Christopher Jakobs
University Hospital Bonn
Network
Latest external collaboration on country level. Dive into details by clicking on the dots.
Publication
Featured researches published by Christopher Jakobs.
PLOS ONE | 2013
Cristina Amparo Hagmann; Anna Maria Herzner; Zeinab Abdullah; Thomas Zillinger; Christopher Jakobs; Christine Schuberth; Christoph Coch; Paul G. Higgins; Hilmar Wisplinghoff; Winfried Barchet; Veit Hornung; Gunther Hartmann; Martin Schlee
The innate immune system senses pathogens by pattern recognition receptors in different cell compartments. In the endosome, bacteria are generally recognized by TLRs; facultative intracellular bacteria such as Listeria, however, can escape the endosome. Once in the cytosol, they become accessible to cytosolic pattern recognition receptors, which recognize components of the bacterial cell wall, metabolites or bacterial nucleic acids and initiate an immune response in the host cell. Current knowledge has been focused on the type I IFN response to Listeria DNA or Listeria-derived second messenger c-di-AMP via the signaling adaptor STING. Our study focused on the recognition of Listeria RNA in the cytosol. With the aid of a novel labeling technique, we have been able to visualize immediate cytosolic delivery of Listeria RNA upon infection. Infection with Listeria as well as transfection of bacterial RNA induced a type-I-IFN response in human monocytes, epithelial cells or hepatocytes. However, in contrast to monocytes, the type-I-IFN response of epithelial cells and hepatocytes was not triggered by bacterial DNA, indicating a STING-independent Listeria recognition pathway. RIG-I and MAVS knock-down resulted in abolishment of the IFN response in epithelial cells, but the IFN response in monocytic cells remained unaffected. By contrast, knockdown of STING in monocytic cells reduced cytosolic Listeria-mediated type-I-IFN induction. Our results show that detection of Listeria RNA by RIG-I represents a non-redundant cytosolic immunorecognition pathway in non-immune cells lacking a functional STING dependent signaling pathway.
Nature Methods | 2013
Eva Bartok; Franz Bauernfeind; Maria G Khaminets; Christopher Jakobs; Brian G. Monks; Katherine A. Fitzgerald; Eicke Latz; Veit Hornung
Measurement of protease activity in living cells or organisms remains a challenging task. We here present a transgene-encoded biosensor that reports the proteolytic activity of caspase-1 in the course of inflammasome activation and that of other proteases in a highly sensitive and specific manner. This protease reporter is based on the biological activity of a pro–interleukin (IL)-1β–Gaussia luciferase (iGLuc) fusion construct, in which pro–IL-1β–dependent formation of protein aggregates renders GLuc enzyme inactive. Cleavage leads to monomerization of this biosensor protein, resulting in a strong gain in luciferase activity. Exchange of the canonical caspase-1 cleavage site in this reporter construct allows the generation of protease biosensors with additional specificities. The high sensitivity, signal-to-background ratio and specificity of the iGLuc system renders it a useful tool to study proteolytic events in mouse and human cells at high throughput and to monitor protease activity in mice in vivo.
PLOS ONE | 2015
Christopher Jakobs; Sven Perner; Veit Hornung
Mice lacking DNase II display a polyarthritis-like disease phenotype that is driven by translocation of self-DNA into the cytoplasm of phagocytic cells, where it is sensed by pattern recognition receptors. While pro-inflammatory gene expression is non-redundantly linked to the presence of STING in these mice, the contribution of the inflammasome pathway has not been explored. To this end, we studied the role of the DNA-sensing inflammasome receptor AIM2 in this self-DNA driven disease model. Arthritis-prone mice lacking AIM2 displayed strongly decreased signs of joint inflammation and associated histopathological findings. This was paralleled with a reduction of caspase-1 activation and pro-inflammatory cytokine production in diseased joints. Interestingly, systemic signs of inflammation that are associated with the lack of DNase II were not dependent on AIM2. Taken together, these data suggest a tissue-specific role for the AIM2 inflammasome as a sensor for endogenous DNA species in the course of a ligand-dependent autoinflammatory condition.
