Publications by authors named "Damien Vitour"

52 Publications

Exploration of binary protein-protein interactions between tick-borne flaviviruses and Ixodes ricinus.

Parasit Vectors 2021 Mar 6;14(1):144. Epub 2021 Mar 6.

UMR 1161 Virologie Laboratoire de Santé Animale, ANSES, INRAE, Ecole Nationale Vétérinaire d'Alfort, Paris-Est Sup, Maisons-Alfort, France.

Background: Louping ill virus (LIV) and tick-borne encephalitis virus (TBEV) are tick-borne flaviviruses that are both transmitted by the major European tick, Ixodes ricinus. Despite the importance of I. ricinus as an arthropod vector, its capacity to acquire and subsequently transmit viruses, known as vector competence, is poorly understood. At the molecular scale, vector competence is governed in part by binary interactions established between viral and cellular proteins within infected tick cells.

Methods: To investigate virus-vector protein-protein interactions (PPIs), the entire set of open reading frames for LIV and TBEV was screened against an I. ricinus cDNA library established from three embryonic tick cell lines using yeast two-hybrid methodology (Y2H). PPIs revealed for each viral bait were retested in yeast by applying a gap repair (GR) strategy, and notably against the cognate protein of both viruses, to determine whether the PPIs were specific for a single virus or common to both. The interacting tick proteins were identified by automatic BLASTX, and in silico analyses were performed to expose the biological processes targeted by LIV and TBEV.

Results: For each virus, we identified 24 different PPIs involving six viral proteins and 22 unique tick proteins, with all PPIs being common to both viruses. According to our data, several viral proteins (pM, M, NS2A, NS4A, 2K and NS5) target multiple tick protein modules implicated in critical biological pathways. Of note, the NS5 and pM viral proteins establish PPI with several tumor necrosis factor (TNF) receptor-associated factor (TRAF) proteins, which are essential adaptor proteins at the nexus of multiple signal transduction pathways.

Conclusion: We provide the first description of the TBEV/LIV-I. ricinus PPI network, and indeed of any PPI network involving a tick-borne virus and its tick vector. While further investigation will be needed to elucidate the role of each tick protein in the replication cycle of tick-borne flaviviruses, our study provides a foundation for understanding the vector competence of I. ricinus at the molecular level. Indeed, certain PPIs may represent molecular determinants of vector competence of I. ricinus for TBEV and LIV, and potentially for other tick-borne flaviviruses.
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http://dx.doi.org/10.1186/s13071-021-04651-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937244PMC
March 2021

The VP3 Protein of Bluetongue Virus Associates with the MAVS Complex and Interferes with the RIG-I-Signaling Pathway.

Viruses 2021 02 2;13(2). Epub 2021 Feb 2.

UMR 1161 Virologie, Laboratory for Animal Health, INRAE, Department of Animal Health, Ecole Nationale Vétérinaire d'Alfort, ANSES, Université Paris-Est, 94700 Maisons-Alfort, France.

Bluetongue virus (BTV), an arbovirus transmitted by biting midges, is a major concern of wild and domestic ruminants. While BTV induces type I interferon (alpha/beta interferon [IFN-α/β]) production in infected cells, several reports have described evasion strategies elaborated by this virus to dampen this intrinsic, innate response. In the present study, we suggest that BTV VP3 is a new viral antagonist of the IFN-β synthesis. Indeed, using split luciferase and coprecipitation assays, we report an interaction between VP3 and both the mitochondrial adapter protein MAVS and the IRF3-kinase IKKε. Overall, this study describes a putative role for the BTV structural protein VP3 in the control of the antiviral response.
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http://dx.doi.org/10.3390/v13020230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913109PMC
February 2021

Interactions of Viral Proteins from Pathogenic and Low or Non-Pathogenic Orthohantaviruses with Human Type I Interferon Signaling.

Viruses 2021 Jan 19;13(1). Epub 2021 Jan 19.

Unité des Stratégies Antivirales, Institut Pasteur, 75015 Paris, France.

Rodent-borne orthohantaviruses are asymptomatic in their natural reservoir, but they can cause severe diseases in humans. Although an exacerbated immune response relates to hantaviral pathologies, orthohantaviruses have to antagonize the antiviral interferon (IFN) response to successfully propagate in infected cells. We studied interactions of structural and nonstructural (NSs) proteins of pathogenic Puumala (PUUV), low-pathogenic Tula (TULV), and non-pathogenic Prospect Hill (PHV) viruses, with human type I and III IFN (IFN-I and IFN-III) pathways. The NSs proteins of all three viruses inhibited the RIG-I-activated IFNβ promoter, while only the glycoprotein precursor (GPC) of PUUV, or its cleavage product Gn/Gc, and the nucleocapsid (N) of TULV inhibited it. Moreover, the GPC of both PUUV and TULV antagonized the promoter of IFN-stimulated responsive elements (ISRE). Different viral proteins could thus contribute to inhibition of IFNβ response in a viral context. While PUUV and TULV strains replicated similarly, whether expressing entire or truncated NSs proteins, only PUUV encoding a wild type NSs protein led to late IFN expression and activation of IFN-stimulated genes (ISG). This, together with the identification of particular domains of NSs proteins and different biological processes that are associated with cellular proteins in complex with NSs proteins, suggested that the activation of IFN-I is probably not the only antiviral pathway to be counteracted by orthohantaviruses and that NSs proteins could have multiple inhibitory functions.
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http://dx.doi.org/10.3390/v13010140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835746PMC
January 2021

Bovine Organospecific Microvascular Endothelial Cell Lines as New and Relevant In Vitro Models to Study Viral Infections.

Int J Mol Sci 2020 Jul 24;21(15). Epub 2020 Jul 24.

Center for Molecular Biophysics UPR4301 CNRS, 45000 Orléans, France.

