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Search Results: 1 - 10 of 694388 matches for " P. J. M. Rottier "
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Retargeting of Viruses to Generate Oncolytic Agents
M. H. Verheije,P. J. M. Rottier
Advances in Virology , 2012, DOI: 10.1155/2012/798526
Abstract: Oncolytic virus therapy is based on the ability of viruses to effectively infect and kill tumor cells without destroying the normal tissues. While some viruses seem to have a natural preference for tumor cells, most viruses require the modification of their tropism to specifically enter and replicate in such cells. This review aims to describe the transductional targeting strategies currently employed to specifically redirect viruses towards surface receptors on tumor cells. Three major strategies can be distinguished; they involve (i) the incorporation of new targeting specificity into a viral surface protein, (ii) the incorporation of a scaffold into a viral surface protein to allow the attachment of targeting moieties, and (iii) the use of bispecific adapters to mediate targeting of a virus to a specified moiety on a tumor cell. Of each strategy key features, advantages and limitations are discussed and examples are given. Because of their potential to cause sustained, multiround infection—a desirable characteristic for eradicating tumors—particular attention is given to viruses engineered to become self-targeted by the genomic expression of a bispecific adapter protein. 1. Introduction Cancer is one of the major health problems of our times. Though the prognosis for people diagnosed with, at least some forms of, cancer has increased considerably, it is more typical a disease of which treatment is initially effective, to be followed later by an irreversible and eventually fatal relapse. Already for decades, cancer treatment is based on three types of approaches: surgery, radio-, and chemotherapy. While the scientific and technological advancements have improved the efficacy of each of these classical approaches tremendously, and while also some new therapies have evolved including immunotherapy, the treatments apparently fail to eradicate all residual tumor cells or metastases completely. Therefore, additional means are urgently required to support or replace the conventional therapies. Hence, a variety of new approaches is currently being explored, one of which is based on the use of viruses. Oncolytic viruses are defined by their ability to specifically kill tumor cells, but to leave the normal tissues unharmed. Their most characteristic features, thus, are their target specificity and their cytolytic capacity. Ideally, they exhibit additional features including, but not limited to, a high reproductive capacity in vivo, the ability to recruit uninfected neighboring cells (syncytia formation), the ability to infect both dividing and nondividing
A Single Immunization with Soluble Recombinant Trimeric Hemagglutinin Protects Chickens against Highly Pathogenic Avian Influenza Virus H5N1
Lisette A. H. M. Cornelissen,Robert P. de Vries,Els A. de Boer-Luijtze,Alan Rigter,Peter J. M. Rottier,Cornelis A. M. de Haan
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0010645
Abstract: The highly pathogenic avian influenza (HPAI) virus H5N1 causes multi-organ disease and death in poultry, resulting in significant economic losses in the poultry industry. In addition, it poses a major public health threat as it can be transmitted directly from infected poultry to humans with very high (60%) mortality rate. Effective vaccination against HPAI H5N1 would protect commercial poultry and would thus provide an important control measure by reducing the likelihood of bird-to-bird and bird-to-human transmission.
