Stefan Jordan
Ludwig Maximilian University of Munich
Network
Latest external collaboration on country level. Dive into details by clicking on the dots.
Publication
Featured researches published by Stefan Jordan.
Immunity | 2016
Hélène Salmon; Juliana Idoyaga; Adeeb Rahman; Marylene Leboeuf; Romain Remark; Stefan Jordan; Maria Casanova-Acebes; Makhzuna Khudoynazarova; Judith Agudo; Navpreet Tung; Svetoslav Chakarov; Christina Rivera; Brandon Hogstad; Marcus Bosenberg; Daigo Hashimoto; Sacha Gnjatic; Nina Bhardwaj; Anna Karolina Palucka; Brian D. Brown; Joshua Brody; Florent Ginhoux; Miriam Merad
Large numbers of melanoma lesions develop resistance to targeted inhibition of mutant BRAF or fail to respond to checkpoint blockade. We explored whether modulation of intratumoral antigen-presenting cells (APCs) could increase responses to these therapies. Using mouse melanoma models, we found that CD103(+) dendritic cells (DCs) were the only APCs transporting intact antigens to the lymph nodes and priming tumor-specific CD8(+) T cells. CD103(+) DCs were required to promote anti-tumoral effects upon blockade of the checkpoint ligand PD-L1; however, PD-L1 inhibition only led to partial responses. Systemic administration of the growth factor FLT3L followed by intratumoral poly I:C injections expanded and activated CD103(+) DC progenitors in the tumor, enhancing responses to BRAF and PD-L1 blockade and protecting mice from tumor rechallenge. Thus, the paucity of activated CD103(+) DCs in tumors limits checkpoint-blockade efficacy and combined FLT3L and poly I:C therapy can enhance tumor responses to checkpoint and BRAF blockade.
Cell Host & Microbe | 2008
Torsten Sacher; Jürgen Podlech; Christian A. Mohr; Stefan Jordan; Zsolt Ruzsics; Matthias J. Reddehase; Ulrich H. Koszinowski
The course of systemic viral infections is determined by the virus productivity of infected cell types and the efficiency of virus dissemination throughout the host. Here, we used a cell-type-specific virus labeling system to quantitatively track virus progeny during murine cytomegalovirus infection. We infected mice that expressed Cre recombinase selectively in vascular endothelial cells or hepatocytes with a murine cytomegalovirus for which Cre-mediated recombination would generate a fluorescently labeled virus. We showed that endothelial cells and hepatocytes produced virus after direct infection. However, in the liver, the main contributor to viral load in the mouse, most viruses were produced by directly infected hepatocytes. Remarkably, although virus produced in hepatocytes spread to hepatic endothelial cells (and vice versa), there was no significant spread from the liver to other organs. Thus, the cell type producing the most viruses was not necessarily the one responsible for virus dissemination within the host.
Journal of Virology | 2011
Stefan Jordan; Johannes Krause; Adrian Prager; Maja Mitrović; Stipan Jonjić; Ulrich H. Koszinowski; Barbara Adler
ABSTRACT Murine cytomegalovirus (MCMV) Smith strain has been cloned as a bacterial artificial chromosome (BAC) named pSM3fr and used for analysis of virus gene functions in vitro and in vivo. When sequencing the complete BAC genome, we identified a frameshift mutation within the open reading frame (ORF) encoding MCMV chemokine homologue MCK-2. This mutation would result in a truncated MCK-2 protein. When mice were infected with pSM3fr-derived virus, we observed reduced virus production in salivary glands, which could be reverted by repair of the frameshift mutation. When looking for the source of the mutation, we consistently found that virus stocks of cell culture-passaged MCMV Smith strain are mixtures of viruses with or without the MCK-2 mutation. We conclude that the MCK-2 mutation in the pSM3fr BAC is the result of clonal selection during the BAC cloning procedure.