Microvascular endothelial cells constitute potential targets for exogenous microorganisms, in particular for vector-borne pathogens. Their phenotypic and functional variations according to the organs they are coming from provide an explanation of the organ selectivity expressed in vivo by pathogens. In order to make available relevant tools for in vitro studies of infection mechanisms, our aim was to immortalize bovine organospecific endothelial cells but also to assess their permissivity to viral infection. Using transfection with SV40 large T antigen, six bovine microvascular endothelial cell lines from various organs and one macrovascular cell line from an umbilical cord were established. They display their own panel of endothelial progenitor/mature markers, as assessed by flow cytometry and RT-qPCR, as well as the typical angiogenesis capacity. Using both Bluetongue and foot-and-mouth disease viruses, we demonstrate that some cell lines are preferentially infected. In addition, they can be transfected and are able to express viral proteins such as BTV8-NS3. Such microvascular endothelial cell lines bring innovative tools for in vitro studies of infection by viruses or bacteria, allowing for the study of host-pathogen interaction mechanisms with the actual in vivo target cells. They are also suitable for applications linked to microvascularization, such as anti-angiogenic and anti-tumor research, growing fields in veterinary medicine.
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http://dx.doi.org/10.3390/ijms21155249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432920PMC
July 2020

Evaluation of a commercial ELISA for detection of epizootic haemorrhagic disease antibodies in domestic and wild ruminant sera.

Transbound Emerg Dis 2020 Nov 14;67(6):2475-2481. Epub 2020 May 14.

Laboratoire de Santé Animale d'Alfort, ANSES, ENVA, INRA, UMR 1161 VIROLOGIE, Université Paris Est, Maisons-Alfort, France.

Bluetongue (BT) and epizootic haemorrhagic disease (EHD) are vector-borne viral diseases affecting domestic and wild ruminants. Both are notifiable under OIE rules. BT and EHD viruses (BTV and EHDV) are closely related Orbiviruses with structural, antigenic and molecular similarities. Both viruses can produce analogous clinical signs in susceptible animals. Serological tests are commonly used for BT and EHD diagnosis and surveillance. Competitive ELISA (c-ELISA) is the most widely used serological test for the specific detection of BTV or EHDV viral protein 7 (VP7) antibodies (Abs). The specificity and sensitivity of the BTV c-ELISA kits available on the market are recognized for the detection of BTV Abs. Concerning EHD, a single commercial EHDV c-ELISA kit (ELISA A kit) commonly used for diagnosis in Europe and Africa was available between 2011 and 2018 but is now no longer on the market. In this study, we evaluated a new commercial c-ELISA to detect ruminant EHDV VP7 Abs in 2,199 serum samples from cattle, sheep, goats, wild deer and zoo animals. The results showed that this ELISA kit is specific and can detect the presence of IgG anti-EHDV VP7 with a very good diagnostic specificity and a satisfactory sensitivity in domestic ruminants, zoo animals and wild deer. Therefore, the evaluated c-ELISA can detect the introduction of EHDV into an area where BTV-seropositive domestic animals are present. The performance of this kit is similar to that of the c-ELISA A kit and can thus be used for diagnosis.
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http://dx.doi.org/10.1111/tbed.13586DOI Listing
November 2020

Experimental infection of calves with seven serotypes of Epizootic Hemorrhagic Disease virus: production and characterization of reference sera.

Vet Ital 2019 Dec 31;55(4):339-346. Epub 2019 Dec 31.

UMR Virologie, INRA, Ecole Nationale Vétérinaire d'Alfort, laboratoire de santé animale d'Alfort, ANSES, Université Paris-Est, 94700 Maisons-Alfort, France.

The aim of this study was to produce reference sera against the seven serotypes of Epizootic hemorrhagic disease virus (EHDV‑1, EHDV‑2, EHDV‑4, EHDV‑5, EHDV‑6, EHDV‑7, and EHDV‑8). In a high containment unit, seven Prim 'Holstein calves were inoculated at day 0 (D0) with the selected strains (1 EHDV serotype per calf ). Blood samples (EDTA and whole blood) were periodically taken from D0 until the end of the experiment (D31). Sera were tested with two commercially available EHDV competitive ELISAs (c‑ELISA). Viral genome was detected from EDTA blood samples using in‑house real‑time RT‑PCR. Sera taken on D31 post infection (pi) were tested and characterized by serum neutralization test (SNT) and virus neutralization test (VNT) (for calibration of reference sera). Viral RNA was first detected at D2 pi in five calves. All infected animals were RT‑PCR positive at D7 pi. Seroconversion was observed between D10 and D23 pi depending on the EHDV serotype. SNT and VNT have allowed to determine the neutralizing antibody titers of each serum and the potential cross‑reactions between serotypes. The two c‑ELISA used in this study showed similar results. The calibrated sera are now available for the serological identification of an EHDV isolated on tissue culture or to be used as positive control in seroneutralization assay.
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http://dx.doi.org/10.12834/VetIt.2104.11179.1DOI Listing
December 2019

Clinical cases of Bluetongue serotype 8 in calves in France in the 2018-2019 winter.

Transbound Emerg Dis 2020 May 8;67(3):1401-1405. Epub 2020 Jan 8.

Epidemiology Unit, Laboratory for Animal Health, ANSES, University Paris Est, Maisons-Alfort, France.

Bluetongue virus serotype 8 (BTV-8) caused an epizootic in Europe in 2006/09. Transplacental transmission of BTV-8 was demonstrated leading to abortions, congenital malformations or nervous clinical signs in newborn calves. BTV-8 re-emerged in France in 2015. Although the re-emergent strain is nearly genetically identical to the one that had circulated in 2006/2009, it has caused very few clinical cases. However, from mid-December 2018 to April 2019, cases of calves with congenital malformations or displaying nervous clinical signs occurred in some departments (French administrative unit) in mainland France. Blood samples from these animals were sent to local laboratories, and the positive ones were confirmed at the French Bluetongue reference laboratory (BT-NRL). Out of 580 samples found positive at the local laboratories, 544 were confirmed as RT-PCR BTV-8 positive. The 36 samples found positive in the local laboratories and negative in the BT-NRL were all at the limit of RT-PCR detection. Hundred eighty-eight of the confirmed samples were also tested for the presence of Schmallenberg virus (SBV) and bovine virus diarrhoea virus (BVDV) infection: 4 were found positive for BVDV and none for SBV. The main clinical signs recorded for 244 calves, for which a reporting form was completed by veterinarians, included nervous clinical signs (81%), amaurosis (72%) and decrease/ no suckling reflex (40%). Hydranencephaly and microphthalmia were reported in 19 calves out of 27 in which a necropsy was practiced after death or euthanasia. These results indicate that the re-emergent strain of BTV-8 can cross the transplacental barrier and cause congenital malformations or nervous clinical signs in calves.
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http://dx.doi.org/10.1111/tbed.13466DOI Listing
May 2020

Red deer () Did Not Play the Role of Maintenance Host for Bluetongue Virus in France: The Burden of Proof by Long-Term Wildlife Monitoring and Snapshots.