CD200 Receptor Controls Sex-Specific TLR7 Responses to Viral Infection
Guruswamy Karnam equal contributor,Tomasz P. Rygiel equal contributor,Matthijs Raaben,Guy C. M. Grinwis,Frank E. Coenjaerts,Maaike E. Ressing,Peter J. M. Rottier,Cornelis A. M. de Haan,Linde Meyaard
PLOS Pathogens , 2012, DOI: 10.1371/journal.ppat.1002710
Abstract: Immunological checkpoints, such as the inhibitory CD200 receptor (CD200R), play a dual role in balancing the immune system during microbial infection. On the one hand these inhibitory signals prevent excessive immune mediated pathology but on the other hand they may impair clearance of the pathogen. We studied the influence of the inhibitory CD200-CD200R axis on clearance and pathology in two different virus infection models. We find that lack of CD200R signaling strongly enhances type I interferon (IFN) production and viral clearance and improves the outcome of mouse hepatitis corona virus (MHV) infection, particularly in female mice. MHV clearance is known to be dependent on Toll like receptor 7 (TLR7)-mediated type I IFN production and sex differences in TLR7 responses previously have been reported for humans. We therefore hypothesize that CD200R ligation suppresses TLR7 responses and that release of this inhibition enlarges sex differences in TLR7 signaling. This hypothesis is supported by our findings that in vivo administration of synthetic TLR7 ligand leads to enhanced type I IFN production, particularly in female Cd200?/? mice and that CD200R ligation inhibits TLR7 signaling in vitro. In influenza A virus infection we show that viral clearance is determined by sex but not by CD200R signaling. However, absence of CD200R in influenza A virus infection results in enhanced lung neutrophil influx and pathology in females. Thus, CD200-CD200R and sex are host factors that together determine the outcome of viral infection. Our data predict a sex bias in both beneficial and pathological immune responses to virus infection upon therapeutic targeting of CD200-CD200R.
J. Rottier,P.S. Kruger,P.J. Pretorius
South African Journal of Industrial Engineering , 2012,
Abstract: The purpose of this paper is to facilitate systematic management of the design of Enterprises throughout their life-cycle by identifying the events (requirements) which should initiate (rejdesign. It identifies the high level capabilities required to execute the design and also provides suggestions about the allocation of design responsibilities to organisational elements.
Protective Efficacy of Newcastle Disease Virus Expressing Soluble Trimeric Hemagglutinin against Highly Pathogenic H5N1 Influenza in Chickens and Mice
Lisette A. H. M. Cornelissen, Olav S. de Leeuw, Mirriam G. Tacken, Heleen C. Klos, Robert P. de Vries, Els A. de Boer-Luijtze, Diana J. van Zoelen-Bos, Alan Rigter, Peter J. M. Rottier, Rob J. M. Moormann, Cornelis A. M. de Haan
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0044447
Abstract: Background Highly pathogenic avian influenza virus (HPAIV) causes a highly contagious often fatal disease in poultry, resulting in significant economic losses in the poultry industry. HPAIV H5N1 also poses a major public health threat as it can be transmitted directly from infected poultry to humans. One effective way to combat avian influenza with pandemic potential is through the vaccination of poultry. Several live vaccines based on attenuated Newcastle disease virus (NDV) that express influenza hemagglutinin (HA) have been developed to protect chickens or mammalian species against HPAIV. However, the zoonotic potential of NDV raises safety concerns regarding the use of live NDV recombinants, as the incorporation of a heterologous attachment protein may result in the generation of NDV with altered tropism and/or pathogenicity. Methodology/Principal Findings In the present study we generated recombinant NDVs expressing either full length, membrane-anchored HA of the H5 subtype (NDV-H5) or a soluble trimeric form thereof (NDV-sH53). A single intramuscular immunization with NDV-sH53 or NDV-H5 fully protected chickens against disease after a lethal challenge with H5N1 and reduced levels of virus shedding in tracheal and cloacal swabs. NDV-sH53 was less protective than NDV-H5 (50% vs 80% protection) when administered via the respiratory tract. The NDV-sH53 was ineffective in mice, regardless of whether administered oculonasally or intramuscularly. In this species, NDV-H5 induced protective immunity against HPAIV H5N1, but only after oculonasal administration, despite the poor H5-specific serum antibody response it elicited. Conclusions/Significance Although NDV expressing membrane anchored H5 in general provided better protection than its counterpart expressing soluble H5, chickens could be fully protected against a lethal challenge with H5N1 by using the latter NDV vector. This study thus provides proof of concept for the use of recombinant vector vaccines expressing a soluble form of a heterologous viral membrane protein. Such vectors may be advantageous as they preclude the incorporation of heterologous membrane proteins into the viral vector particles.
