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Grant Mcfadden - One of the best experts on this subject based on the ideXlab platform.
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rna helicase a dhx9 forms unique cytoplasmic anti viral granules that restrict oncolytic Myxoma Virus replication in human cancer cells
Journal of Virology, 2021Co-Authors: Masmudur M. Rahman, Mário Abrantes, Nissin Moussatche, Ami D Gutierrezjensen, Honor L Glenn, Grant McfaddenAbstract:RNA helicase A/DHX9 is required for diverse RNA-related essential cellular functions and antiviral responses and is hijacked by RNA Viruses to support their replication. Here, we show that during the late replication stage in human cancer cells of Myxoma Virus (MYXV), a member of the double-stranded DNA (dsDNA) poxVirus family that is being developed as an oncolytic Virus, DHX9, forms unique granular cytoplasmic structures, which we named "DHX9 antiviral granules." These DHX9 antiviral granules are not formed if MYXV DNA replication and/or late protein synthesis is blocked. When formed, DHX9 antiviral granules significantly reduced nascent protein synthesis in the MYXV-infected cancer cells. MYXV late gene transcription and translation were also significantly compromised, particularly in nonpermissive or semipermissive human cancer cells where MYXV replication is partly or completely restricted. Directed knockdown of DHX9 significantly enhanced viral late protein synthesis and progeny Virus formation in normally restrictive cancer cells. We further demonstrate that DHX9 is not a component of the canonical cellular stress granules. DHX9 antiviral granules are induced by MYXV, and other poxViruses, in human cells and are associated with other known cellular components of stress granules, dsRNA and Virus encoded dsRNA-binding protein M029, a known interactor with DHX9. Thus, DHX9 antiviral granules function by hijacking poxviral elements needed for the cytoplasmic viral replication factories. These results demonstrate a novel antiviral function for DHX9 that is recruited from the nucleus into the cytoplasm, and this step can be exploited to enhance oncolytic virotherapy against the subset of human cancer cells that normally restrict MYXV. IMPORTANCE The cellular DHX9 has both proviral and antiviral roles against diverse RNA and DNA Viruses. In this article, we demonstrate that DHX9 can form unique antiviral granules in the cytoplasm during Myxoma Virus (MYXV) replication in human cancer cells. These antiviral granules sequester viral proteins and reduce viral late protein synthesis and thus regulate MYXV, and other poxViruses, that replicate in the cytoplasm. In addition, we show that in the absence of DHX9, the formation of DHX9 antiviral granules can be inhibited, which significantly enhanced oncolytic MYXV replication in human cancer cell lines where the Virus is normally restricted. Our results also show that DHX9 antiviral granules are formed after viral infection but not by common nonviral cellular stress inducers. Thus, our study suggests that DHX9 has antiviral activity in human cancer cells, and this pathway can be targeted for enhanced activity of oncolytic poxViruses against even restrictive cancer cells.
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coinfections of novel polyomaVirus anelloViruses and a recombinant strain of Myxoma Virus myxv tol identified in iberian hares
Viruses, 2020Co-Authors: Grant Mcfadden, Simona Kraberger, Arvind Varsani, Christian Gortázar, Ana Aguedapinto, Michael C Lund, Pedro J EstevesAbstract:Viruses are ubiquitous in nature; however, very few have been identified in the Leporid species. In the fall of 2018, an outbreak of Myxomatosis in Iberian hares (Lepus granatensis) was reported in Spain and a novel recombinant Myxoma Virus strain (MYXV-Tol) was identified. To investigate variability within the recombinant region of the MYXV-Tol and identify any potential viral coinfections, samples (ear, eyelid or vaginal) of Iberian hares were collected from Spain and analyzed. The presence of the recombinant region of the MYXV-Tol was confirmed in six out of eleven samples analyzed. Additionally, a polyomaVirus (family Polyomaviridae), representing a putative new species, and anelloViruses (family Anelloviridae) belonging to two putative species were identified, some as coinfection with the recombinant MYXV-Tol. The two polyomaVirus genomes were identified in two hares and share >99% genome-wide identity. Based on the analysis of their large T-antigen, the new polyomaVirus clusters in a distant clade from other mammals sharing <64% amino acid identity. A total of 14 anelloViruses were identified, which share 63-99% genome-wide identity. Overall, our results show a coinfection of different DNA Viruses in the studied samples and raise awareness regarding the extensive unsampled diversity of Viruses in hares.