Methods of Molecular Biology | 2013
Christopher Jakobs; Eva Bartok; Andrej Kubarenko; Franz Bauernfeind; Veit Hornung
Immunoblotting for caspase-1 is the gold-standard method of detecting inflammasome activation. In contrast to IL-1β-based readouts, it can be used in an experimental setup independent of de novo gene expression. Here, we present protocols for the preparation and precipitation of supernatant samples containing activated caspase-1 as well as protocols for polyacrylamide gel electrophoresis (PAGE) and protein immunoblotting.
Vaccine | 2017
Emmanuelle Schaedler; Christelle Remy-Ziller; Julie Hortelano; Nadine Kehrer; Marie-Christine Claudepierre; Tanja Gatard; Christopher Jakobs; Xavier Préville; Antoine F. Carpentier; Karola Rittner
TG4010 is an immunotherapeutic vaccine based on Modified Vaccinia virus Ankara (MVA) encoding the human tumor-associated antigen MUC1 and human IL-2. In combination with first-line standard of care chemotherapy in advanced metastatic non-small-cell lung cancer (NSCLC), repeated subcutaneous injection of TG4010 improved progression-free survival in phase 2b clinical trials. In preclinical tumor models, MVATG9931, the research version of TG4010, conferred antigen-specific responses against the weak antigen human MUC1. The combination of a suboptimal dose of MVATG9931 and the type B TLR9 ligand Litenimod (Li28) markedly increased survival in a subcutaneous RMA-MUC1 tumor model compared to the treatment with MVATG9931 or Li28 alone. The requirements for this protection were (i) de novo synthesis of MUC1, (ii) Li28 delivered several hours after MVATG9931 at the same site, (iii) at least two vaccination cycles, and (iv) implantation of MUC1-positive tumor cells in the vicinity to the vaccination site. Subcutaneously injected MVATG9931 allowed transient local gene expression and induced the local accumulation of MCP-1, RANTES, M-CSF, IL-15/IL-15R and IP-10. After repeated injection, CD4+ and CD8+ T lymphocytes, B lymphocytes, NK cells, pDCs, neutrophils, and macrophages accumulated around the injection site, local RANTES levels remained high. Delayed injection of Li28 into this environment, led to further accumulation of macrophages, the secretion of IL-18 and IL-1 beta, and an increase of the percentage of activated CD69+ NK cell. Combination treatment augmented the number of activated CD86+ DCs in the draining lymph nodes and increased the percentage of KLRG1+ CD127-CD8+ T cells at the injection site. In vivo depletion of macrophages around the injection site by Clodronate liposomes reduced local IL-18 levels and diminished survival rates significantly. Thus, sequential administration of MVATG9931 and Li28 improves local innate and adaptive immune defense against tumors, arguing for intratumoral delivery of this peculiar sequential combination therapy.
Journal of Immunology | 2015
Erhan Yakut; Christopher Jakobs; Adriana Peric; Gabriela Michel; Nelli Baal; Gregor Bein; Bernhard Brüne; Veit Hornung; Holger Hackstein
Extracorporeal photopheresis (ECP) is a widely used clinical cell-based therapy exhibiting efficacy in heterogenous immune-mediated diseases such as cutaneous T cell lymphoma, graft-versus-host disease, and organ allograft rejection. Despite its documented efficacy in cancer immunotherapy, little is known regarding the induction of immunostimulatory mediators by ECP. In this article, we show that ECP promotes marked release of the prototypic immunostimulatory cytokine IL-1β. ECP primes IL-1β production and activates IL-1β maturation and release in the context of caspase-1 activation in monocytes and myeloid dendritic cells. Of interest, IL-1β maturation by ECP was fully intact in murine cells deficient in caspase-1, suggesting the predominance of an inflammasome-independent pathway for ECP-dependent IL-1β maturation. Clinically, patient analysis revealed significantly increased IL-1β production in stimulated leukapheresis concentrates and peripheral blood samples after ECP. Collectively, these results provide evidence for promotion of IL-1β production by ECP and offer new insight into the immunostimulatory capacity of ECP.
PLOS ONE | 2018
Christopher Jakobs; Sven Perner; Veit Hornung
[This corrects the article DOI: 10.1371/journal.pone.0131702.].