Science | 2016
Alex Rialdi; Laura Campisi; Nan Zhao; Arvin Lagda; Colette Pietzsch; Jessica Sook Yuin Ho; Luis Martinez-Gil; Romain Fenouil; Xiaoting Chen; Megan R. Edwards; Giorgi Metreveli; Stefan Jordan; Zuleyma Peralta; César Muñoz-Fontela; Nicole M. Bouvier; Miriam Merad; Jian Jin; Matthew T. Weirauch; Sven Heinz; Christopher Benner; Harm van Bakel; Christopher F. Basler; Adolfo García-Sastre; Alexander Bukreyev; Ivan Marazzi
Unwinding DNA and unleasing inflammation Fighting infections often comes with collateral damage, which sometimes can be deadly. For instance, in septic shock, the overwhelming release of inflammatory mediators drives multi-organ failure. Rialdi et al. now report a potential new therapeutic target for controlling excessive inflammation: the DNA unwinding enzyme topoisomerase I (Top1) (see the Perspective by Pope and Medzhitov). Upon infection, Top1 specifically localizes to the promoters of pathogen-induced genes and promotes their transcription by helping to recruit RNA polymerase II. Pharmacological inhibition of Top1 in a therapeutic setting increased survival in several mouse models of severe microbially induced inflammation. Science, this issue p. 10.1126/science.aad7993; see also p. 1058 Depletion or chemical inhibition of Top1 suppresses the host response against influenza and Ebola viruses, as well as bacterial products. INTRODUCTION Infection causes inflammation, which contributes to pathogen clearance and organismal survival. The balance between the intensity and resolution of an inflammatory response is key for the fitness of the organism. Sepsis, for example, is a life-threatening condition caused by an excessive host response to infection, which in turn leads to multi-organ failure and death. Worldwide, millions of people each year succumb to sepsis. With an overall mortality rate of 20 to 50%, sepsis is the 10th leading cause of death (more than HIV and breast cancer) in the United States, according to the Centers for Disease Control and Prevention. Estimates indicate that 250,000 to 500,000 people die from sepsis annually in the United States. Children and the elderly are especially vulnerable to sepsis; it is the most common cause of death in infants and children. Childhood pneumonia, often caused by virus-bacteria co-infection, leads to septic shock and lung destruction. This occurs after bacterial invasion even in the presence of an appropriate antibiotic therapy. Finding remedies to treat sepsis and diseases associated with detrimental acute inflammatory reactions is thus pivotal for humankind. RATIONALE We reasoned that if excessive inflammation in response to infection leads to lethal consequences, dampening inflammation could be advantageous for the host. At least two strategies could be used to suppress inflammatory responses associated with infection. One is indirect and targets the pathogen (antibiotics). The second one, which we used, directly acts on the host response itself. In such a strategy, the suppression of acute inflammation would bypass the fatal outcome associated with overt inflammation and would “buy time” to allow the host immune response to eliminate the pathogen. After microbial invasion, many steps could be targeted between the early phases of the cellular response (sensing of the pathogen and signal transduction) and the information flow from DNA to RNA to proteins that act as inflammatory mediators (i.e., cytokines). We decided to identify and chemically inhibit cellular factors that act at the DNA (chromatin) level and play a primary role in activating the expression of inflammatory genes. RESULTS We found that chemical inhibition of topoisomerase 1 (Top1), an enzyme that unwinds DNA, suppresses the expression of infection-induced genes with little to no effect on housekeeping gene expression and without cellular damage. In vitro, depletion or chemical inhibition of Top1 in epithelial cells and macrophages suppresses the host response against influenza and Ebola viruses as well as bacterial products. At the mechanistic level, as shown by chemical genetics and epigenetic approaches, Top1 inhibition primarily suppresses RNA polymerase II (RNAPII) activity at pathogen-associated molecular pattern (PAMP)–induced genes. These genes require SWI/SNF chromatin remodeling for activation and display unique genetic and epigenetic features, such as the presence of IRF3 binding sites, low basal levels of RNAPII, histone H3 Lys27 acetylation marks, DNA hypersensitivity, and CpG islands. This gene “signature” of specificity was also validated using public data sets. In vivo, Top1 inhibition therapy rescued 70 to 90% mortality caused by exacerbated inflammation in three mouse models: acute bacteria infection, liver failure, and virus-bacteria co-infection. Strikingly, one to three doses of inhibitors were sufficient for the protective effect in all models, without overt side effects. CONCLUSION The inflammatory immune response against microbes is essential in protecting us against infections. In some cases, such as highly pathogenic and pandemic infections, the organism turns against itself and responds too acutely, with an excessive inflammation that can have fatal consequences. Our results suggest that a therapy based on Top1 inhibition could save millions of people affected by sepsis, pandemics, and many congenital deficiencies associated with acute inflammatory episodes and “cytokine storms.” CREDIT: RYGER/SHUTTERSTOCK The host innate immune response is the first line of defense against pathogens and is orchestrated by the concerted expression of genes induced by microbial stimuli. Deregulated expression of these genes is linked to the initiation and progression of diseases associated with exacerbated inflammation. We identified topoisomerase 1 (Top1) as a positive regulator of RNA polymerase II transcriptional activity at pathogen-induced genes. Depletion or chemical inhibition of Top1 suppresses the host response against influenza and Ebola viruses as well as bacterial products. Therapeutic pharmacological inhibition of Top1 protected mice from death in experimental models of lethal inflammation. Our results indicate that Top1 inhibition could be used as therapy against life-threatening infections characterized by an acutely exacerbated immune response.