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oncolytic virotherapy with Myxoma Virus
Journal of Clinical Medicine, 2020Co-Authors: Masmudur M. Rahman, Grant McfaddenAbstract:Oncolytic Viruses are one of the most promising novel therapeutics for malignant cancers. They selectively infect and kill cancer cells while sparing the normal counterparts, expose cancer- specific antigens and activate the host immune system against both viral and tumor determinants. Oncolytic Viruses can be used as monotherapy or combined with existing cancer therapies to become more potent. Among the many types of oncolytic Viruses that have been developed thus far, members of poxViruses are the most promising candidates against diverse cancer types. This review summarizes recent advances that are made with oncolytic Myxoma Virus (MYXV), a member of the LeporipoxVirus genus. Unlike other oncolytic Viruses, MYXV infects only rabbits in nature and causes no harm to humans or any other non-leporid animals. However, MYXV can selectively infect and kill cancer cells originating from human, mouse and other host species. This selective cancer tropism and safety profile have led to the testing of MYXV in various types of preclinical cancer models. The next stage will be successful GMP manufacturing and clinical trials that will bring MYXV from bench to bedside for the treatment of currently intractable malignancies.
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Genetic Characterization of a Recombinant Myxoma Virus in the Iberian Hare (Lepus granatensis).
Viruses, 2019Co-Authors: Ana Águeda-pinto, Ana Lemos De Matos, Grant Mcfadden, María Ángeles Risalde, Mário Abrantes, Simona Kraberger, Arvind Varsani, Christian Gortázar, Pedro José EstevesAbstract:Myxomatosis is a lethal disease in wild European and domestic rabbits (Oryctolagus cuniculus), which is caused by a Myxoma Virus (MYXV) infection—a leporipoxVirus that is found naturally in some Sylvilagus rabbit species in South America and California. The introduction of MYXV into feral European rabbit populations of Australia and Europe, in the early 1950s, demonstrated the best-documented field example of host–Virus coevolution, following a cross-species transmission. Recently, a new cross-species jump of MYXV has been suggested in both Great Britain and Spain, where European brown hares (Lepus europaeus) and Iberian hares (Lepus granatensis) were found dead with lesions consistent with those observed in Myxomatosis. To investigate the possibility of a new cross-species transmission event by MYXV, tissue samples collected from a wild Iberian hare found dead in Spain (Toledo region) were analyzed and deep sequenced. Our results reported a new MYXV isolate (MYXV Toledo) in the tissues of this species. The genome of this new Virus was found to encode three disruptive genes (M009L, M036L, and M152R) and a novel ~2.8 kb recombinant region, which resulted from an insertion of four novel poxviral genes towards the 3’ end of the negative strand of its genome. From the open reading frames inserted into the MYXV Toledo Virus, a new orthologue of a poxVirus host range gene family member was identified, which was related to the MYXV gene M064R. Overall, we confirmed the identity of a new MYXV isolate in Iberian hares, which, we hypothesized, was able to more effectively counteract the host defenses in hares and start an infectious process in this new host.
