditional chemotherapy drugs actinomycin D or etoposide, but not doxorubicin, enhanced reovirus-induced apoptosis in a p53-dependent manner. Furthermore, NF-κB activation and expression of p53-target genes (p21 and bax) were important for the p53-dependent enhancement of cell death. Our results show that p53 status affects the efficacy of combination therapy involving reovirus. Choosing the right combination partner for reovirus and a low dosage of the drug may help to both enhance reovirus-induced cancer elimination and reduce drug toxicity.

Oncolytic Reovirus in Canine Mast Cell Tumor

Hwang, Chung Chew; Umeki, Saori; Kubo, Masahito; Hayashi, Toshiharu; Shimoda, Hiroshi; Mochizuki, Masami; Maeda, Ken; Baba, Kenji; Hiraoka, Hiroko; Coffey, Matt; Okuda, Masaru; Mizuno, Takuya
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 20/09/2013 Português
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The usage of reovirus has reached phase II and III clinical trials in human cancers. However, this is the first study to report the oncolytic effects of reovirus in veterinary oncology, focusing on canine mast cell tumor (MCT), the most common cutaneous tumor in dogs. As human and canine cancers share many similarities, we hypothesized that the oncolytic effects of reovirus can be exploited in canine cancers. The objective of this study was to determine the oncolytic effects of reovirus in canine MCT in vitro, in vivo and ex vivo. We demonstrated that MCT cell lines were highly susceptible to reovirus as indicated by marked cell death, high production of progeny virus and virus replication. Reovirus induced apoptosis in the canine MCT cell lines with no correlation to their Ras activation status. In vivo studies were conducted using unilateral and bilateral subcutaneous MCT xenograft models with a single intratumoral reovirus treatment and apparent reduction of tumor mass was exhibited. Furthermore, cell death was induced by reovirus in primary canine MCT samples in vitro. However, canine and murine bone marrow-derived mast cells (BMCMC) were also susceptible to reovirus. The combination of these results supports the potential value of reovirus as a therapy in canine MCT but warrants further investigation on the determinants of reovirus susceptibility.

Activated Ras Signaling Pathways and Reovirus Oncolysis: An Update on the Mechanism of Preferential Reovirus Replication in Cancer Cells

Gong, Jun; Mita, Monica M.
Fonte: Frontiers Media S.A. Publicador: Frontiers Media S.A.
Tipo: Artigo de Revista Científica
Publicado em 26/06/2014 Português
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The development of wild-type, unmodified Type 3 Dearing strain reovirus as an anticancer agent has currently expanded to 32 clinical trials (both completed and ongoing) involving reovirus in the treatment of cancer. It has been more than 30 years since the potential of reovirus as an anticancer agent was first identified in studies that demonstrated the preferential replication of reovirus in transformed cell lines but not in normal cells. Later investigations have revealed the involvement of activated Ras signaling pathways (both upstream and downstream) and key steps of the reovirus infectious cycle in promoting preferential replication in cancer cells with reovirus-induced cancer cell death occurring through necrotic, apoptotic, and autophagic pathways. There is increasing evidence that reovirus-induced antitumor immunity involving both innate and adaptive responses also contributes to therapeutic efficacy though this discussion is beyond the scope of this article. Here, we review our current understanding of the mechanism of oncolysis contributing to the broad anticancer activity of reovirus. Further understanding of reovirus oncolysis is critical in enhancing the clinical development and efficacy of reovirus.

Proteolytic Disassembly of Viral Outer Capsid Proteins Is Crucial for Reovirus-Mediated Type-I Interferon Induction in Both Reovirus-Susceptible and Reovirus-Refractory Tumor Cells