PMC | 2017
Rebecca Baum; Shrutie Sharma; Jason M. Organ; Christopher Jakobs; Veit Hornung; David B. Burr; Ann Marshak-Rothstein; Katherine A. Fitzgerald; Ellen M. Gravallese
Cytosolic DNA sensors detect microbial DNA and promote type I interferon (IFN) and proinflammatory cytokine production through the adaptor stimulator of IFN genes (STING) to resolve infection. Endogenous DNA also engages the STING pathway, contributing to autoimmune disease. This study sought to identify the role of STING in regulating bone formation and to define the bone phenotype and its pathophysiologic mechanisms in arthritic mice double deficient in DNase II and IFN‐α/β/ω receptor (IFNAR) (DNase II−/−/IFNAR−/− double‐knockout [DKO] mice) compared with controls.
Cancer immunology research | 2017
Jim Barsoum; Marcel Renn; Christine Schuberth; Christopher Jakobs; Anna Schwickart; Martin Schlee; Jasper G. van den Boorn; Gunther Hartmann
We describe a novel immunotherapy approach in which a natural viral defense system is harnessed to stimulate anti-tumor immunity. Cancer immunotherapy has revolutionized oncology in recent years, yet many tumors become resistant or do not respond to current treatments such as checkpoint inhibitors. Stimulation of the innate immune system opens a new therapeutic strategy that could be combined effectively with other immunotherapeutic regimens. The ubiquitously expressed cytosolic RNA receptor retinoic acid inducible gene I (RIG-I) recognizes double-stranded RNA bearing a 59-triphosphate. RIG-I plays a prominent role in antiviral defense. Its activation induces apoptosis preferentially in tumor cells and simultaneously activates the innate immune system via type I interferon (IFN) signaling. We developed an optimized, fully synthetic oligonucleotide, designated RGT100, which is a RIG-I selective ligand. RGT100 activates the RIG-I pathway leading to the induction of cytokines, including IFN-α and IFN-β. The treatment of tumor-bearing mice with RGT100 induced potent anti-tumor activity against large established B16 melanoma and CT26 colon carcinoma tumors. RGT100 also was efficacious in a spontaneous melanoma model. Histological and flow cytometric analysis of the tumors revealed infiltration and activation of immune cells after RGT100 treatment. RGT100 induced a strong and durable type I IFN response in tumors. Treatment of subcutaneous tumors by intratumor injection led to efficacy of both the treated tumors as well as untreated contralateral tumors. Furthermore, systemic delivery of RGT100 was efficacious against both local subcutaneous B16 melanoma as well as lung metastases. Data support both rapid natural killer (NK) cell-mediated and long-term T cell-mediated anti-tumor activities. Depletion of NK cells blocked the immediate anti-tumor activity of RGT100. In summary, Rigontec9s RIG-I-selective ligand RGT100 shows strong anti-tumor activity in several clinically relevant mouse tumor models, while bearing an advantageous safety profile. RGT100 is rapidly progressing toward clinical evaluation in cancer patients. This agent will be evaluated both for single-agent activity as well as in combination with checkpoint inhibitors. Citation Format: Jim Barsoum, Marcel Renn, Christine Schuberth, Christopher Jakobs, Anna Schwickart, Martin Schlee, Jasper van den Boorn, Gunther Hartmann. Selective stimulation of RIG-I with a novel synthetic RNA induces strong anti-tumor immunity in mouse tumor models. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B44.
Arthritis & Rheumatism | 2016
Rebecca Baum; Shruti Sharma; Jason M. Organ; Christopher Jakobs; Veit Hornung; David B. Burr; Ann Marshak-Rothstein; Katherine A. Fitzgerald; Ellen M. Gravallese
Cytosolic DNA sensors detect microbial DNA and promote type I interferon (IFN) and proinflammatory cytokine production through the adaptor stimulator of IFN genes (STING) to resolve infection. Endogenous DNA also engages the STING pathway, contributing to autoimmune disease. This study sought to identify the role of STING in regulating bone formation and to define the bone phenotype and its pathophysiologic mechanisms in arthritic mice double deficient in DNase II and IFN‐α/β/ω receptor (IFNAR) (DNase II−/−/IFNAR−/− double‐knockout [DKO] mice) compared with controls.