Institute of Virology and Immunoprophylaxis IVI


Institute of Virology and Immunoprophylaxis IVI

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Meurens F.,French National Institute for Agricultural Research | Summerfield A.,Institute of Virology and Immunoprophylaxis IVI | Nauwynck H.,Ghent University | Saif L.,Ohio State University | Gerdts V.,University of Saskatchewan
Trends in Microbiology | Year: 2012

An animal model to study human infectious diseases should accurately reproduce the various aspects of disease. Domestic pigs (Sus scrofa domesticus) are closely related to humans in terms of anatomy, genetics and physiology, and represent an excellent animal model to study various microbial infectious diseases. Indeed, experiments in pigs are much more likely to be predictive of therapeutic treatments in humans than experiments in rodents. In this review, we highlight the numerous advantages of the pig model for infectious disease research and vaccine development and document a few examples of human microbial infectious diseases for which the use of pigs as animal models has contributed to the acquisition of new knowledge to improve both animal and human health. © 2011 Elsevier Ltd.

Baumann A.,Institute of Virology and Immunoprophylaxis IVI | Baumann A.,University of Bern | Mateu E.,Autonomous University of Barcelona | Murtaugh M.P.,University of Minnesota | Summerfield A.,Institute of Virology and Immunoprophylaxis IVI
Veterinary Research | Year: 2013

Porcine reproductive and respiratory syndrome (PRRS) virus (PRRSV) infections are characterized by prolonged viremia and viral shedding consistent with incomplete immunity. Type I interferons (IFN) are essential for mounting efficient antiviral innate and adaptive immune responses, but in a recent study, North American PRRSV genotype 2 isolates did not induce, or even strongly inhibited, IFN-α in plasmacytoid dendritic cells (pDC), representing "professional IFN-α-producing cells". Since inhibition of IFN-α expression might initiate PRRSV pathogenesis, we further characterized PRRSV effects and host modifying factors on IFN-α responses of pDC. Surprisingly, a variety of type 1 and type 2 PRRSV directly stimulated IFN-α secretion by pDC. The effect did not require live virus and was mediated through the TLR7 pathway. Furthermore, both IFN-γ and IL-4 significantly enhanced the pDC production of IFN-α in response to PRRSV exposure. PRRSV inhibition of IFN-α responses from enriched pDC stimulated by CpG oligodeoxynucleotides was weak or absent. VR-2332, the prototype genotype 2 PRRSV, only suppressed the responses by 34%, and the highest level of suppression (51%) was induced by a Chinese highly pathogenic PRRSV isolate. Taken together, these findings demonstrate that pDC respond to PRRSV and suggest that suppressive activities on pDC, if any, are moderate and strain-dependent. Thus, pDC may be a source of systemic IFN-α responses reported in PRRSV-infected animals, further contributing to the puzzling immunopathogenesis of PRRS. © 2013 Baumann et al.; licensee BioMed Central Ltd.

Casaubon J.,University of Bern | Chaignat V.,Institute of Virology and Immunoprophylaxis IVI | Vogt H.-R.,University of Bern | Michel A.O.,University of Bern | And 2 more authors.
BMC Veterinary Research | Year: 2013

Background: In 2006, bluetongue virus serotype 8 (BTV-8) was detected for the first time in central Europe. Measures to control the infection in livestock were implemented in Switzerland but the question was raised whether free-ranging wildlife could be a maintenance host for BTV-8. Furthermore Toggenburg orbivirus (TOV), considered as a potential 25th BTV serotype, was detected in 2007 in domestic goats in Switzerland and wild ruminants were considered a potential source of infection. To assess prevalences of BTV-8 and TOV infections in wildlife, we conducted a serological and virological survey in red deer, roe deer, Alpine chamois and Alpine ibex between 2009 and 2011. Because samples originating from wildlife carcasses are often of poor quality, we also documented the influence of hemolysis on test results, and evaluated the usefulness of confirmatory tests. Results: Ten out of 1,898 animals (0.5%, 95% confidence interval 0.3-1.0%) had detectable antibodies against BTV-8 and BTV-8 RNA was found in two chamois and one roe deer (0.3%, 0.1-0.8%). Seroprevalence was highest among red deer, and the majority of positive wild animals were sampled close to areas where outbreaks had been reported in livestock. Most samples were hemolytic and the range of the optical density percentage values obtained in the screening test increased with increasing hemolysis. Confirmatory tests significantly increased specificity of the testing procedure and proved to be applicable even on poor quality samples. Nearly all samples confirmed as positive had an optical density percentage value greater than 50% in the ELISA screening. Conclusions: Prevalence of BTV-8 infection was low, and none of the tested animals were positive for TOV. Currently, wild ruminants are apparently not a reservoir for these viruses in Switzerland. However, we report for the first time BTV-8 RNA in Alpine chamois. This animal was found at high altitude and far from a domestic outbreak, which suggests that the virus could spread into/through the Alps. Regarding testing procedures, hemolysis did not significantly affect test results but confirmatory tests proved to be necessary to obtain reliable prevalence estimates. The cut-off value recommended by the manufacturer for the screening test was applicable for wildlife samples. © 2013 Casaubon et al.; licensee BioMed Central Ltd.