Competition between Influenza A Virus Genome Segments
Ivy Widjaja,Erik de Vries,Peter J. M. Rottier,Cornelis A. M. de Haan
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0047529
Abstract: Influenza A virus (IAV) contains a segmented negative-strand RNA genome. How IAV balances the replication and transcription of its multiple genome segments is not understood. We developed a dual competition assay based on the co-transfection of firefly or Gaussia luciferase-encoding genome segments together with plasmids encoding IAV polymerase subunits and nucleoprotein. At limiting amounts of polymerase subunits, expression of the firefly luciferase segment was negatively affected by the presence of its Gaussia luciferase counterpart, indicative of competition between reporter genome segments. This competition could be relieved by increasing or decreasing the relative amounts of firefly or Gaussia reporter segment, respectively. The balance between the luciferase expression levels was also affected by the identity of the untranslated regions (UTRs) as well as segment length. In general it appeared that genome segments displaying inherent higher expression levels were more efficient competitors of another segment. When natural genome segments were tested for their ability to suppress reporter gene expression, shorter genome segments generally reduced firefly luciferase expression to a larger extent, with the M and NS segments having the largest effect. The balance between different reporter segments was most dramatically affected by the introduction of UTR panhandle-stabilizing mutations. Furthermore, only reporter genome segments carrying these mutations were able to efficiently compete with the natural genome segments in infected cells. Our data indicate that IAV genome segments compete for available polymerases. Competition is affected by segment length, coding region, and UTRs. This competition is probably most apparent early during infection, when limiting amounts of polymerases are present, and may contribute to the regulation of segment-specific replication and transcription.
Biogenesis and Dynamics of the Coronavirus Replicative Structures
Marne C. Hagemeijer,Peter J.M. Rottier,Cornelis A.M. de Haan
Viruses , 2012, DOI: 10.3390/v4113245
Abstract: Coronaviruses are positive-strand RNA viruses that are important infectious agents of both animals and humans. A common feature among positive-strand RNA viruses is their assembly of replication-transcription complexes in association with cytoplasmic membranes. Upon infection, coronaviruses extensively rearrange cellular membranes into organelle-like replicative structures that consist of double-membrane vesicles and convoluted membranes to which the nonstructural proteins involved in RNA synthesis localize. Double-stranded RNA, presumably functioning as replicative intermediate during viral RNA synthesis, has been detected at the double-membrane vesicle interior. Recent studies have provided new insights into the assembly and functioning of the coronavirus replicative structures. This review will summarize the current knowledge on the biogenesis of the replicative structures, the membrane anchoring of the replication-transcription complexes, and the location of viral RNA synthesis, with particular focus on the dynamics of the coronavirus replicative structures and individual replication-associated proteins.
Manipulation of the Porcine Epidemic Diarrhea Virus Genome Using Targeted RNA Recombination
Chunhua Li, Zhen Li, Yong Zou, Oliver Wicht, Frank J. M. van Kuppeveld, Peter J. M. Rottier, Berend Jan Bosch
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0069997
Abstract: Porcine epidemic diarrhea virus (PEDV) causes severe economic losses in the swine industry in China and other Asian countries. Infection usually leads to an acute, often lethal diarrhea in piglets. Despite the impact of the disease, no system is yet available to manipulate the viral genome which has severely hampered research on this virus until today. We have established a reverse genetics system for PEDV based on targeted RNA recombination that allows the modification of the 3′-end of the viral genome, which encodes the structural proteins and the ORF3 protein. Using this system, we deleted the ORF3 gene entirely from the viral genome and showed that the ORF3 protein is not essential for replication of the virus in vitro. In addition, we inserted heterologous genes (i.e. the GFP and Renilla luciferase genes) at two positions in the viral genome, either as an extra expression cassette or as a replacement for the ORF3 gene. We demonstrated the expression of both GFP and Renilla luciferase as well as the application of these viruses by establishing a convenient and rapid virus neutralization assay. The new PEDV reverse genetics system will enable functional studies of the structural proteins and the accessory ORF3 protein and will allow the rational design and development of next generation PEDV vaccines.
