Career opportunity for PhD and Postdocs in the newly funded SFB/Transregio 237June 25, 2018
About the Transregio
The SFB/TR is an interdisciplinary research network between the University of Bonn, the TU Dresden and the LMU Munich with participation of the University Marburg, the TU Munich and the MPI for Biochemistry Munich.
About the Science
Projects within the SFB/TR237 cover the diverse pathways involved in Nucleic Acid Immunity that have fundamental implications for human health and disease.
- Mechanisms and functional consequences of Y-DNA immune sensingHartmann, Gunther; Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, and Schmidt, Florian I.; Institute of Innate Immunity, University of Bonn
During pathogen infection or cell damage, DNA accumulating in the cytosol of cells can activate innate immune responses. We propose to use alpaca nanobodies as novel tools to study how short HIV-1-derived DNA secondary structures activate DNA sensors in unique ways. Reporter-based assays will elucidate how DNA-induced antiviral type I interferon signaling and pro-inflammatory inflammasome activation is coordinated at the single cell level. We will further identify novel cellular adaptors required, and delineate which additional short DNA species activate the respective sensors in the context of DNA damage.
- Role of RNA modifications in infection and immune tolerance
Bauer, Stefan; Institute for Immunology, Phillips University Marburg
The innate immune system relies on Toll-like receptors and RIG-I like helicases to sense bacterial and viral RNA. RNA modifications such as 2’-O-ribose / base methylation or the occurrence of pseudouridinenegatively modulate the immune sensing of RNA. We will investigate the role of bacterial tRNA methylase trmH in immune evasion and characterize the importance of the eukaryotic RNA modifying enzymes fibrillarin, TAR binding protein 1, and dyskerin pseudouridine synthetase 1 (DKC1) for the generation of modified self RNA preventing immune activation and induction of autoimmunity.
- Recognition of pathogenic RNA in mosquitoes
Kümmerer, Beate; Virology, University of Bonn; and Schlee, Martin; Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn
RNA virus based mosquito-borne diseases cause a substantial morbidity worldwide. Innate antiviral RNA receptors are well defined in vertebrates but hardly studied in insects. We found that flavivirus replication is impaired in vertebrate and mosquito cells if mRNA cap N1-2'O-methylation is lacking, indicating conserved virus RNA recognition motifs. Screening RNA recognition motifs as stimuli or bait in interactome approaches, we aim to identify RNA receptors and characterize antiviral responses in mosquitoes. In a virus mutagenesis reverse genetics approach we aim to identify viral antagonists of mosquito innate RNA receptor pathways and their interacting antiviral host proteins.
- Structural mechanisms of self-nucleic acid sensing by cGAS
Hopfner, Karl-Peter; Gene Center,Ludwig-Maximilians-Universität München (LMU, Munich)
We will interrogate how cGAS detects DNA of self-origin, in particular damaged DNA, cytosolic chromatin and mitochondrial DNA. We recently showed that cGAS forms higher-order ladder-like structures on long and U-turn DNA, suggesting that stabilization of cGAS dimers and multimers is critical for DNA sensing. Using structural, biochemical and cell based studies, we aim at revealing now whether and how branched nucleic acids, cGAS’ N-terminal domain and HMGB/HIN200 host factors help formation of active cGAS dimer and multimers and therefore understand mechanisms of self-sensing.
- Effects of pyroptosis on nucleic acid metabolism and immune sensing Bartok, Eva; Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn
The discrimination between physiological and pathological forms of cell death is critical to an appropriate immune response. In our preliminary work, we observed that pyroptotic cell death renders cellular corpses and their DNA immunostimulatory. Moreover, our data demonstrate that this effect is critically dependent on the presence of both the lysosomal endonuclease DNase II in pyroptotic cells and of cytosolic Three prime Repair Exonuclease 1 (TREX1) in recipient phagocytes: DNase II generates 3´-monophosphate termini (3’P DNA), rendering DNA resistant to degradation by TREX1. In this project, we aim to expand on these initial findings and investigate how this effect contributes to the recognition of intracellular pathogens during pyroptosis. In addition, we will investigate the role of the endogenous 3’ phosphatase PNKP in controlling these responses.