Frontiers in Immunology | 2012
Laura Chiossone; Sandra Audonnet; Bruno Chetaille; Lionel Chasson; Catherine Farnarier; Yaël Berda-Haddad; Stefan Jordan; Ulrich H. Koszinowski; Marc Dalod; K. Mazodier; Daniela Novick; Charles A. Dinarello; Eric Vivier; G. Kaplanski
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition due to the association of an infectious agent with lymphocyte cytotoxicity defects, either of congenital genetic origin in children or presumably acquired in adults. In HLH patients, an excess of lymphocyte or macrophage cytokines, such as IFN-γ and TNFα is present in serum. In animal models of the disease, IFN-γ and TNF-α have been shown to play a central pathogenic role. In humans, unusually high concentrations of IL-18, an inducer of IFN-γ, and TNF-α have been reported, and are associated with an imbalance between IL-18 and its natural inhibitor IL-18 binding protein (IL-18BP) resulting in an excess of free IL-18. Here we studied whether IL-18BP could reduce disease severity in an animal model of HLH. Mouse cytomegalovirus infection in perforin-1 knock-out mice induced a lethal condition similar to human HLH characterized by cytopenia with marked inflammatory lesions in the liver and spleen as well as the presence of hemophagocytosis in bone marrow. IL-18BP treatment decreased hemophagocytosis and reversed liver as well as spleen damage. IL-18BP treatment also reduced both IFN-γ and TNF-α production by CD8+ T and NK cells, as well as Fas ligand expression on NK cell surface. These data suggest that IL-18BP is beneficial in an animal model of HLH and in combination with anti-infectious therapy may be a promising strategy to treat HLH patients.
PLOS Pathogens | 2011
Torsten Sacher; Joachim Andrassy; Aivars Kalnins; Lars Dölken; Stefan Jordan; Jürgen Podlech; Zsolt Ruzsics; Karl-Walter Jauch; Matthias J. Reddehase; Ulrich H. Koszinowski
Cytomegalovirus (CMV) is frequently transmitted by solid organ transplantation and is associated with graft failure. By forming the boundary between circulation and organ parenchyma, endothelial cells (EC) are suited for bidirectional virus spread from and to the transplant. We applied Cre/loxP-mediated green-fluorescence-tagging of EC-derived murine CMV (MCMV) to quantify the role of infected EC in transplantation-associated CMV dissemination in the mouse model. Both EC- and non-EC-derived virus originating from infected Tie2-cre + heart and kidney transplants were readily transmitted to MCMV-naïve recipients by primary viremia. In contrast, when a Tie2-cre + transplant was infected by primary viremia in an infected recipient, the recombined EC-derived virus poorly spread to recipient tissues. Similarly, in reverse direction, EC-derived virus from infected Tie2-cre + recipient tissues poorly spread to the transplant. These data contradict any privileged role of EC in CMV dissemination and challenge an indiscriminate applicability of the primary and secondary viremia concept of virus dissemination.