Viruses 2019 09 27;11(10). Epub 2019 Sep 27.

UMR Virologie, INRA, Ecole Nationale Vétérinaire d'Alfort, laboratoire de santé animale d'Alfort, ANSES, Université Paris-Est, 94700 Maisons-Alfort, France, (C.V.).

Bluetongue virus (BTV) is a -borne pathogen infecting both domestic and wild ruminants. In Europe, the Red Deer () (RD) is considered a potential BTV reservoir, but persistent sylvatic cycle has not yet been demonstrated. In this paper, we explored the dynamics of BTV1 and BTV8 serotypes in the RD in France, and the potential role of that species in the re-emergence of BTV8 in livestock by 2015 (i.e., 5 years after the former last domestic cases). We performed 8 years of longitudinal monitoring (2008-2015) among 15 RD populations and 3065 individuals. We compared communities and feeding habits within domestic and wild animal environments (51,380 samples). diversity (>30 species) varied between them, but bridge-species able to feed on both wild and domestic hosts were abundant in both situations. Despite the presence of competent vectors in natural environments, BTV1 and BTV8 strains never spread in RD along the green corridors out of the domestic outbreak range. Decreasing antibody trends with no PCR results two years after the last domestic outbreak suggests that seropositive young RD were not recently infected but carried maternal antibodies. We conclude that RD did not play a role in spreading or maintaining BTV in France.
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http://dx.doi.org/10.3390/v11100903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832957PMC
September 2019

Bluetongue Virus in France: An Illustration of the European and Mediterranean Context since the 2000s.

Viruses 2019 07 23;11(7). Epub 2019 Jul 23.

UMR Virologie, INRA, Ecole Nationale Vétérinaire d'Alfort, laboratoire de santé animale d'Alfort, ANSES, Université Paris-Est, 94700 Maisons-Alfort, France.

Bluetongue (BT) is a non-contagious animal disease transmitted by midges of the genus. The etiological agent is the BT virus (BTV) that induces a variety of clinical signs in wild or domestic ruminants. BT is included in the notifiable diseases list of the World Organization for Animal Health (OIE) due to its health impact on domestic ruminants. A total of 27 BTV serotypes have been described and additional serotypes have recently been identified. Since the 2000s, the distribution of BTV has changed in Europe and in the Mediterranean Basin, with continuous BTV incursions involving various BTV serotypes and strains. These BTV strains, depending on their origin, have emerged and spread through various routes in the Mediterranean Basin and/or in Europe. Consequently, control measures have been put in place in France to eradicate the virus or circumscribe its spread. These measures mainly consist of assessing virus movements and the vaccination of domestic ruminants. Many vaccination campaigns were first carried out in Europe using attenuated vaccines and, in a second period, using exclusively inactivated vaccines. This review focuses on the history of the various BTV strain incursions in France since the 2000s, describing strain characteristics, their origins, and the different routes of spread in Europe and/or in the Mediterranean Basin. The control measures implemented to address this disease are also discussed. Finally, we explain the circumstances leading to the change in the BTV status of France from BTV-free in 2000 to an enzootic status since 2018.
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http://dx.doi.org/10.3390/v11070672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669443PMC
July 2019

Novel Function of Bluetongue Virus NS3 Protein in Regulation of the MAPK/ERK Signaling Pathway.

J Virol 2019 08 30;93(16). Epub 2019 Jul 30.

UMR Virologie, INRA, École Nationale Vétérinaire d'Alfort, ANSES, Université Paris-Est, Maisons-Alfort, France

Bluetongue virus (BTV) is an arbovirus transmitted by blood-feeding midges to a wide range of wild and domestic ruminants. In this report, we showed that BTV, through its nonstructural protein NS3 (BTV-NS3), is able to activate the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway, as assessed by phosphorylation levels of ERK1/2 and the translation initiation factor eukaryotic translation initiation factor 4E (eIF4E). By combining immunoprecipitation of BTV-NS3 and mass spectrometry analysis from both BTV-infected and NS3-transfected cells, we identified the serine/threonine-protein kinase B-Raf (BRAF), a crucial player in the MAPK/ERK pathway, as a new cellular interactor of BTV-NS3. BRAF silencing led to a significant decrease in the MAPK/ERK activation by BTV, supporting a model wherein BTV-NS3 interacts with BRAF to activate this signaling cascade. This positive regulation acts independently of the role of BTV-NS3 in counteracting the induction of the alpha/beta interferon response. Furthermore, the intrinsic ability of BTV-NS3 to bind BRAF and activate the MAPK/ERK pathway is conserved throughout multiple serotypes/strains but appears to be specific to BTV compared to other members of genus. Inhibition of MAPK/ERK pathway with U0126 reduced viral titers, suggesting that BTV manipulates this pathway for its own replication. Altogether, our data provide molecular mechanisms that unravel a new essential function of NS3 during BTV infection. Bluetongue virus (BTV) is responsible of the arthropod-borne disease bluetongue (BT) transmitted to ruminants by blood-feeding midges. In this report, we found that BTV, through its nonstructural protein NS3 (BTV-NS3), interacts with BRAF, a key component of the MAPK/ERK pathway. In response to growth factors, this pathway promotes cell survival and increases protein translation. We showed that BTV-NS3 enhances the MAPK/ERK pathway, and this activation is BRAF dependent. Treatment of MAPK/ERK pathway with the pharmacologic inhibitor U0126 impairs viral replication, suggesting that BTV manipulates this pathway for its own benefit. Our results illustrate, at the molecular level, how a single virulence factor has evolved to target a cellular function to increase its viral replication.
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http://dx.doi.org/10.1128/JVI.00336-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6675888PMC
August 2019

Evaluation of an IGM-specific ELISA for early detection of bluetongue virus infections in domestic ruminants sera.

Transbound Emerg Dis 2019 Jan 23;66(1):537-545. Epub 2018 Nov 23.

Laboratoire de Santé Animale d'Alfort, Université Paris Est, ANSES, ENVA, INRA, UMR 1161 VIROLOGIE, Maisons-Alfort, France.