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Genetic characterization of a recombinant Myxoma Virus leap into the Iberian hare (Lepus granatensis)
bioRxiv, 2019Co-Authors: Ana Águeda-pinto, Ana Lemos De Matos, Grant Mcfadden, María Ángeles Risalde, Mário Abrantes, Simona Kraberger, Arvind Varsani, Christian Gortázar, Pedro José EstevesAbstract:Abstract Myxomatosis is a lethal disease of wild European and domestic rabbits (Oryctolagus cuniculus) caused by a Myxoma Virus (MYXV) infection, a leporipoxVirus that is found naturally in some Sylvilagus rabbit species in South America and California. The introduction of MYXV in the early 1950s into feral European rabbit populations in Australia and Europe demonstrate the best documented field example of host-Virus coevolution following a cross-species transmission. Recently, a new cross-species jump of MYXV has been suggested in both Great Britain and Spain, where European brown hares (Lepus europaeus) and Iberian hares (Lepus granatensis) were found dead with lesions consistent with those observed in Myxomatosis. To investigate the possibility of a new cross-species transmission event by MYXV, tissue samples collected from a wild Iberian hare found dead in Spain (Toledo region) were analyzed and deep sequenced. Our results report a new MYXV strain (MYXV Toledo) in the tissues of this species. The genome of this new strain encodes three disrupted genes (M009L, M036L and M152R) and a novel 2.8 KB recombinant region that resulted from an insertion of four novel poxviral genes towards the 5’ end of its genome. From the open reading frames inserted into the MYXV Toledo strain, a new orthologue of a poxVirus host range gene family member was identified which is related to the MYXV gene M064R. Overall, we confirmed the identity of a new MYXV strain in Iberian hares that we hypothesize was able to more effectively counteract the host defenses in hares and start an infectious process in this new host.
Nicholas Johnson - One of the best experts on this subject based on the ideXlab platform.
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Molecular species identification, host preference and detection of Myxoma Virus in the Anopheles maculipennis complex (Diptera: Culicidae) in southern England, UK
Parasites & Vectors, 2015Co-Authors: Victor A. Brugman, Chris Weland, David G. Westcott, Sean W J Prosser, Luis M. Hernández-triana, Nicholas JohnsonAbstract:Background Determining the host feeding patterns of mosquitoes by identifying the origin of their blood-meals is an important part of understanding the role of vector species in current and future disease transmission cycles. Collecting large numbers of blood-fed mosquitoes from the field is difficult, therefore it is important to maximise the information obtained from each specimen. This study aimed to use mosquito genome sequence to identify the species within Anopheles maculipennis sensu lato ( An. maculipennis s.l.), identify the vertebrate hosts of field-caught blood-fed An. maculipennis s.l. , and to test for the presence of Myxoma Virus ( Poxviridae , genus LeporipoxVirus ) in specimens found to have fed on the European rabbit ( Oryctolagus cuniculus ). Methods Blood-fed An. maculipennis s.l. were collected from resting sites at Elmley Nature Reserve, Kent, between June and September 2013. Hosts that An. maculipennis s.l. had fed on were determined by a PCR-sequencing approach based on the partial amplification of the mitochondrial cytochrome C oxidase subunit I gene. Mosquitoes were then identified to species by sequencing a region of the internal transcribed spacer-2 . DNA extracts from all mosquitoes identified as having fed on rabbits were subsequently screened using PCR for the presence of Myxoma Virus. Results A total of 94 blood-fed Anopheles maculipennis s.l. were collected, of which 43 (46 %) provided positive blood-meal identification results. Thirty-six of these specimens were identified as Anopheles atroparvus , which had fed on rabbit ( n = 33, 92 %) and cattle ( n = 3, 8 %). Seven mosquitoes were identified as Anopheles messeae, which had fed on cattle ( n = 6, 86 %) and dog ( n = 1, 14 %). Of the 33 An. atroparvus that contained rabbit blood, nine (27 %) were positive for Myxoma Virus. Conclusions Results demonstrate that a single DNA extract from a blood-fed mosquito can be successfully used for molecular identification of members of the An. maculipennis complex, blood-meal identification, and for the targeted detection of a Myxoma Virus. This study shows that An. atroparvus has a strong feeding preference for both healthy and Myxoma-infected rabbits, providing evidence that this species may play a significant role in the transmission of Myxomatosis among wild rabbit populations in the United Kingdom (UK).