Husser L.,Institute of Virology and Immunoprophylaxis IVI | Alves M.P.,University of Bern | Ruggli N.,Institute of Virology and Immunoprophylaxis IVI | Summerfield A.,Institute of Virology and Immunoprophylaxis IVI
Virus Research | Year: 2011

Pathogen recognition receptors are essential for antiviral host immune responses. These specialized receptors detect conserved viral compounds and induce type I interferons (IFN) and pro-inflammatory cytokines. Here we evaluated the contribution of RIG-I, MDA-5 and TLR3 to the recognition of classical swine fever (CSFV), foot-and-mouth disease virus (FMDV), vesicular stomatitis virus (VSV) and influenza A virus (IAV) to IFN-β responses in the porcine epithelial cell line PK-15. To this end, we identified porcine gene specific small interfering RNA sequences and employed a lentivirus (LV)-based system to deliver the corresponding short hairpin RNA. With this, gene knockdown cell lines were created and tested with regard to the knockdown levels over time and following IFN-β stimulation. During several passages of the transduced cells, the expression of both the reporter gene eGFP and the reduced RNA levels of the targeted gene were stable, although the latter was relatively variable. IFN-β induced IFN-responsive genes such as RIG-I, but the levels of the silenced cell line remained reduced compared to the control cells. Based on virus-induced IFN-β mRNA responses, our results indicate that in PK-15 cells FMDV-detection is solely mediated by MDA-5, whereas VSV and IAV are mainly detected by RIG-I with a minor contribution of MDA-5, and CSFV is sensed by MDA-5, RIG-I and TLR3. © 2011 Elsevier B.V.

Husser L.,Institute of Virology and Immunoprophylaxis IVI | Ruggli N.,Institute of Virology and Immunoprophylaxis IVI | Summerfield A.,Institute of Virology and Immunoprophylaxis IVI
Journal of Interferon and Cytokine Research | Year: 2012

A hallmark of acute classical swine fever is the high interferon (IFN)-α levels found in the serum early after infection, followed by an inflammatory cytokine storm. Plasmacytoid dendritic cells (pDCs) represent the only known cell type that produces IFN-α upon classical swine fever virus (CSFV) infection in vitro. In primary target cells of the virus the viral protein Npro inhibits the induction of type I IFN via the degradation of IRF3. We hypothesized that the early systemic pDC-derived IFN-α response sensitizes immune cells for enhanced responsiveness and augment cytokine responses after CSFV infection through the upregulation of IRF7. Therefore, bone marrow-derived granulocyte macrophage-colony stimulating factor (GM-CSF)-induced DCs, were pretreated with IFN-β or conditioned medium from CSFV-activated enriched pDC, and expression of the pro-inflammatory cytokines interleukin (IL)-1β, IL-6, and IFN-α was assessed after infection with wild-type CSFV and with an Npro mutant [Npro(D 136N)] unable to interact with IRF3 and IRF7. While type I IFN treatment sensitized the DCs for enhanced IFN and cytokine responses after stimulation with influenza virus, lipopolysaccharide or poly(I):poly(C), this was not observed for CSFV. In contrast, the Npro(D136N) mutant CSFV induced elevated IFN-α responses in type I IFN-pretreated GM-CSF DCs. These results indicate that CSFV has evolved to prevent type I IFN sensitization in infected cells through the action of the Npro. © Copyright 2012, Mary Ann Liebert, Inc. 2012.

Suter R.,Institute of Virology and Immunoprophylaxis IVI | Summerfield A.,Institute of Virology and Immunoprophylaxis IVI | Thomann-Harwood L.J.,Institute of Virology and Immunoprophylaxis IVI | McCullough K.C.,Institute of Virology and Immunoprophylaxis IVI | And 2 more authors.
Vaccine | Year: 2011

Virus replicon particles (VRP) are genetically engineered infectious virions incapable of generating progeny virus due to partial or complete deletion of at least one structural gene. VRP fulfil the criteria of a safe vaccine and gene delivery system. With VRP derived from classical swine fever virus (CSF-VRP), a single intradermal vaccination protects from disease. Spreading of the challenge virus in the host is however not completely abolished. Parameters that are critical for immunogenicity of CSF-VRP are not well characterized. Considering the importance of type I interferon (IFN-α/β) to immune defence development, we generated IFN-α/β-inducing VRP to determine how this would influence vaccine efficacy. We also evaluated the effect of co-expressing granulocyte macrophage colony-stimulating factor (GM-CSF) in the vaccine context. The VRP were capable of long-term replication in cell culture despite the presence of IFN-α/β. In vivo, RNA replication was essential for the induction of an immune response. IFN-α/β-inducing and GM-CSF-expressing CSF-VRP were similar to unmodified VRP in terms of antibody and peripheral T-cell responses, and in reducing the blood levels of challenge virus RNA. Importantly, the IFN-α/β-inducing VRP did show increased efficacy over the unmodified VRP in terms of B-cell and T-cell responses, when tested with secondary immune responses by in vitro restimulation assay. © 2010 Elsevier Ltd.