Competitive-ELISA (c-ELISA) is the most widely used serological test for the detection of Bluetongue virus (BTV) viral protein 7 (VP7) antibodies (Ab). However, these BTV c-ELISAs cannot to distinguish between IgG and IgM. IgM Ab are generated shortly after the primary immune response against an infectious agent, indicating a recent infection or exposure to antigens, such as after vaccination. Because the BTV genome or anti-VP7 Ab can be detected in ruminant blood months after infection, BTV diagnostic tools cannot discriminate between recent and old infections. In this study, we evaluated an IgM-capture ELISA prototype to detect ruminant anti-BTV VP7 IgM on 1,650 serum samples from cattle, sheep, or goats. Animals were BTV-naive, infected, or/and vaccinated with BTV-1, -2, -4, -8, -9, -16, or -27, and we also included 30 sera from cattle infected with the Epizootic haemorrhagic disease virus (EHDV) serotype 6. Results demonstrated that this ELISA kit is specific and can detect the presence of IgM with satisfactory diagnostic specificity and sensitivity from 1 to 5 weeks after BTV infection in domestic ruminants (for goats and cattle; for sheep, at least up to 24 days). The peak of anti-VP7 IgM was reached when the level of infectious viruses and BTV RNA in blood were the highest. The possibility of detecting BTV-RNA in IgM-positive sera allows the amplification and sequencing of the partial RNA segment 2 (encoding the serotype specific to VP2) to determine the causative BTV serotype/strain. Therefore, BTV IgM ELISA can detect the introduction of BTV (or EHDV) in an area with BTV-seropositive domestic animals regardless of their serological BTV status. This approach may also be of particular interest for retrospective epidemiological studies on frozen serum samples.
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http://dx.doi.org/10.1111/tbed.13060DOI Listing
January 2019

Emergence of bluetongue virus serotype 4 in mainland France in November 2017.

Transbound Emerg Dis 2018 Oct 8;65(5):1158-1162. Epub 2018 Jun 8.

UMR 1161 ANSES/INRA/ENVA, Université Paris-Est ANSES Maisons-Alfort, Maisons-Alfort, France.

In November 2017, a 15-day-old calf located in France (Haute-Savoie department) was found positive for bluetongue virus (BTV) RNA by RT-PCR. Laboratory investigations allowed the isolation and identification of the serotype: BTV-4. The analysis of the full viral genome showed that all the 10 genome segments were closely related to BTV-4 strains involved in a large BT outbreak in the Balkan Peninsula, in Italy since 2014 and in Corsica since the end of October 2016. These results together with epidemiological data suggest that BTV-4 has been introduced to mainland France from Corsica or Italy where BTV-4 outbreaks have been reported in summer and autumn 2016. This is the first report of the introduction of BTV-4 in mainland France.
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http://dx.doi.org/10.1111/tbed.12919DOI Listing
October 2018

Fetopathic effects of experimental Schmallenberg virus infection in pregnant goats.

Vet Microbiol 2017 Nov 14;211:141-149. Epub 2017 Oct 14.

Université Paris-Est, ANSES, Laboratoire de Santé Animale, UMR 1161 Virologie ANSES-INRA-ENVA, 14 rue Pierre et Marie Curie, 94704 Maisons-Alfort, France.

Schmallenberg virus (SBV) is an emerging virus responsible for congenital malformations in the offspring of domestic ruminants. It is speculated that infection of pregnant dams may also lead to a significant number of unrecognized fetal losses during the early period of gestation. To assess the pathogenic effects of SBV infection of goats in early pregnancy, we inoculated dams at day 28 or 42 of gestation and followed the animals until day 55 of gestation. Viremia in the absence of clinical signs was detected in all virus-inoculated goats. Fetal deaths were observed in several goats infected at day 28 or 42 of gestation and were invariably associated with the presence of viral genomic RNA in the affected fetuses. Among the viable fetuses, two displayed lesions in the central nervous system (porencephaly) in the presence of viral genome and antigen. All fetuses from goats infected at day 42 and the majority of fetuses from goats infected at day 28 of gestation contained viral genomic RNA. Viral genome was widely distributed in these fetuses and their respective placentas, and infectious virus could be isolated from several organs and placentomes of the viable fetuses. Our results show that fetuses of pregnant goats are susceptible to vertical SBV infection during early pregnancy spanning at least the period between day 28 and 42 of gestation. The outcomes of experimental SBV infection assessed at day 55 of gestation include fetal mortalities, viable fetuses displaying lesions of the central nervous system, as well as viable fetuses without any detectable lesion.
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http://dx.doi.org/10.1016/j.vetmic.2017.10.011DOI Listing
November 2017

Bluetongue Virus: From BTV-1 to BTV-27.

Adv Virus Res 2017 22;99:161-197. Epub 2017 Sep 22.

UMR1161 Virologie, ANSES, INRA, Ecole Nationale Vétérinaire d'Alfort, Université Paris-Est, Maisons-Alfort, France.

Bluetongue virus (BTV) is the type species of genus Orbivirus within family Reoviridae. Bluetongue virus is transmitted between its ruminant hosts by the bite of Culicoides spp. midges. Severe BT cases are characterized by symptoms including hemorrhagic fever, particularly in sheep, loss of productivity, and death. To date, 27 BTV serotypes have been documented. These include novel isolates of atypical BTV, which have been almost fully characterized using deep sequencing technologies and do not rely on Culicoides vectors for their transmission among hosts. Due to its high economic impact, BT is an Office International des Epizooties (OIE) listed disease that is strictly controlled in international commercial exchanges. During the 20th century, BTV has been endemic in subtropical regions. In the last 15 years, novel strains of nine "typical" BTV serotypes (1, 2, 4, 6, 8, 9, 11, 14, and 16) invaded Europe, some of which caused disease in naive sheep and unexpectedly in bovine herds (particularly serotype 8). Over the past few years, three novel "atypical" serotypes (25-27) were characterized during sequencing studies of animal samples from Switzerland, Kuwait, and France, respectively. Classical serotype-specific inactivated vaccines, although expensive, were very successful in controlling outbreaks as shown with the northern European BTV-8 outbreak which started in the summer of 2006. Technological jumps in deep sequencing methodologies made rapid full characterizations of BTV genome from isolates/tissues feasible. Next-generation sequencing (NGS) approaches are powerful tools to study the variability of BTV genomes on a fine scale. This paper provides information on how NGS impacted our knowledge of the BTV genome.
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http://dx.doi.org/10.1016/bs.aivir.2017.08.003DOI Listing
May 2018

Ring trial 2016 for Bluetongue virus detection by real-time RT-PCR in France.