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Molecular species identification, host preference and detection of Myxoma Virus in the Anopheles maculipennis complex (Diptera: Culicidae) in southern England, UK
Parasites & Vectors, 2015Co-Authors: Victor A. Brugman, Chris Weland, David G. Westcott, Sean W J Prosser, Luis M. Hernández-triana, Nicholas JohnsonAbstract:Determining the host feeding patterns of mosquitoes by identifying the origin of their blood-meals is an important part of understanding the role of vector species in current and future disease transmission cycles. Collecting large numbers of blood-fed mosquitoes from the field is difficult, therefore it is important to maximise the information obtained from each specimen. This study aimed to use mosquito genome sequence to identify the species within Anopheles maculipennis sensu lato (An. maculipennis s.l.), identify the vertebrate hosts of field-caught blood-fed An. maculipennis s.l. , and to test for the presence of Myxoma Virus (Poxviridae, genus LeporipoxVirus) in specimens found to have fed on the European rabbit (Oryctolagus cuniculus). Blood-fed An. maculipennis s.l. were collected from resting sites at Elmley Nature Reserve, Kent, between June and September 2013. Hosts that An. maculipennis s.l. had fed on were determined by a PCR-sequencing approach based on the partial amplification of the mitochondrial cytochrome C oxidase subunit I gene. Mosquitoes were then identified to species by sequencing a region of the internal transcribed spacer-2. DNA extracts from all mosquitoes identified as having fed on rabbits were subsequently screened using PCR for the presence of Myxoma Virus. A total of 94 blood-fed Anopheles maculipennis s.l. were collected, of which 43 (46 %) provided positive blood-meal identification results. Thirty-six of these specimens were identified as Anopheles atroparvus, which had fed on rabbit (n = 33, 92 %) and cattle (n = 3, 8 %). Seven mosquitoes were identified as Anopheles messeae, which had fed on cattle (n = 6, 86 %) and dog (n = 1, 14 %). Of the 33 An. atroparvus that contained rabbit blood, nine (27 %) were positive for Myxoma Virus. Results demonstrate that a single DNA extract from a blood-fed mosquito can be successfully used for molecular identification of members of the An. maculipennis complex, blood-meal identification, and for the targeted detection of a Myxoma Virus. This study shows that An. atroparvus has a strong feeding preference for both healthy and Myxoma-infected rabbits, providing evidence that this species may play a significant role in the transmission of Myxomatosis among wild rabbit populations in the United Kingdom (UK).
Victor A. Brugman - One of the best experts on this subject based on the ideXlab platform.
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Molecular species identification, host preference and detection of Myxoma Virus in the Anopheles maculipennis complex (Diptera: Culicidae) in southern England, UK
Parasites & Vectors, 2015Co-Authors: Victor A. Brugman, Chris Weland, David G. Westcott, Sean W J Prosser, Luis M. Hernández-triana, Nicholas JohnsonAbstract:Background Determining the host feeding patterns of mosquitoes by identifying the origin of their blood-meals is an important part of understanding the role of vector species in current and future disease transmission cycles. Collecting large numbers of blood-fed mosquitoes from the field is difficult, therefore it is important to maximise the information obtained from each specimen. This study aimed to use mosquito genome sequence to identify the species within Anopheles maculipennis sensu lato ( An. maculipennis s.l.), identify the vertebrate hosts of field-caught blood-fed An. maculipennis s.l. , and to test for the presence of Myxoma Virus ( Poxviridae , genus LeporipoxVirus ) in specimens found to have fed on the European rabbit ( Oryctolagus cuniculus ). Methods Blood-fed An. maculipennis s.l. were collected from resting sites at Elmley Nature Reserve, Kent, between June and September 2013. Hosts that An. maculipennis s.l. had fed on were determined by a PCR-sequencing approach based on the partial amplification of the mitochondrial cytochrome C oxidase subunit I gene. Mosquitoes were then identified to species by sequencing a region of the internal transcribed spacer-2 . DNA extracts from all mosquitoes identified as having fed on rabbits were subsequently screened using PCR for the presence of Myxoma Virus. Results A total of 94 blood-fed Anopheles maculipennis s.l. were collected, of which 43 (46 %) provided positive blood-meal identification results. Thirty-six of these specimens were identified as Anopheles atroparvus , which had fed on rabbit ( n = 33, 92 %) and cattle ( n = 3, 8 %). Seven mosquitoes were identified as Anopheles messeae, which had fed on cattle ( n = 6, 86 %) and dog ( n = 1, 14 %). Of the 33 An. atroparvus that contained rabbit blood, nine (27 %) were positive for Myxoma Virus. Conclusions Results demonstrate that a single DNA extract from a blood-fed mosquito can be successfully used for molecular identification of members of the An. maculipennis complex, blood-meal identification, and for the targeted detection of a Myxoma Virus. This study shows that An. atroparvus has a strong feeding preference for both healthy and Myxoma-infected rabbits, providing evidence that this species may play a significant role in the transmission of Myxomatosis among wild rabbit populations in the United Kingdom (UK).