Katayama, Yuki; Terasawa, Yuichi; Tachibana, Masashi; Mizuguchi, Hiroyuki; Sakurai, Fuminori
Fonte: Hindawi Publishing Corporation Publicador: Hindawi Publishing Corporation
Tipo: Artigo de Revista Científica
Português
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Oncolytic reovirus induces innate immune responses, which contribute to the antitumor activity of reovirus, following in vivo application. Reovirus-induced innate immune responses have been relatively well characterized in immune cells and mouse embryonic fibroblasts cells; however, the mechanisms and profiles of reovirus-induced innate immune responses in human tumor cells have not been well understood. In particular, differences in reovirus-induced innate immune responses between reovirus-susceptible and reovirus-refractory tumor cells remain unknown, although the intracellular trafficking of reovirus differs between these tumor cells. In this study, we examined reovirus-induced upregulation of interferon- (IFN-) β and of the proapoptotic gene, Noxa, in reovirus-susceptible and -refractory tumor cells. IFN-β and Noxa were significantly induced by reovirus via the IFN-β promoter stimulator-1 (IPS-1) signaling in both types of tumor cells. Inhibition of cathepsins B and L, which are important for disassembly of reovirus outer capsid proteins and escape into cytoplasm, largely suppressed reovirus-induced upregulation of IFN-β and Noxa expression in not only reovirus-susceptible but also reovirus-refractory tumor cells. These results indicated that in both reovirus-susceptible and reovirus-refractory tumor cells...

Dendritic cells and T cells deliver oncolytic reovirus for tumour killing despite pre-existing anti-viral immunity

Ilett, EJ; Prestwich, RJ; Kottke, T; Errington, F; Thompson, JM; Harrington, KJ; Pandha, HS; Coffey, M; Selby, PJ; Vile, RG; Melcher, AA
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
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Reovirus is a naturally occurring oncolytic virus currently in early clinical trials. However, the rapid induction of neutralizing antibodies represents a major obstacle to successful systemic delivery. This study addresses, for the first time, the ability of cellular carriers in the form of T cells and dendritic cells (DC) to protect reovirus from systemic neutralization. In addition, the ability of these cellular carriers to manipulate the subsequent balance of anti-viral versus anti-tumour immune response is explored. Reovirus, either neat or loaded onto DC or T cells, was delivered intravenously into reovirus-naive or reovirus-immune C57Bl/6 mice bearing lymph node B16tk melanoma metastases. Three and 10 days after treatment, reovirus delivery, carrier cell trafficking, metastatic clearance and priming of anti-tumour/anti-viral immunity were assessed. In naive mice, reovirus delivered either neat or through cell carriage was detectable in the tumour-draining lymph nodes 3 days after treatment, though complete clearance of metastases was only obtained when the virus was delivered on T cells or mature DC (mDC); neat reovirus or loaded immature DC (iDC) gave only partial early tumour clearance. Furthermore, only T cells carrying reovirus generated anti-tumour immune responses and long-term tumour clearance; reovirus-loaded DC...

Structural and functional studies of the reovirus attachment protein sigma1 and its interaction with the receptor JAM-A; Strukturelle und funktionelle Studien am Zelladsorptionsprotein sigma1 des Reovirus und seiner Interaktion mit dem Rezeptor JAM-A

Kirchner, Eva
Fonte: Universidade de Tubinga Publicador: Universidade de Tubinga
Tipo: Dissertação
Português
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The attachment of viruses to host cells and subsequent viral entry are key steps in viral infection. Receptor recognition also serves an essential function in target cell selection. Mammalian orthoreoviruses (reoviruses) are highly tractable experimental models for studies of virus-receptor interactions and viral pathogenesis. Furthermore, they show promise as vectors for oncolytics and vaccines. Similarly to many other viruses, reoviruses use cell-surface carbohydrates and a cell adhesion molecule as receptors. How the usage of multiple receptors contributes to viral attachment is still unclear, and general rules for receptor recognition at an atomic level have not yet been established. In this thesis, structural properties and receptor binding mechanisms of the reovirus attachment protein sigma1 were analyzed. sigma1 contains an unusal trimerization motif, the aspartic acid cluster, at its trimer interface. A sigma1 protein, in which one of the aspartic acids of the cluster was mutated to asparagine (D345N), was analyzed regarding binding to the reovirus receptor JAM-A, and its crystal structure was solved to high resolution. The analysis of the D345N mutant provides information about the protonation state of the aspartic acids and the forces holding the sigma1 trimer together. Moreover...

Étude de la protéine sigma 1 de réovirus par génétique inverse.