Vet Med Sci 2017 May 16;3(2):107-114. Epub 2017 Apr 16.

ANSES/INRA/ENVA-UPECUMR 1161 Virologie14 rue Pierre et Marie CURIE-94700Maisons AlfortFrance.

Since the unexpected emergence of BTV-8 in Northern Europe and the incursion of BTV-8 and 1 in France in 2006-2007, molecular diagnosis has considerably evolved. Several real-time RT-PCR (rtRT-PCR) methods have been developed and published, and are currently being used in many countries across Europe for BTV detection and typing. In France, the national reference laboratory (NRL) for orbiviruses develops and validates 'ready-to-use' kits with private companies for viral RNA detection. The regional laboratories network that was set up to deal with a heavy demand for analyses has used these available kits. From 2007, ring tests were organized to monitor the performance of the French laboratories. This study presents the results of 63 regional laboratories in the ring trial organized in 2016. Blood samples were sent to the laboratories. Participants were asked to use the rtRT-PCR methods in place in their laboratory, for detection of all BTV serotypes and specifically BTV-8. The French regional laboratories are able to detect and genotype BTV in affected animals. Despite the use of several methods (i.e. RNA extraction and different commercial rtRT-PCRs), the network is homogeneous. The ring trial demonstrated that the French regional veterinary laboratories have reliable and robust BTV diagnostic tools for BTV genome detection.
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http://dx.doi.org/10.1002/vms3.63DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5488199PMC
May 2017

Nonstructural Protein NSs of Schmallenberg Virus Is Targeted to the Nucleolus and Induces Nucleolar Disorganization.

J Virol 2017 Jan 16;91(1). Epub 2016 Dec 16.

ANSES, UMR1161 Virologie, Laboratory for Animal Health, Maisons-Alfort, France

Schmallenberg virus (SBV) was discovered in Germany in late 2011 and then spread rapidly to many European countries. SBV is an orthobunyavirus that causes abortion and congenital abnormalities in ruminants. A virus-encoded nonstructural protein, termed NSs, is a major virulence factor of SBV, and it is known to promote the degradation of Rpb1, a subunit of the RNA polymerase II (Pol II) complex, and therefore hampers global cellular transcription. In this study, we found that NSs is mainly localized in the nucleus of infected cells and specifically appears to target the nucleolus through a nucleolar localization signal (NoLS) localized between residues 33 and 51 of the protein. NSs colocalizes with nucleolar markers such as B23 (nucleophosmin) and fibrillarin. We observed that in SBV-infected cells, B23 undergoes a nucleolus-to-nucleoplasm redistribution, evocative of virus-induced nucleolar disruption. In contrast, the nucleolar pattern of B23 was unchanged upon infection with an SBV recombinant mutant with NSs lacking the NoLS motif (SBVΔNoLS). Interestingly, unlike wild-type SBV, the inhibitory activity of SBVΔNoLS toward RNA Pol II transcription is impaired. Overall, our results suggest that a putative link exists between NSs-induced nucleolar disruption and its inhibitory function on cellular transcription, which consequently precludes the cellular antiviral response and/or induces cell death.

Importance: Schmallenberg virus (SBV) is an emerging arbovirus of ruminants that spread in Europe between 2011 and 2013. SBV induces fetal abnormalities during gestation, with the central nervous system being one of the most affected organs. The virus-encoded NSs protein acts as a virulence factor by impairing host cell transcription. Here, we show that NSs contains a nucleolar localization signal (NoLS) and induces disorganization of the nucleolus. The NoLS motif in the SBV NSs is absolutely necessary for virus-induced inhibition of cellular transcription. To our knowledge, this is the first report of nucleolar functions for NSs within the Bunyaviridae family.
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http://dx.doi.org/10.1128/JVI.01263-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5165206PMC
January 2017

The Golgi apparatus acts as a platform for TBK1 activation after viral RNA sensing.

BMC Biol 2016 08 18;14:69. Epub 2016 Aug 18.

INSERM, UMR_S 1197, Hôpital Paul Brousse, Villejuif, France.

Background: After viral infection and the stimulation of some pattern-recognition receptors, TANK-binding kinase I (TBK1) is activated by K63-linked polyubiquitination followed by trans-autophosphorylation. While the activated TBK1 induces type I interferon production by phosphorylating the transcription factor IRF3, the precise molecular mechanisms underlying TBK1 activation remain unclear.

Results: We report here the localization of the ubiquitinated and phosphorylated active form of TBK1 to the Golgi apparatus after the stimulation of RIG-I-like receptors (RLRs) or Toll-like receptor-3 (TLR3), due to TBK1 K63-linked ubiquitination on lysine residues 30 and 401. The ubiquitin-binding protein optineurin (OPTN) recruits ubiquitinated TBK1 to the Golgi apparatus, leading to the formation of complexes in which TBK1 is activated by trans-autophosphorylation. Indeed, OPTN deficiency in various cell lines and primary cells impairs TBK1 targeting to the Golgi apparatus and its activation following RLR or TLR3 stimulation. Interestingly, the Bluetongue virus NS3 protein binds OPTN at the Golgi apparatus, neutralizing its activity and thereby decreasing TBK1 activation and downstream signaling.

Conclusions: Our results highlight an unexpected role of the Golgi apparatus in innate immunity as a key subcellular gateway for TBK1 activation after RNA virus infection.
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http://dx.doi.org/10.1186/s12915-016-0292-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991008PMC
August 2016

Bluetongue virus serotype 27: detection and characterization of two novel variants in Corsica, France.

J Gen Virol 2016 09 19;97(9):2073-2083. Epub 2016 Jul 19.

Université Paris Est, ANSES, ENVA, INRA, UMR 1161 VIROLOGIE, Laboratoire de Santé Animale d'Alfort, Maisons-Alfort, France.