- Degradation of viral or immunostimulatory RNA in infected cells
Pichlmair, Andreas; Institut für Virologie, Technical University of Munich (TUM, Munich)
Successful elimination of viral infections requires targeting and degradation of viral nucleic acids. Surprisingly little is known regarding molecular mechanisms that are specifically targeting viral RNA and yet do not affect cellular RNA such as messenger, ribosomal or transfer RNA. This proposal aims at elucidating the half-life of viral nucleic acid and functional characterization of pathways and proteins that are involved in this process. We anticipate that this knowledge will allow us to gain insights in successful elimination of viruses and in physiological processes that aim to remove stimulatory RNA under steady state conditions
- Molecular mechanisms of ‘Superkiller-like’ RNA helicases
Conti, Elena; Max Planck Institute of Biochemistry, Martinsried/Munich
Increasing evidence implicates the RNA exosome, a major complex in cellular RNA decay mechanisms, as a player in viral immunity and autoimmunity. The RNA exosome is a powerful RNA-degrading machine, but in itself lacks specificity. Superkiller-like helicases are believed to assist the exosome by recognizing specific RNAs and targeting them for degradation, but the molecular mechanisms are poorly understood. In this project, we will study Superkiller-like helicases that have been linked to the regulation of RIGI-like receptors, aiming to understand how they function at the molecular level and the basis for their malfunction in disease mutants.
- DNA damage response signaling mediated antiviral response
Hornung, Veit; Gene Center and Department of Biochemistry, LMU, Munich
DNA damage response (DDR) cascades entail networks of pathways that signal upon the detection of respective lesions to initiate processes geared at the restoration of genomic integrity. At the same time a plethora of antiviral transcripts are induced in the context of DDR, which implies a direct or indirect connection of these pathways to antiviral sensing or defense. Here, we want to elucidate under what circumstances this antiviral DDR response pathway is triggered, map the underlying signal transduction cascade and characterize how it diverges or overlaps with canonical pattern recognition receptor pathways leading to antiviral immune responses.
- Molecular Mechanism and Pathophysiology of Nucleic Acid induced CARD9 signaling
Ruland, Jürgen; Institute of Clinical Chemistry and Pathobiochemistry, TUM, Munich
We have previously identified unique inflammatory pathways that are activated upon RNA or DNA sensing by RIG-I-like helicases or Rad50, which are controlled by the adapter proteins CARD9 and BCL10. These pathways mediate canonical NF-κB activation for pro-inflammatory cytokine production and CARD9 can in addition activate type I IFN production. As the pathophysiological roles and regulatory mechanisms of CARD9/BCL10 signaling during nucleic acid induced sterile inflammation are unknown, we propose to dissect the function of CARD9/BCL10 signaling in nucleic acid-driven inflammatory disease and the regulatory mechanisms that control CARD9 signaling after cytosolic RNA or DNA detection.
- Role of UNC93B1 nucleic acid sensing TLR function
Latz, Eicke;Institute of Innate Immunity, University of Bonn
Several members of the Toll-like receptor (TLR) family can detect DNA, RNA and their degradation products in endosomal compartments of cells and a range of checkpoints have evolved that restrict the activation of nucleic acid sensing TLRs to prevent excessive activity. We will study how UNC93B1, a protein critical for the function of endosomal TLRs, regulates the half-life of nucleic acid sensing TLRs, enables their export from the ER into the secretory pathway and promotes their correct trafficking to different endosomal sites to influence the quantity and quality of cell signaling.
- Contribution of cellular stress to RNA virus PAMP recognition
Conzelmann, Karl-Klaus; Max von Pettenkofer-Institute & Gene Center, LMU, Munich
This project addresses the fundamental question how persistent RNA viruses can go unrecognized by the innate immune system. The analysis of isogenic persistent and acute rabies rhabdoviruses provided experimental evidence for contribution of cellular stress sensors to virus PAMP recognition and induction of an antiviral response. Upon determination of the stress types involved it will be determined whether stress can prime RLR sensors for better recognition of viral RNA, or whether endogenous danger signals (DAMPs) are produced that synergize with viral RNA in cell activation.