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Molecular species identification, host preference and detection of Myxoma Virus in the Anopheles maculipennis complex (Diptera: Culicidae) in southern England, UK
Parasites & Vectors, 2015Co-Authors: Victor A. Brugman, Chris Weland, David G. Westcott, Sean W J Prosser, Luis M. Hernández-triana, Nicholas JohnsonAbstract:Determining the host feeding patterns of mosquitoes by identifying the origin of their blood-meals is an important part of understanding the role of vector species in current and future disease transmission cycles. Collecting large numbers of blood-fed mosquitoes from the field is difficult, therefore it is important to maximise the information obtained from each specimen. This study aimed to use mosquito genome sequence to identify the species within Anopheles maculipennis sensu lato (An. maculipennis s.l.), identify the vertebrate hosts of field-caught blood-fed An. maculipennis s.l. , and to test for the presence of Myxoma Virus (Poxviridae, genus LeporipoxVirus) in specimens found to have fed on the European rabbit (Oryctolagus cuniculus). Blood-fed An. maculipennis s.l. were collected from resting sites at Elmley Nature Reserve, Kent, between June and September 2013. Hosts that An. maculipennis s.l. had fed on were determined by a PCR-sequencing approach based on the partial amplification of the mitochondrial cytochrome C oxidase subunit I gene. Mosquitoes were then identified to species by sequencing a region of the internal transcribed spacer-2. DNA extracts from all mosquitoes identified as having fed on rabbits were subsequently screened using PCR for the presence of Myxoma Virus. A total of 94 blood-fed Anopheles maculipennis s.l. were collected, of which 43 (46 %) provided positive blood-meal identification results. Thirty-six of these specimens were identified as Anopheles atroparvus, which had fed on rabbit (n = 33, 92 %) and cattle (n = 3, 8 %). Seven mosquitoes were identified as Anopheles messeae, which had fed on cattle (n = 6, 86 %) and dog (n = 1, 14 %). Of the 33 An. atroparvus that contained rabbit blood, nine (27 %) were positive for Myxoma Virus. Results demonstrate that a single DNA extract from a blood-fed mosquito can be successfully used for molecular identification of members of the An. maculipennis complex, blood-meal identification, and for the targeted detection of a Myxoma Virus. This study shows that An. atroparvus has a strong feeding preference for both healthy and Myxoma-infected rabbits, providing evidence that this species may play a significant role in the transmission of Myxomatosis among wild rabbit populations in the United Kingdom (UK).
Colin Macaulay - One of the best experts on this subject based on the ideXlab platform.