Mouse Hepatitis Coronavirus RNA Replication Depends on GBF1-Mediated ARF1 Activation
Monique H. Verheije,Matthijs Raaben,Muriel Mari,Eddie G. te Lintelo,Fulvio Reggiori,Frank J. M. van Kuppeveld,Peter J. M. Rottier,Cornelis A. M. de Haan
PLOS Pathogens , 2008, DOI: 10.1371/journal.ppat.1000088
Abstract: Coronaviruses induce in infected cells the formation of double membrane vesicles, which are the sites of RNA replication. Not much is known about the formation of these vesicles, although recent observations indicate an important role for the endoplasmic reticulum in the formation of the mouse hepatitis coronavirus (MHV) replication complexes (RCs). We now show that MHV replication is sensitive to brefeldin A (BFA). Consistently, expression of a dominant-negative mutant of ARF1, known to mimic the action of the drug, inhibited MHV infection profoundly. Immunofluorescence analysis and quantitative electron microscopy demonstrated that BFA did not block the formation of RCs per se, but rather reduced their number. MHV RNA replication was not sensitive to BFA in MDCK cells, which are known to express the BFA-resistant guanine nucleotide exchange factor GBF1. Accordingly, individual knockdown of the Golgi-resident targets of BFA by transfection of small interfering RNAs (siRNAs) showed that GBF1, but not BIG1 or BIG2, was critically involved in MHV RNA replication. ARF1, the cellular effector of GBF1, also appeared to be involved in MHV replication, as siRNAs targeting this small GTPase inhibited MHV infection significantly. Collectively, our results demonstrate that GBF1-mediated ARF1 activation is required for efficient MHV RNA replication and reveal that the early secretory pathway and MHV replication complex formation are closely connected.
A Protective and Safe Intranasal RSV Vaccine Based on a Recombinant Prefusion-Like Form of the F Protein Bound to Bacterium-Like Particles
Alan Rigter, Ivy Widjaja, Hanneke Versantvoort, Frank E. J. Coenjaerts, Maarten van Roosmalen, Kees Leenhouts, Peter J. M. Rottier, Bert Jan Haijema, Cornelis A. M. de Haan
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0071072
Abstract: Respiratory syncytial virus (RSV) is an important cause of respiratory tract disease in infants and the elderly. Currently, no licensed vaccine against RSV is available. Here we describe the development of a safe and effective intranasal subunit vaccine that is based on recombinant fusion (F) protein bound to the surface of immunostimulatory bacterium-like particles (BLPs) derived from the food-grade bacterium Lactococcus lactis. Different variants of F were analyzed with respect to their conformation and reactivity with neutralizing antibodies, assuming that F proteins mimicking the metastable prefusion form of RSV F expose a more extensive and relevant epitope repertoire than F proteins corresponding to the postfusion structure. Our results indicate that the recombinant soluble ectodomain of RSV F readily adopts a postfusion conformation, generation of which cannot be prevented by C-terminal addition of a trimerization motif, but whose formation is prevented by mutation of the two furin cleavage sites in F. While the putative postfusion form of F is recognized well by the monoclonal antibody Palivizumab, this is much less so for the more potently neutralizing, prefusion-specific antibodies D25 and AM22. Both addition of the trimerization motif and mutation of the furin cleavage sites increased the reactivity of F with D25 and AM22, with the highest reactivity being observed for F proteins in which both these features were combined. Intranasal vaccination of mice or cotton rats with BLPs loaded with this latter prefusion-like F protein (BLP-F), resulted in the potent induction of F-specific immunoglobulins and in significantly decreased virus titers in the lungs upon RSV challenge. Moreover, and in contrast to animals vaccinated with formalin-inactivated RSV, animals that received BLP-F exhibited high levels of F-specific secretory IgA in the nose and RSV-neutralizing antibodies in sera, but did not show symptoms of enhanced disease after challenge with RSV.
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