- Defining predictors of anti-viral immunity in the yellow fever vaccination model using gene polymorphisms and early innate response patterns
Krug, Anne; Institute for Immunology, LMU; and Rothenfusser, Simon; Division of Clinical Pharmacology, LMU, Munich
Using the life-attenuated yellow fever virus (YF17D) vaccination as a model of an acute self-limiting RNA virus infection in humans, we will determine how cooperation of different nucleic acid sensors and antigen presenting cell subpopulations induces early innate responses which are critical for generating effective and long lasting adaptive immunity. Linking cell-type specific gene expression with genome-wide SNP analysis in 250 vaccinees will determine expression quantitative trait loci (eQTLs) influencing YF17D-induced gene expression. Therby we will identify new factors regulating nucleic acid sensing pathways and investigate the genetic basis of inter-individual variability in innate and adaptive antiviral immunity.
- Immune sensing of nucleic acids in the pathophysiology of immune complex glomerulonephritis associated with chronic viral infection
Abdullah, Zeinab; Institute of Experimental Immunology, University of Bonn; and Kurts, Christian; Institute of Experimental Immunology, University of Bonn
A common clinical complication in patients with chronic HIV and HCV infections is the development of Immune complex-glomerulonephritis (IC-GN), characterized by enhanced levels of virus ICs, autoantibodies and IFN-I. To identify the pathophysiological cellular and molecular underpinning mechanisms, we will investigate the relevance of sensing nucleic acids from the virus, NETs and dead host cells and the microbiota for autoantibody and IC-GN development using the neo-LCMV infection. Specifically, we will determine the role of RNA and DNA sensing by RIG-like helicases, STING or TLR (7, 9 or 3) in the development of autoantibodies, interferonopathy and IC-GN development.
- Cellular and molecular mechanisms of nucleic acid recognition in ANCA-associated pulmonary vasculitis
Garbi, Natalio; Institute of Experimental Immunology, University of Bonn; and Teichmann, Lino; Department of Internal Medicine III, University of Bonn
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are a group of life-threatening autoimmune diseases that can affect multiple organs. Using a novel model of pulmonary AAV established in our laboratory, we have identified the STING signaling pathway to be critical in disease development, indicating a principal role for nucleic acid detection. The goal of our study is to delineate how nucleic acid recognition via the STING axis and other nucleic acid sensing pathways promotes disease, define the immune cell subsets that contribute to AAV and elucidate the mechanism by which microbial products and ANCAs synergize in the activation nucleic acid sensors.
- Mechanisms of pathogenic activation of cytosolic nucleic acid sensors and type I IFN responses by endogenous nucleic acids
Roers, Axel; Institute for Immunology, Technische Universität Dresden
One cause of aberrant type I interferon (IFN) production in Aicardi-Goutières syndrome and Lupus is loss of cytosolic 3’ repair exonuclease 1 (TREX1), which leads to chronic activation of the cytosolic DNA sensor cGAS. To identify source and nature of the unknown ligand triggering cGAS in TREX1-deficient cells, we will define conditions under whichTREX1-/-cells produce IFN and assess whether their IFN response depends on cell cycle, mitosis or senescence. We will determine whether active DNA repair or genome instability are prerequisites for IFN release by TREX1-/-cells and we will screen for genes that are essential for the IFN response in the absence of TREX1
- Uncontrolled type I interferon responses in pediatric autoinflammatory diseases with vascular inflammation
Rösen-Wolff, Angela; Department of Pediatrics, Technische Universität Dresden
Type I interferonopathies are often associated with vasculitis. Activating mutations in STING, a key adapter in cGAS-dependent cytosolic DNA sensing, were shown to cause a lethal condition characterized by severe systemic vasculitis (STING-associated vasculopathy with onset in infancy; SAVI). We introduced a SAVI-associated mutation into the locus encoding STING in mice, tmem173, and found that these tmem173N154S knock-in animals strikingly recapitulate key features of the human disease. The aim of the present project is to answer the questions which cytokines mediate vascular pathology, which proinflammtory factors contribute in addition to type I IFN and which cell types play a role in vasculitis induced by uncontrolled activity of STING. In addition we want to study if pathology resulting from constitutive STING activation can be treated by inhibition of individual cytokines or their signaling or by bone marrow transplantation.
