Merkler, Doron

[["dc.bibliographiccitation.artnumber","e51"],["dc.bibliographiccitation.firstpage","0501"],["dc.bibliographiccitation.issue","6"],["dc.bibliographiccitation.journal","PLoS Pathogens"],["dc.bibliographiccitation.lastpage","0512"],["dc.bibliographiccitation.volume","2"],["dc.contributor.author","Bergthaler, Andreas"],["dc.contributor.author","Gerber, Nicolas U."],["dc.contributor.author","Merkler, Doron"],["dc.contributor.author","Horvath, Edit"],["dc.contributor.author","de la Torre, Juan Carlos"],["dc.contributor.author","Pinschewer, Daniel D."],["dc.date.accessioned","2019-07-09T11:53:46Z"],["dc.date.available","2019-07-09T11:53:46Z"],["dc.date.issued","2006-06-02"],["dc.description.abstract","Arenaviruses such as Lassa fever virus cause significant mortality in endemic areas and represent potential bioterrorist weapons. The occurrence of arenaviral hemorrhagic fevers is largely confined to Third World countries with a limited medical infrastructure, and therefore live-attenuated vaccines have long been sought as a method of choice for prevention. Yet their rational design and engineering have been thwarted by technical limitations. In addition, viral genes had not been identified that are needed to cause disease but can be deleted or substituted to generate live-attenuated vaccine strains. Lymphocytic choriomeningitis virus, the prototype arenavirus, induces cell-mediated immunity against Lassa fever virus, but its safety for humans is unclear and untested. Using this virus model, we have developed the necessary methodology to efficiently modify arenavirus genomes and have exploited these techniques to identify an arenaviral Achilles' heel suitable for targeting in vaccine design. Reverse genetic exchange of the viral glycoprotein for foreign glycoproteins created attenuated vaccine strains that remained viable although unable to cause disease in infected mice. This phenotype remained stable even after extensive propagation in immunodeficient hosts. Nevertheless, the engineered viruses induced T cell–mediated immunity protecting against overwhelming systemic infection and severe liver disease upon wild-type virus challenge. Protection was established within 3 to 7 d after immunization and lasted for approximately 300 d. The identification of an arenaviral Achilles' heel demonstrates that the reverse genetic engineering of live-attenuated arenavirus vaccines is feasible. Moreover, our findings offer lymphocytic choriomeningitis virus or other arenaviruses expressing foreign glycoproteins as promising live-attenuated arenavirus vaccine candidates."],["dc.identifier.doi","10.1371/journal.ppat.0020051"],["dc.identifier.fs","53953"],["dc.identifier.pmid","16751848"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/8004"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/60491"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation.issn","1553-7366"],["dc.rights","CC BY 2.5"],["dc.rights.uri","https://creativecommons.org/licenses/by/2.5"],["dc.title","Envelope Exchange for the Generation of Live-Attenuated Arenavirus Vaccines"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e1000836"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","PLoS Pathogens"],["dc.bibliographiccitation.volume","6"],["dc.contributor.author","Flatz, Lukas"],["dc.contributor.author","Rieger, Toni"],["dc.contributor.author","Merkler, Doron"],["dc.contributor.author","Bergthaler, Andreas"],["dc.contributor.author","Regen, Tommy"],["dc.contributor.author","Schedensack, Mariann"],["dc.contributor.author","Bestmann, Lukas"],["dc.contributor.author","Verschoor, Admar"],["dc.contributor.author","Kreutzfeldt, Mario"],["dc.contributor.author","Brueck, Wolfgang"],["dc.contributor.author","Hanisch, Uwe-Karsten"],["dc.contributor.author","Guenther, Stephan"],["dc.contributor.author","Pinschewer, Daniel D."],["dc.date.accessioned","2018-11-07T08:45:46Z"],["dc.date.available","2018-11-07T08:45:46Z"],["dc.date.issued","2010"],["dc.description.abstract","Lassa virus (LASV), the causative agent of Lassa fever (LF), is endemic in West Africa, accounting for substantial morbidity and mortality. In spite of ongoing research efforts, LF pathogenesis and mechanisms of LASV immune control remain poorly understood. While normal laboratory mice are resistant to LASV, we report that mice expressing humanized instead of murine MHC class I (MHC-I) failed to control LASV infection and develop severe LF. Infection of MHC-I knockout mice confirmed a key role for MHC-I-restricted T cell responses in controlling LASV. Intriguingly we found that T cell depletion in LASV-infected HHD mice prevented disease, irrespective of high-level viremia. Widespread activation of monocyte/macrophage lineage cells, manifest through inducible NO synthase expression, and elevated IL-12p40 serum levels indicated a systemic inflammatory condition. The absence of extensive monocyte/macrophage activation in T cell-depleted mice suggested that T cell responses contribute to deleterious innate inflammatory reactions and LF pathogenesis. Our observations in mice indicate a dual role for T cells, not only protecting from LASV, but also enhancing LF pathogenesis. The possibility of T cell-driven enhancement and immunopathogenesis should be given consideration in future LF vaccine development."],["dc.identifier.doi","10.1371/journal.ppat.1000836"],["dc.identifier.isi","000277720400040"],["dc.identifier.pmid","20360949"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/6892"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/20525"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Public