Brochu-Lafontaine, Virginie
Fonte: Université de Montréal Publicador: Université de Montréal
Tipo: Thèse ou Mémoire numérique / Electronic Thesis or Dissertation
Português
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Réovirus, connu sous le nom REOLYSIN®, est présentement à l'étude à titre d'agent oncolytique. Or, la spécificité du virus pour les cellules cancéreuses pourrait être optimisée par une modification au niveau de la protéine d'attachement σ1. La présente étude vise à démontrer qu'une telle amélioration est possible par l'utilisation de la méthode nouvellement décrite de génétique inverse. Par cette technique, il est possible d'ajouter un polypeptide d'une longueur de quarante acides aminés à l'extrémité C-terminale de σ1. Il est aussi possible d'engendrer des virus mutés en leur site d'activité mucinolytique. Les virus nouvellement créés démontrent une efficacité de réplication diminuée, mais demeurent infectieux. Contrairement aux méthodes traditionnellement utilisées avec réovirus, la méthode de génétique inverse permet de conserver les mutations engendrées, par substitution ou addition, au cours des cycles de réplication. Une telle étude démontre qu'il serait possible de modifier le tropisme de réovirus.; Reovirus, also known under the tradename REOLYSIN®, is currently under clinical trial as an oncolytic agent. The specificity of the virus for transformed (cancerous) cells could be improved by modifications of the σ1 attachment protein. This study presents two ways to achieve this improvement by using a newly developed method of reverse genetics for double-stranded RNA viruses. As a proof of concept...

Estudos com reovirus isolado de galinha-d’angola (Numida meleagridis); Studies with reovirus isolated from guinea fowls (Numida meleagridis)

Ito, Nair Massako Ratayama; Jerez, José Antonio; Miyaji, Claudio Issamu; Capellaro, Clotilde Eugênea Margarida Peduti Dal Molin; Catroxo, Márcia Helena Braga
Fonte: Universidade de São Paulo. Faculdade de Medicina Veterinária e Zootecnia Publicador: Universidade de São Paulo. Faculdade de Medicina Veterinária e Zootecnia
Tipo: info:eu-repo/semantics/article; info:eu-repo/semantics/publishedVersion; ; ; ; ; ; Formato: application/pdf
Publicado em 01/01/1996 Português
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Este trabalho descreve algumas propriedades de um reovírus que foi isolado de pâncreas e intestino de galinhasd’angolaque padeciam de uma enterite transmissível. Coronavírus foi isolado do rim das mesmas aves. O reovírusde galinhas-d’angola é patogênico para embriões de galinha-d’angola, de pata e de galinha mas não reproduziu osachados de campo, quando inoculado em angolinhas, e nem foi patogênico para pintos e patinhos inoculados experimentalmente.; This paper describes some properties of a reovirus isolated from the pancreas and intestines of guinea fowls suffering from a transmissible enteritis. Coronavirus was also recovered from kidneys of the same birds. The guinea fowl reovirus is pathogenic for guinea fowl, duck and chicken embryos, but it does not reproduce by itself the field findings when inoculated in day-old guinea poults, nor was it found to be pathogenic for chicks and ducklings on experimental infection..

Transient high level mammalian reovirus replication in a bat epithelial cell line occurs without cytopathic effect

Sandekian, Véronique; Lim, Debbie; Prud'homme, Patrick; Lemay, Guy
Fonte: Elsevier Publicador: Elsevier
Tipo: Artigo de Revista Científica
Português
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Mammalian reoviruses exhibit a large host range and infected cells are generally killed; however, most studies examined only a few cell types and host species, and are probably not representative of all possible interactions between virus and host cell. Many questions thus remain concerning the nature of cellular factors that affect viral replication and cell death. In the present work, it was observed that replication of the classical mammalian reovirus serotype 3 Dearing in a bat epithelial cell line, Tb1.Lu, does not result in cell lysis and is rapidly reduced to very low levels. Prior uncoating of virions by chymotrypsin treatment, to generate infectious subviral particles, increased the initial level of infection but without any significant effect on further viral replication or cell survival. Infected cells remain resistant to virus reinfection and secrete an antiviral factor, most likely interferon, that is protective against the unrelated encephalomyocarditis virus. Although, the transformed status of a cell is believed to promote reovirus replication and viral “oncolysis”, resistant Tb1.Lu cells exhibit a classical phenotype of transformed cells by forming colonies in semisolid soft agar medium. Further transduction of Tb.Lu cells with a constitutively-active Ras oncogene does not seem cell growth or reovirus effect on these cells. Infected Tb1.Lu cells can produce low-level of infectious virus for a long time without any apparent effect...