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suppression of collagen induced arthritis with a serine proteinase inhibitor serpin derived from Myxoma Virus
Clinical Immunology, 2014Co-Authors: Ernest Brahn, Grant Mcfadden, Alexandra Lucas, Sarah Lee, Colin MacaulayAbstract:Many Viruses encode virulence factors to facilitate their own survival by modulating a host's inflammatory response. One of these factors, secreted from cells infected with Myxoma Virus, is the serine proteinase inhibitor (serpin) Serp-1. Because Serp-1 had demonstrated anti-inflammatory properties in arterial injury models and viral infections, it was cloned and evaluated for therapeutic efficacy in collagen-induced arthritis (CIA). Clinical severity was significantly lower in the Serp-1 protocols (p<0.0001) and blinded radiographs indicated that the Serp-1 group had significantly less erosions than the controls (p<0.01). Delayed-type hypersensitivity was lower in the Serp-1 group but antibody titers to type II collagen were not significantly altered. Recipients had minimal histopathologic synovial changes and did not develop neutralizing antibodies to Serp-1. These results indicate that Serp-1 impedes the pathogenesis of CIA and suggests that the therapeutic potential of serine proteinase inhibitors in inflammatory joint diseases, such as rheumatoid arthritis, should be investigated further.
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suppression of collagen induced arthritis with a serine proteinase inhibitor serpin derived from Myxoma Virus
Clinical Immunology, 2014Co-Authors: Ernest Brahn, Grant Mcfadden, Alexandra Lucas, Sarah Lee, Colin MacaulayAbstract:Abstract Many Viruses encode virulence factors to facilitate their own survival by modulating a host's inflammatory response. One of these factors, secreted from cells infected with Myxoma Virus, is the serine proteinase inhibitor (serpin) Serp-1. Because Serp-1 had demonstrated anti-inflammatory properties in arterial injury models and viral infections, it was cloned and evaluated for therapeutic efficacy in collagen-induced arthritis (CIA). Clinical severity was significantly lower in the Serp-1 protocols (p
Jacqueline Gelfi - One of the best experts on this subject based on the ideXlab platform.
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Early infections by Myxoma Virus of young rabbits (Oryctolagus cuniculus) protected by maternal antibodies activate their immune system and enhance herd immunity in wild populations.
Veterinary Research, 2014Co-Authors: Stéphane Marchandeau, David Fouchet, Dominique Pontier, Jean-sébastien Guitton, Jérôme Letty, Jacky Aubineau, Francis Berger, Yves Léonard, Alain Roobrouck, Jacqueline GelfiAbstract:: The role of maternal antibodies is to protect newborns against acute early infection by pathogens. This can be achieved either by preventing any infection or by allowing attenuated infections associated with activation of the immune system, the two strategies being based on different cost/benefit ratios. We carried out an epidemiological survey of Myxomatosis, which is a highly lethal infectious disease, in two distant wild populations of rabbits to describe the epidemiological pattern of the disease. Detection of specific IgM and IgG enabled us to describe the pattern of immunity. We show that maternal immunity attenuates early infection of juveniles and enables activation of their immune system. This mechanism associated with steady circulation of the Myxoma Virus in both populations, which induces frequent reinfections of immune rabbits, leads to the maintenance of high immunity levels within populations. Thus, Myxomatosis has a low impact, with most infections being asymptomatic. This work shows that infection of young rabbits protected by maternal antibodies induces attenuated disease and activates their immune system. This may play a major role in reducing the impact of a highly lethal disease when ecological conditions enable permanent circulation of the pathogen.