- The role of SAMHD1 in controlling the innate immune response to endogenous nucleic acids
Behrendt, Rayk; Institute for Immunology, Technische Universität Dresden
SAMHD1 is a deoxyribonucleoside triphosphate (dNTP) triphosphohydrolase (dNTPase), which degrades cellular dNTPs into nucleosides and inorganic triphosphate in a cell cycle-dependent manner. Deficiency for SAMHD1 is associated with systemic autoimmunity and cancer. On a molecular level, loss of SAMHD1 causes a spontaneous activation of the type I IFN System and DNA damage by so far unknown mechanisms. We aim to investigate how alterations in the dNTP levels caused by loss of SAMHD1 affect the intracellular nucleic acid sensing pathways, how this causes genome instability, whether this leads to an increased mutation rate and which mechanisms control the mutational burden in SAMHD1-deficient cells. Finally, we ask whether loss of SAMHD1 is sufficient to cause neoplastic transformation.
- Intracellular nucleic acid sensing as a trigger of type I interferon-driven autoimmunity affecting muscle and skin
Günther, Claudia; Department of Dermatology, Technische Universität Dresden
Type I interferon (IFN)-driven autoimmunity can be induced by inappropriate activation of intracellular innate immune nucleic acid sensor pathways. This novel pathogenic principle is relevant in an expanding spectrum of diseases. Our project focuses on two conditions in which muscle and skin are affected. We will analyse the molecular pathway leading from repeat expansion mutations to autoimmunity in patients with myotonic dystrophy and will investigate the role of cell intrinsic innate nucleic acid sensing in the pathogenesis of the autoimmune disease dermatomyositis.
- Phenotypic and genetic dissection of type I interferonopathies
Lee-Kirsch, Min Ae; Department of Pediatrics, Technische Universität Dresden
The prototypic type I interferonopathy is Aicardi-Goutières syndrome, an infancy-onset inflammatory encephalopathy causing severe neurological impairment. Understanding the mechanisms leading to neurodegeneration will be important for the development of specific therapeutic approaches. We want to establish neuronal cells from patient-derived reprogrammed induced pluripotent stem cells to investigate the consequences of constitutive type I IFN activation in a cell type-specific manner. In addition, we want to characterize a putative novel type I interferonopathy caused by mutations in a non-inflammasome forming NOD-like receptor.
- Characterization of autoimmune disorders in a RIG-I mutant mouse model
Kato, Hiroki; Institute of Cardiovascular Immunology, University of Bonn
Singleton Merten syndrome (SMS) is an autosomal-dominant multi-system disorder characterized by dental dysplasia, aortic calcification, glaucoma, osteoporosis and psoriasis, and no fundamental treatment is currently available. Recently gain-of-function mutations in DDX58 encoding human RIG-I, a cytoplasmic viral RNA sensor have been discovered in SMS patients; however, the mechanism by which the constitutively active RIG-I mutants cause the pathogenesis of SMS remains to be clarified. Generating mice expressing SMS-related RIG-I mutant protein, we herein aim to elusidate the mechanisms of SMS onset and development, to establish effective treatments targeting RIG-I-mediated signaling pathway, and finally to determine environmental and behavioral risk factors driving the onset SMS pathologies.
About the Candidates
The ideal candidates will be highly motivated and team oriented, with a strong interest in immunology and a first class academic degree in a life science related discipline.
PhD candidates: should have a Master's degree or equivalent for PhD positions, a strong background in molecular biomedicine , molecular biology, biochemistry or cell biology.
Postdoctoral candidates: should have an outstanding scientific track record including publications in peer reviewed journals.