La génétique inverse dans l'étude des réovirus: Progrès, obstacles et développements futurs

Lemay, Guy
Fonte: John Libbey Eurotext Publicador: John Libbey Eurotext
Tipo: Artigo de Revista Científica
Português
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En génétique dite « classique », l’examen d’un phénotype conduit à l’étude des gènes impliqués dans son obtention. La génétique inverse est une méthode expérimentale très puissante dans laquelle, au contraire, le matériel génétique est modifié et utilisé pour reconstruire un organisme complet, afin de déterminer le résultat de ces modifications. Cette approche est spécialement bien adaptée à l'étude des virus, compte tenu de la relative simplicité et de la petite taille de leurs génomes; l’obstacle principal demeure de récupérer des virus infectieux à partir de génomes viraux clonés. Au cours des années, cet exploit a été accompli pour des représentants de presque toutes les familles de virus de mammifères. Jusqu’à récemment, les Reoviridae, virus à génome d'ARN bicaténaire segmenté, faisaient toutefois exception. Dans cette revue, les progrès réalisés vers la mise au point de la génétique inverse pour l'étude du réovirus seront discutés. La génétique inverse pourrait avoir un impact majeur dans l'optimisation de nouvelles souches de réovirus pour leur utilisation en thérapie comme agents oncolytiques et pour le développement de vaccins dans le cas des rotavirus et des orbivirus. Les travaux actuels font toutefois ressortir les limites de l'approche...

Amino acid substitutions in σ1 and μ1 outer capsid proteins are selected during mammalian reovirus adaptation to Vero cells

Jabre, Roland; Sandekian, Véronique; Lemay, Guy
Fonte: Elsevier Publicador: Elsevier
Tipo: Artigo de Revista Científica
Português
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Establishment of viral persistence in cell culture has previously led to the selection of mammalian reovirus mutants, although very few of those have been characterized in details. In the present study, reovirus was adapted to Vero cells that, in contrast to classically-used L929 cells, are inefficient in supporting the early steps of reovirus uncoating and are also unable to produce interferon as an antiviral response once infection occurs. The Vero cell-adapted reovirus exhibits amino acids substitutions in both the σ1 and μ1 proteins. This contrasts with uncoating mutants from persistently-infected L929 cells, and various other cell types, that generally harbor amino acids substitutions in the σ3 outer capsid protein. The Vero cell-adapted virus remained sensitive to an inhibitor of lysosomal proteases; furthermore, in the absence of selective pressure for its maintenance, t he virus has partially lost its ability to resist interferon. The positions of the amino acids substitutions on the known protein structures suggest an effect on binding of the viral σ1 protein to the cell surface and on μ1 disassembly from the outer capsid.; L'établissement de la persistance virale en culture cellulaire a précédemment mené à la sélection de mutants de réovirus...

Further characterization and determination of the single amino acid change in the tsI138 reovirus thermosensitive mutant

Lemay, Guy; Bisaillon, Martin
Fonte: NRC Research Press Publicador: NRC Research Press
Tipo: Artigo de Revista Científica
Português
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Many temperature-sensitive mutants have been isolated in early studies of mammalian reovirus. However, the bio- logical properties and nature of the genetic alterations remain incompletely explored for most of these mutants. The mutation harbored by the tsI138 mutant was already assigned to the L3 gene encoding the l1 protein. In the present study, this mu- tant was further studied as a possible tool to establish the role of the putative l1 enzymatic activities in viral multiplication. It was observed that synthesis of viral proteins is only marginally reduced, while it was difficult to recover viral particles at the nonpermissive temperature. A single nucleotide substitution resulting in an amino acid change was found; the position of this amino acid is consistent with a probable defect in assembly of the inner capsid at the nonpermissive temperature.; Plusieurs mutants thermosensibles ont été rapidement isolés dès le début de l’étude du réovirus de mammifères. Cependant, les propriétés biologiques et la nature des changements génétiques demeurent peu connues pour la plupart de ces mutants. La mutation au sein du mutant tsI138 a déjà été localisée comme étant présente sur le gène L3 codant pour la protéine l1. Dans la présente étude...