Library Science"],["dc.relation.issn","1553-7366"],["dc.rights","CC BY 2.5"],["dc.rights.uri","https://creativecommons.org/licenses/by/2.5"],["dc.title","T Cell-Dependence of Lassa Fever Pathogenesis"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","535"],["dc.bibliographiccitation.issue","6"],["dc.bibliographiccitation.journal","CNS Drugs"],["dc.bibliographiccitation.lastpage","558"],["dc.bibliographiccitation.volume","28"],["dc.contributor.author","Du Pasquier, Renaud A."],["dc.contributor.author","Pinschewer, Daniel D."],["dc.contributor.author","Merkler, Doron"],["dc.date.accessioned","2018-11-07T09:39:02Z"],["dc.date.available","2018-11-07T09:39:02Z"],["dc.date.issued","2014"],["dc.description.abstract","Multiple sclerosis (MS) is a life-long, potentially debilitating disease of the central nervous system (CNS). MS is considered to be an immune-mediated disease, and the presence of autoreactive peripheral lymphocytes in CNS compartments is believed to be critical in the process of demyelination and tissue damage in MS. Although MS is not currently a curable disease, several disease-modifying therapies (DMTs) are now available, or are in development. These DMTs are all thought to primarily suppress autoimmune activity within the CNS. Each therapy has its own mechanism of action (MoA) and, as a consequence, each has a different efficacy and safety profile. Neurologists can now select therapies on a more individual, patient-tailored basis, with the aim of maximizing potential for long-term efficacy without interruptions in treatment. The MoA and clinical profile of MS therapies are important considerations when making that choice or when switching therapies due to suboptimal disease response. This article therefore reviews the known and putative immunological MoAs alongside a summary of the clinical profile of therapies approved for relapsing forms of MS, and those in late-stage development, based on published data from pivotal randomized, controlled trials."],["dc.description.sponsorship","Novartis Pharma AG, Basel, Switzerland"],["dc.identifier.doi","10.1007/s40263-014-0160-8"],["dc.identifier.isi","000344613300005"],["dc.identifier.pmid","24723124"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/10243"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/33196"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Adis Int Ltd"],["dc.relation.issn","1179-1934"],["dc.relation.issn","1172-7047"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","Immunological Mechanism of Action and Clinical Profile of Disease-Modifying Treatments in Multiple Sclerosis"],["dc.type","review"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e1000080"],["dc.bibliographiccitation.firstpage","789"],["dc.bibliographiccitation.issue","4"],["dc.bibliographiccitation.journal","PLoS Biology"],["dc.bibliographiccitation.lastpage","799"],["dc.bibliographiccitation.volume","7"],["dc.contributor.author","Bergthaler, Andreas"],["dc.contributor.author","Flatz, Lukas"],["dc.contributor.author","Verschoor, Admar"],["dc.contributor.author","Hegazy, Ahmed N."],["dc.contributor.author","Holdener, Martin"],["dc.contributor.author","Fink, Katja"],["dc.contributor.author","Eschli, Bruno"],["dc.contributor.author","Merkler, Doron"],["dc.contributor.author","Sommerstein, Rami"],["dc.contributor.author","Horvath, Edit"],["dc.contributor.author","Fernandez, Marylise"],["dc.contributor.author","Fitsche, Andre"],["dc.contributor.author","Senn, Beatrice M."],["dc.contributor.author","Verbeek, J. Sjef"],["dc.contributor.author","Odermatt, Bernhard"],["dc.contributor.author","Siegrist, Claire-Anne"],["dc.contributor.author","Pinschewer, Daniel D."],["dc.date.accessioned","2018-11-07T08:31:25Z"],["dc.date.available","2018-11-07T08:31:25Z"],["dc.date.issued","2009"],["dc.description.abstract","CD8 T cells are recognized key players in control of persistent virus infections, but increasing evidence suggests that assistance from other immune mediators is also needed. Here, we investigated whether specific antibody responses contribute to control of lymphocytic choriomeningitis virus (LCMV), a prototypic mouse model of systemic persistent infection. Mice expressing transgenic B cell receptors of LCMV-unrelated specificity, and mice unable to produce soluble immunoglobulin M (IgM) exhibited protracted viremia or failed to resolve LCMV. Virus control depended on immunoglobulin class switch, but neither on complement cascades nor on Fc receptor gamma chain or Fc gamma receptor IIB. Cessation of viremia concurred with the emergence of viral envelope-specific antibodies, rather than with neutralizing serum activity, and even early nonneutralizing IgM impeded viral persistence. This important role for virus-specific antibodies may be similarly underappreciated in other primarily T cell-controlled infections such as HIV and hepatitis C virus, and we suggest this contribution of antibodies be given consideration in future strategies for vaccination and immunotherapy."],["dc.identifier.doi","10.1371/journal.pbio.1000080"],["dc.identifier.isi","000266500000008"],["dc.identifier.pmid","19355789"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/5808"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/17118"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Public Library Science"],["dc.relation.issn","1544-9173"],["dc.rights","CC BY 2.5"],["dc.rights.uri","https://creativecommons.org/licenses/by/2.5"],["dc.title","Impaired Antibody Response Causes Persistence of Prototypic T Cell-Contained Virus"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]