During the compulsory vaccination programme against bluetongue virus serotype 1 (BTV-1) in Corsica (France) in 2014, a BTV strain belonging to a previously uncharacterized serotype (BTV-27) was isolated from asymptomatic goats. The present study describes the detection and molecular characterization of two additional distinct BTV-27 variants found in goats in Corsica in 2014 and 2015. The full coding genome of these two novel BTV-27 variants show high homology (90-93 % nucleotide/93-95 % amino acid) with the originally described BTV-27 isolate from Corsican goats in 2014. These three variants constitute the novel serotype BTV-27 ('BTV-27/FRA2014/v01 to v03'). Phylogenetic analyses with the 26 other established BTV serotypes revealed the closest relationship to BTV-25 (SWI2008/01) (80 % nucleotide/86 % amino acid) and to BTV-26 (KUW2010/02) (73-74 % nucleotide/80-81 % amino acid). However, highest sequence homologies between individual segments of BTV-27/FRA2014/v01-v03 with BTV-25 and BTV-26 vary. All three variants share the same segment 2 nucleotype with BTV-25. Neutralization assays of anti-BTV27/FRA2014/v01-v03 sera with a reassortant virus containing the outer capsid proteins of BTV-25 (BTV1VP2/VP5 BTV25) further confirmed that BTV-27 represents a distinct BTV serotype. Relationships between the variants and with BTV-25 and BTV-26, hypotheses about their origin, reassortment events and evolution are discussed.
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http://dx.doi.org/10.1099/jgv.0.000557DOI Listing
September 2016

Complete Genome Sequence of Bluetongue Virus Serotype 8, Which Reemerged in France in August 2015.

Genome Announc 2016 Apr 14;4(2). Epub 2016 Apr 14.

Anses, Laboratory of Ploufragan, Unit of Viral Genetics and Biosafety, Ploufragan, France.

We announce here the complete genome sequence (coding and noncoding) of the bluetongue virus (BTV) serotype 8, isolated from a ram in Allier department, France, 2015. Sequence analysis confirms the reemergence of the BTV-8 strain that previously circulated in France until 2009 and other European countries until 2010.
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http://dx.doi.org/10.1128/genomeA.00163-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4832148PMC
April 2016

Turnover Rate of NS3 Proteins Modulates Bluetongue Virus Replication Kinetics in a Host-Specific Manner.

J Virol 2015 Oct 5;89(20):10467-81. Epub 2015 Aug 5.

UMR754, Université Claude Bernard Lyon 1, Institut National de la Recherche Agronomique, Ecole Pratique des Hautes Etudes, SFR BioSciences Gerland, Lyon, France

Unlabelled: Bluetongue virus (BTV) is an arbovirus transmitted to livestock by midges of the Culicoides family and is the etiological agent of a hemorrhagic disease in sheep and other ruminants. In mammalian cells, BTV particles are released primarily by virus-induced cell lysis, while in insect cells they bud from the plasma membrane and establish a persistent infection. BTV possesses a ten-segmented double-stranded RNA genome, and NS3 proteins are encoded by segment 10 (Seg-10). The viral nonstructural protein 3 (NS3) plays a key role in mediating BTV egress as well as in impeding the in vitro synthesis of type I interferon in mammalian cells. In this study, we asked whether genetically distant NS3 proteins can alter BTV-host interactions. Using a reverse genetics approach, we showed that, depending on the NS3 considered, BTV replication kinetics varied in mammals but not in insects. In particular, one of the NS3 proteins analyzed harbored a proline at position 24 that leads to its rapid intracellular decay in ovine but not in Culicoides cells and to the attenuation of BTV virulence in a mouse model of disease. Overall, our data reveal that the genetic variability of Seg-10/NS3 differentially modulates BTV replication kinetics in a host-specific manner and highlight the role of the host-specific variation in NS3 protein turnover rate.

Importance: BTV is the causative agent of a severe disease transmitted between ruminants by biting midges of Culicoides species. NS3, encoded by Seg-10 of the BTV genome, fulfills key roles in BTV infection. As Seg-10 sequences from various BTV strains display genetic variability, we assessed the impact of different Seg-10 and NS3 proteins on BTV infection and host interactions. In this study, we revealed that various Seg-10/NS3 proteins alter BTV replication kinetics in mammals but not in insects. Notably, we found that NS3 protein turnover may vary in ovine but not in Culicoides cells due to a single amino acid residue that, most likely, leads to rapid and host-dependent protein degradation. Overall, this study highlights that genetically distant BTV Seg-10/NS3 influence BTV biological properties in a host-specific manner and increases our understanding of how NS3 proteins contribute to the outcome of BTV infection.
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http://dx.doi.org/10.1128/JVI.01541-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4580187PMC
October 2015

Induction and control of the type I interferon pathway by Bluetongue virus.

Virologie (Montrouge) 2015 Aug;19(4):178-186

UMR1161 Anses-Inra-Enva, 23, avenue du Général-de-Gaulle, 94704 Maisons-Alfort, France.

Upon viral infection, infected cells mount an antiviral response that culminates with the production of type I IFN (IFN-α/β) and other pro-inflammatory cytokines that control the infection. Production of type I IFN occurs both in vivo and in vitro in response to Bluetongue virus (BTV), an arthropod-borne virus, but the underlying mechanisms responsible for this event remained unknown until recently. This review describes the recent advances in the identification of cellular sensors and signalling pathways involved in this process. In non-hematopoietic cells, expression of IFN-β in response to BTV infection depends on the activation of the RNA helicases retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). In contrast, induction of IFN-α/β synthesis in sheep primary plasmacytoid dendritic cells (pDCs) required the MyD88 adaptor independently of the Toll-like receptor 7 (TLR7), as well as the kinases dsRNA-activated protein kinase (PKR) and stress-activated protein kinase (SAPK)/Jun N-terminal protein kinase (JNK). In order to counteract this antiviral response, most of viruses have elaborated mechanisms to hinder its action. This review also describes the ability of BTV to interfere with the IFN pathway and the recent findings describing the non-structural viral protein NS3 as a powerful antagonist of the host cellular response.
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http://dx.doi.org/10.1684/vir.2015.0615DOI Listing
August 2015

Duplex Real-Time RT-PCR Assays for the Detection and Typing of Epizootic Haemorrhagic Disease Virus.

PLoS One 2015 10;10(7):e0132540. Epub 2015 Jul 10.

ANSES/INRA/ENVA-UPEC, UMR 1161 Virologie, 23 avenue du général de Gaulle-94700 Maisons Alfort-France.