Liniger M.,Institute of Virology and Immunoprophylaxis IVI | Summerfield A.,Institute of Virology and Immunoprophylaxis IVI | Ruggli N.,Institute of Virology and Immunoprophylaxis IVI
PLoS ONE | Year: 2012

Chickens lack the retinoic acid-inducible gene I (RIG-I) and sense avian influenza virus (AIV) infections by means of the melanoma differentiation-associated gene 5 product (chMDA5). Plasmid-driven expression of the N-terminal half of chMDA5 containing the caspase activation and recruitment domains [chMDA5(1-483)] triggers interferon-β responses in chicken cells. We hypothesized that mimicking virus infection by chMDA5(1-483) expression may enhance vaccine-induced adaptive immunity. In order to test this, the potential genetic adjuvant properties of chMDA5(1-483) were evaluated in vivo in combination with a suboptimal quantity of a plasmid DNA vaccine expressing haemagglutinin (HA) of H5N1 AIV. Co-administration of the HA plasmid with plasmid DNA for chMDA5(1-483) expression resulted in approximately 10-fold higher HA-specific antibody responses than injection of the HA plasmid mixed with empty vector DNA as control. Accordingly, compared with HA DNA vaccination alone, the chMDA5(1-483)-adjuvanted HA DNA vaccine mediated enhanced protection against a lethal H5N1 challenge infection in chickens, with reduced clinical signs and cloacal virus shedding. These data demonstrate that innate immune activation by expression of signaling domains of RIG-I-like receptors can be exploited to enhance vaccine efficacy. © 2012 Liniger et al.

Ottiger H.-P.,Institute of Virology and Immunoprophylaxis IVI
Biologicals | Year: 2010

The European Pharmacopoeia (Ph. Eur.) requires avian viral vaccines to be free of adventitious agents. Purity testing is an essential quality requirement of immunological veterinary medicinal products (IVMPs) and testing for extraneous agents includes monitoring for many different viruses. Conventional virus detection methods include serology or virus culture, however, molecular tests have become a valid alternative testing method. Nucleic acid testing (NAT) is fast, highly sensitive and has a higher degree of discrimination than conventional approaches. These advantages have led to the development and standardization of polymerase chain reaction (PCR) assays for the detection of avian leucosis virus, avian orthoreovirus, infectious bursal disease virus, infectious bronchitis virus, Newcastle disease virus, infectious laryngotracheitis virus, influenza A virus, Marek's disease virus, turkey rhinotracheitis virus, egg drop syndrome virus, chicken anaemia virus, avian adenovirus and avian encephalomyelitis virus. This paper reviews the development, standardization and assessment of PCR for extraneous agent testing in IVMPs with examples from an Official Medicines Control Laboratory (OMCL). © 2010 The International Association for Biologicals.

Zimmer G.,Institute of Virology and Immunoprophylaxis IVI
Viruses | Year: 2010

RNA replicons are derived from either positive- or negative-strand RNA viruses. They represent disabled virus vectors that are not only avirulent, but also unable to revert to virulence. Due to autonomous RNA replication, RNA replicons are able to drive high level, cytosolic expression of recombinant antigens stimulating both the humoral and the cellular branch of the immune system. This review provides an update on the available literature covering influenza virus vaccines based on RNA replicons. The pros and cons of these vaccine strategies will be discussed and future perspectives disclosed. © 2010 by the authors.

Mueller M.,Institute of Virology and Immunoprophylaxis IVI | Renzullo S.,Institute of Virology and Immunoprophylaxis IVI | Brooks R.,Institute of Virology and Immunoprophylaxis IVI | Ruggli N.,Institute of Virology and Immunoprophylaxis IVI | Hofmann M.A.,Institute of Virology and Immunoprophylaxis IVI
PLoS ONE | Year: 2010

Since the advent of highly pathogenic variants of avian influenza virus (HPAIV), the main focus of avian influenza research has been the characterization and detection of HPAIV hemagglutinin (HA) from H5 and H7 subtypes. However, due to the high mutation and reassortation rate of influenza viruses, in theory any influenza strain may acquire increased pathogenicity irrespective of its subtype. A comprehensive antigenic characterization of influenza viruses encompassing all 16 HA and 9 neuraminidase subtypes will provide information useful for the design of differential diagnostic tools, and possibly, vaccines. We have expressed recombinant HA proteins from 3 different influenza virus HA subtypes in the baculovirus system. These proteins were used to generate polyclonal rabbit antisera, which were subsequently employed in epitope scanning analysis using peptide libraries spanning the entire HA. Here, we report the identification and characterization of linear, HA subtype-specific as well as inter subtype-conserved epitopes along the HA proteins. Selected subtype-specific epitopes were shown to be suitable for the differentiation of anti-HA antibodies in an ELISA. © 2010 Mueller et al.

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