Medical Microbiology and Immunology | 2008
Torsten Sacher; Stefan Jordan; Christian A. Mohr; Aurore Vidy; Annelies Weyn; Zsolt Ruszics; Ulrich H. Koszinowski
Cytomegalovirus (CMV), a prototypic β-herpesvirus, is an important human pathogen causing protean clinical manifestations in immature and immunocompromised patients. Mechanisms of infection can be studied in a mouse model. Mouse cytomegalovirus (MCMV) resembles in pathogenesis its human counterpart in many ways. Although MCMV infection is studied extensively on the level of organs, the contribution of specific cell types to viral replication in vivo is still elusive. Here we describe our approach based on the the Cre/loxP-system to investigate MCMV infection at the level of cell types in vivo. Using bacterial artificial chromosome (BAC)-technology, we created an MCMV virus containing an enhanced green fluorescent protein (egfp) reporter-gene which is not expressed due to a ‘Stop’ cassette flanked by two loxP-sites between promoter and coding sequence. Infection of cre-transgenic mice with this reporter virus results in the deletion of the ‘Stop’ cassette and expression of EGFP in a cell type-specific manner. Using this conditional gene expression system we are able to quantify viral productivity in specific cell types and to determine their contribution to viral dissemination in vivo. Furthermore, the deletion of viral genes can be used to screen for cell type-specificity of viral gene functions. Hence, conditional MCMV mutants allow the study of herpesvirus biology on the level of cell types in vivo.
Journal of Experimental Medicine | 2016
Tihana Lenac Roviš; Paola Kučan Brlić; Noa S. Kaynan; Vanda Juranić Lisnić; Ilija Brizić; Stefan Jordan; Adriana Tomić; Daria Kveštak; Marina Babic; Pinchas Tsukerman; Marco Colonna; Ulrich H. Koszinowski; Martin Messerle; Ofer Mandelboim; Astrid Krmpotić; Stipan Jonjić
Jonjic et al. show that inflammatory macrophages play an essential role in the control of murine CMV (MCMV) infection through a DNAM-1–PVR pathway.
Cell Host & Microbe | 2013
Stefan Jordan; Zsolt Ruzsics; Maja Mitrović; Thomas Baranek; Jurica Arapović; Astrid Krmpotić; Eric Vivier; Marc Dalod; Stipan Jonjić; Lars Dölken; Ulrich H. Koszinowski
The immune response against a variety of pathogens can lead to activation of blood formation at ectopic sites, a process termed extramedullary hematopoiesis (EMH). The underlying mechanisms of EMH have been enigmatic. Investigating splenic EMH in mice infected with murine cytomegalovirus (MCMV), we find that, while cells of the adaptive immune system were dispensable for EMH, natural killer (NK) cells were essential. EMH required recognition of infected cells via activating NK cell receptors Ly49H or NKG2D, and correspondingly, viral interference with NK cell recognition abolished EMH. Surprisingly, development of EMH was not induced by NK cell-derived cytokines but was dependent on perforin-mediated cytotoxicity in order to control virus spread. Spreading virus reduced the numbers of F4/80(+) macrophages that were crucial for inflammatory EMH. Hence, whereas MCMV suppresses inflammation-induced EMH, NK cells confine virus spread, thereby protecting extramedullary hematopoietic niches and facilitating EMH.
Molecular Cancer Therapeutics | 2015
Sara Cuadrado-Castano; Juan Ayllon; Mena Mansour; Janis de la Iglesia-Vicente; Stefan Jordan; Shashank Tripathi; Adolfo García-Sastre; Enrique Villar
Newcastle disease virus (NDV) is considered a promising agent for cancer therapy due to its oncolytic properties. These include preferential replication in transformed cells, induction of innate and adaptive immune responses within tumors, and cytopathic effects in infected tumor cells due to the activation of apoptosis. To enhance the latter and thus possibly enhance the overall oncolytic activity of NDV, we generated a recombinant NDV encoding the human TNF receptor Fas (rNDV-B1/Fas). rNDV-B1/Fas replicates to similar titers as its wild-type (rNDV-B1) counterpart; however, overexpression of Fas in infected cells leads to higher levels of cytotoxicity correlated with faster and increased apoptosis responses, in which both the intrinsic and extrinsic pathways are activated earlier. Furthermore, in vivo studies in syngeneic murine melanoma models show an enhancement of the oncolytic properties of rNDV-B1/Fas, with major improvements in survival and tumor remission. Altogether, our data suggest that upregulation of the proapoptotic function of NDV is a viable approach to enhance its antitumor properties and adds to the currently known, rationally based strategies to design optimized therapeutic viral vectors for the treatment of cancer. Mol Cancer Ther; 14(5); 1247–58. ©2015 AACR.