Epizootic haemorrhagic disease virus (EHDV) may cause severe clinical episodes in some species of deer and sometimes in cattle. Laboratory diagnosis provides a basis for the design and timely implementation of disease control measures. There are seven distinct EHDV serotypes, VP2 coding segment 2 being the target for serotype specificity. This paper reports the development and validation of eight duplex real-time RT-PCR assays to simultaneously amplify the EHDV target (S9 for the pan-EHDV real-time RT-PCR assay and S2 for the serotyping assays) and endogenous control gene Beta-actin. Analytical and diagnostic sensitivity and specificity, inter- and intra-assay variation and efficiency were evaluated for each assay. All were shown to be highly specific and sensitive.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0132540PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4498883PMC
April 2016

Benefits of PCR and decentralization of diagnosis in regional laboratories in the management of Bluetongue in France.

Vet Ital 2015 Oct-Dec;51(4):393-9

UPE, ANSES, INRA, ENVA, UMR 1161 ANSES/INRA/ENVA, Laboratoire de santé animale d'Alfort, 14 rue Pierre et Marie Curie, Maisons-Alfort, France.

Since 1998, Bluetongue virus (BTV) serotypes 1, 2, 4, 6, 8, 9, 11 and 16 have spread throughout Europe. In 2006, BTV serotype 8 (BTV‑8) emerged unexpectedly in Northern Europe, in countries such as Belgium, France, Germany, Luxembourg, and the Netherlands, to spread rapidly in the following year throughout the rest of Europe. In 2007, BTV‑1 spread in Southern Europe, in Spain and in South of France. In 2008, 2 more BTV serotypes were detected in Northern Europe: BTV‑6 in the Netherlands and in Germany, and BTV‑11 in Belgium. The European incursion of BTV has caused considerable economic losses, including direct losses from mortality and reduced production, as well as indirect losses generated by ensuing bans on trade of ruminants between infected and non-infected areas. Given the significance of the disease, all affected countries have established control and eradication measures that have evolved together with the availability of detection and prevention tools such as Polymerase Chain Reaction (PCR) tests and vaccines, respectively. This paper describes how the French National Reference Laboratory for BT has managed diagnosis during the fast and massive spread of BTV‑1 and 8 in 2007 and 2008.
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http://dx.doi.org/10.12834/VetIt.512.3148.2DOI Listing
December 2016

Evaluation of adaptive immune responses and heterologous protection induced by inactivated bluetongue virus vaccines.

Vaccine 2015 Jan 11;33(4):512-8. Epub 2014 Dec 11.

ANSES, UMR 1161 Virologie ANSES-INRA-ENVA, 23 avenue du Général de Gaulle, 94704 Maisons-Alfort, France.

Eradication of bluetongue virus is possible, as has been shown in several European countries. New serotypes have emerged, however, for which there are no specific commercial vaccines. This study addressed whether heterologous vaccines would help protect against 2 serotypes. Thirty-seven sheep were randomly allocated to 7 groups of 5 or 6 animals. Four groups were vaccinated with commercial vaccines against BTV strains 2, 4, and 9. A fifth positive control group was given a vaccine against BTV-8. The other 2 groups were unvaccinated controls. Sheep were then challenged by subcutaneous injection of either BTV-16 (2 groups) or BTV-8 (5 groups). Taken together, 24/25 sheep from the 4 experimental groups developed detectable antibodies against the vaccinated viruses. Furthermore, sheep that received heterologous vaccines showed significantly reduced viraemia and clinical scores for BTV-16 when compared to unvaccinated controls. Reductions in clinical signs and viraemia among heterologously vaccinated sheep were not as common after challenge with BTV-8. This study shows that heterologous protection can occur, but that it is difficult to predict if partial or complete protection will be achieved following inactivated-BTV vaccination.
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http://dx.doi.org/10.1016/j.vaccine.2014.11.053DOI Listing
January 2015

Novel bluetongue virus in goats, Corsica, France, 2014.

Emerg Infect Dis 2014 Dec;20(12):2123-5

During 2000-2013, 4 genotypes of bluetongue virus (BTV) were detected in Corsica, France. At the end of 2013, a compulsory BTV-1 vaccination campaign was initiated among domestic ruminants; biological samples from goats were tested as part of a corresponding monitoring program. A BTV strain with nucleotide sequences suggestive of a novel serotype was detected.
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http://dx.doi.org/10.3201/eid2012.140924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4257820PMC
December 2014

Identification of bluetongue virus and epizootic hemorrhagic disease virus serotypes in French Guiana in 2011 and 2012.

Vet Microbiol 2014 Nov 22;174(1-2):78-85. Epub 2014 Sep 22.

ANSES/INRA/ENVA-UPEC, UMR 1161 Virologie, 23 avenue du général de Gaulle, 94700 Maisons Alfort, France. Electronic address:

In French Guiana, the sero- and viro-prevalence of Bluetongue virus (BTV) is high but the circulating serotypes remain unknown. No data are available regarding the prevalence of Epizootic hemorrhagic disease (EHD). This study was conducted to assess the prevalence and to identify the circulating serotypes of these two Orbiviruses in this region (BTV and EHDV). Blood samples were collected in main livestock areas, from 122 young cattle between June and August 2011, to perform virological (PCR and viral isolation) and serological (ELISA) analyses. Moreover, samples from sheep and goat showing BTV-like clinical signs and from newly imported animals were analyzed using the same assays. Results confirmed an important viral circulation, with viro- and seroprevalence of 85% and 84% and 60% and 40% for BTV and EHDV, respectively. Ten Orbivirus serotypes were identified (BTV-1, 2, 6, 10, 12, 13, 17 and 24, EHDV-1 and 6). The circulation of many serotypes in intertropical America and in the Caribbean region underlines the need to establish measures to monitor and control animal movements.
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http://dx.doi.org/10.1016/j.vetmic.2014.09.006DOI Listing
November 2014

Dual modulation of type I interferon response by bluetongue virus.

J Virol 2014 Sep 9;88(18):10792-802. Epub 2014 Jul 9.