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MNF, an ankyrin repeat protein of Myxoma Virus, is part of a native cellular SCF complex during viral infection
Virology Journal, 2010Co-Authors: Sophie Blanié, Stephane Bertagnoli, Jacqueline Gelfi, Christelle Camus-bouclainvilleAbstract:Myxoma Virus (MYXV), a member of the Poxviridae family, is the agent responsible for Myxomatosis, a fatal disease in the European rabbit (Oryctolagus cuniculus). Like all poxViruses, MYXV is known for encoding multiple proteins that regulate cellular signaling pathways. Among them, four proteins share the same ANK/PRANC structure: M148R, M149R, MNF (Myxoma Nuclear factor) and M-T5, all of them described as virulence factors. This family of poxVirus proteins, recently identified, has drawn considerable attention for its potential role in modulating the host ubiquitin-proteasome system during viral infection. To date, many members of this novel protein family have been shown to interact with SCF components, in vitro. Here, we focus on MNF gene, which has been shown to express a nuclear protein presenting nine ANK repeats, one of which has been identified as a nuclear localization signal. In transfection, MNF has been shown to colocalise with the transcription factor NF-κB in the nucleus of TNFα-stimulated cells. Functionally, MNF is a critical virulence factor since its deletion generates an almost apathogenic Virus. In this study, to pursue the investigation of proteins interacting with MNF and of its mechanism of action, we engineered a recombinant MYXV expressing a GFP-linked MNF under the control of MNF native promoter. Infection of rabbits with MYXV-GFPMNF recombinant Virus provided the evidence that the GFP fusion does not disturb the main function of MNF. Hence, cells were infected with MYXV-GFPMNF and immunoprecipitation of the GFPMNF fusion protein was performed to identify MNF's partners. For the first time, endogenous components of SCF (Cullin-1 and Skp1) were co-precipitated with an ANK Myxoma Virus protein, expressed in an infectious context, and without over-expression of any protein.
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Myxoma Virus leukemia associated protein is responsible for major histocompatibility complex class i and fas cd95 down regulation and defines scrapins a new group of surface cellular receptor abductor proteins
Journal of Virology, 2002Co-Authors: Jeanluc Guerin, Stephane Bertagnoli, Jacqueline Gelfi, Severine Boullier, Maxence Delverdier, Frederiqueanne Bellanger, Ingo Drexler, Gerd Sutter, Frederique MessudpetitAbstract:Down-modulation of major histocompatibility class I (MHC-I) molecules is a viral strategy for survival in the host. Myxoma Virus, a member of the Poxviridae family responsible for rabbit Myxomatosis, can down-modulate the expression of MHC-I molecules, but the viral factor(s) has not been described. We cloned and characterized a gene coding for an endoplasmic reticulum (ER)-resident protein containing an atypical zinc finger and two transmembrane domains, which we called Myxoma Virus leukemia-associated protein (MV-LAP). MV-LAP down-regulated surface MHC-I and Fas-CD95 molecules upon transfection; the mechanism probably involves an exacerbation of endocytosis and was lost when the ER retention signal was removed. In addition, the lytic activity of MHC-I-restricted antigen-specific cytolytic T lymphocytes (CTL) against Myxoma Virus-infected antigen-presenting target cells was significantly reduced, revealing a strong correlation between MHC-I down-regulation by MV-LAP and CTL killing in vitro. In vivo experiments with a knockout Virus showed that MV-LAP is a virulence factor, potentially involved in the immunosuppression characteristic of Myxomatosis. Data bank analysis revealed that MV-LAP has homologs in herpesViruses and other poxViruses. We propose the name “scrapins” to define a new group of ER-resident surface cellular receptor abductor proteins. The down-regulation of cell surface molecules by scrapins probably helps protect infected cells during viral infections.
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protection against Myxomatosis and rabbit viral hemorrhagic disease with recombinant Myxoma Viruses expressing rabbit hemorrhagic disease Virus capsid protein
Journal of Virology, 1996Co-Authors: Stephane Bertagnoli, S. Laurent, Jean-françois Vautherot, Denis Rasschaert, Jacqueline Gelfi, Le G Gall, E Boilletot, F Petit, Corine Boucrautbaralon, Alain MilonAbstract:Two Myxoma Virus-rabbit hemorrhagic disease Virus (RHDV) recombinant Viruses were constructed with the SG33 strain of Myxoma Virus to protect rabbits against Myxomatosis and rabbit viral hemorrhagic disease. These recombinant Viruses expressed the RHDV capsid protein (VP60). The recombinant protein, which is 60 kDa in size, was antigenic, as revealed by its reaction in immunoprecipitation with antibodies raised against RHDV. Both recombinant Viruses induced high levels of RHDV- and Myxoma Virus-specific antibodies in rabbits after immunization. Inoculations by the intradermal route protected animals against virulent RHDV and Myxoma Virus challenges.