ANSES, INRA, ENVA, UPEC, UMR 1161 Virology, Maisons-Alfort, France

Unlabelled: Bluetongue virus (BTV) is a double-stranded RNA (dsRNA) virus that causes an economically important disease in ruminants. BTV infection is a strong inducer of type I interferon (IFN-I) in multiple cell types. It has been shown recently that BTV and, more specifically, the nonstructural protein NS3 of BTV are able to modulate the IFN-I synthesis pathway. However, nothing is known about the ability of BTV to counteract IFN-I signaling. Here, we investigated the effect of BTV on the IFN-I response pathway and, more particularly, the Janus tyrosine kinase (JAK)/signal transducer and activator of transcription protein (STAT) signaling pathway. We found that BTV infection triggered the expression of IFN-stimulated genes (ISGs) in A549 cells. However, when BTV-infected cells were stimulated with external IFN-I, we showed that activation of the IFN-stimulated response element (ISRE) promoter and expression of ISGs were inhibited. We found that this inhibition involved two different mechanisms that were dependent on the time of infection. After overnight infection, BTV blocked specifically the phosphorylation and nuclear translocation of STAT1. This inhibition correlated with the redistribution of STAT1 in regions adjacent to the nucleus. At a later time point of infection, BTV was found to interfere with the activation of other key components of the JAK/STAT pathway and to induce the downregulation of JAK1 and TYK2 protein expression. Overall, our study indicates for the first time that BTV is able to interfere with the JAK/STAT pathway to modulate the IFN-I response.

Importance: Bluetongue virus (BTV) causes a severe disease in ruminants and has an important impact on the livestock economy in areas of endemicity such as Africa. The emergence of strains, such as serotype 8 in Europe in 2006, can lead to important economic losses due to commercial restrictions and prophylactic measures. It has been known for many years that BTV is a strong inducer of type I interferon (IFN-I) in vitro and in vivo in multiple cell types. However, the ability of BTV to interact with the IFN-I system remains unclear. Here, we report that BTV is able to modulate the IFN-I response by interfering with the Janus tyrosine kinase (JAK)/signal transducer and activator of transcription protein (STAT) signaling pathway. These findings contribute to knowledge of how BTV infection interferes with the host's innate immune response and becomes pathogenic. This will also be important for the design of efficacious vaccine candidates.
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http://dx.doi.org/10.1128/JVI.01235-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4178850PMC
September 2014

Immunisation with bacterial expressed VP2 and VP5 of bluetongue virus (BTV) protect α/β interferon-receptor knock-out (IFNAR(-/-)) mice from homologous lethal challenge.

Vaccine 2014 Jul 2;32(32):4059-67. Epub 2014 Jun 2.

Vector-borne Viral Diseases Programme, The Pirbright Institute, Pirbright, Woking, Surrey GU240NF, United Kingdom. Electronic address:

BTV-4 structural proteins VP2 (as two domains: VP2D1 and VP2D2), VP5 (lacking the first 100 amino acids: VP5Δ1-100) and full-length VP7, expressed in bacteria as soluble glutathione S-transferase (GST) fusion-proteins, were used to immunise Balb/c and α/β interferon receptor knock-out (IFNAR(-/-)) mice. Neutralising antibody (NAbs) titres (expressed as log10 of the reciprocal of the last dilution of mouse serum which reduced plaque number by ≥50%) induced by the VP2 domains ranged from 1.806 to 2.408 in Balb/c and IFNAR(-/-) mice. The immunised IFNAR(-/-) mice challenged with a homologous live BTV-4 survived and failed to develop signs of infection (ocular discharge and apathy). Although subsequent attempts to isolate virus were unsuccessful (possibly reflecting presence of neutralising antibodies), a transient/low level viraemia was detected by real time RT-PCR. In contrast, mice immunised with the two VP2 domains with or without VP5Δ1-100 and VP7, then challenged with the heterologous serotype, BTV-8, all died by day 7 post-infection. We conclude that immunisation with bacterially-expressed VP2 domains can induce strong serotype-specific NAb responses. Bacterial expression could represent a cost effective and risk-free alternative to the use of live or inactivated vaccines, particularly if viruses prove to be difficult to propagate in cell culture (like BTV-25). A vaccine based on bacterially expressed VP2 and VP5 of BTV is also DIVA-compatible.
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http://dx.doi.org/10.1016/j.vaccine.2014.05.056DOI Listing
July 2014

Evidence of excretion of Schmallenberg virus in bull semen.

Vet Res 2014 Apr 4;45:37. Epub 2014 Apr 4.

LNCR - Laboratoire National de Contrôle des Reproducteurs, 13 rue Jouet, 94704 Maisons-Alfort, France.

Schmallenberg virus (SBV) is a novel orthobunyavirus, discovered in Germany in late 2011. It mainly infects cattle, sheep and goats and could lead to congenital infection, causing abortion and fetal abnormalities. SBV is transmitted by biting midges from the Culicoides genus and there is no evidence that natural infection occurs directly between ruminants. Here, we could detect SBV RNA in infected bull semen using qRT-PCR (three bulls out of seven tested positive; 29 positive semen batches out of 136). We also found that highly positive semen batches from SBV infected bulls can provoke an acute infection in IFNAR-/- mice, suggesting the potential presence of infectious virus in the semen of SBV infected bulls.
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http://dx.doi.org/10.1186/1297-9716-45-37DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3994198PMC
April 2014

Induction and control of the type I interferon pathway by Bluetongue virus.

Virus Res 2014 Mar 7;182:59-70. Epub 2013 Nov 7.

UMR1161 ANSES-INRA-ENVA, 23 Avenue du Général de Gaulle, 94704 Maisons-Alfort, France. Electronic address:

The innate immune response is the first line of defence against viruses, involving the production of type I IFN (IFN-α/β) and other pro-inflammatory cytokines that control the infection. It also shapes the adaptive immune response generated by both T and B cells. Production of type I IFN occurs both in vivo and in vitro in response to Bluetongue virus (BTV), an arthropod-borne virus. However, the mechanisms responsible for the production of IFN-β in response to BTV remained unknown until recently and are still not completely understood. In this review, we describe the recent advances in the identification of cellular sensors and signalling pathways involved in this process. The RNA helicases retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) were shown to be involved in the expression of IFN-β as well as in the control of BTV infection in non-haematopoietic cells. In contrast, induction of IFN-α/β synthesis in sheep primary plasmacytoid dendritic cells (pDCs) required the MyD88 adaptor independently of the Toll-like receptor 7 (TLR7), as well as the kinases dsRNA-activated protein kinase (PKR) and stress-activated protein kinase (SAPK)/Jun N-terminal protein kinase (JNK). As type I IFN is essential for the establishment of an antiviral cellular response, most of viruses have elaborated counteracting mechanisms to hinder its action. This review also addresses the ability of BTV to interfere with IFN-β synthesis and the recent findings describing the non-structural viral protein NS3 as a powerful antagonist of the host cellular response.
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http://dx.doi.org/10.1016/j.virusres.2013.10.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7114367PMC
March 2014