Ingo B Autenrieth

Universitätsklinikum Tübingen, Tübingen, Baden-Württemberg, Germany

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Publications (218)974.61 Total impact

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    ABSTRACT: Injection of Yersinia outer proteins (Yops) into host cells by a type III secretion system is an important immune evasion mechanism of Yersinia enterocolitica (Ye). In this process Ye invasin (Inv) binds directly while Yersinia adhesin A (YadA) binds indirectly via extracellular matrix (ECM) proteins to β1 integrins on host cells. Although leukocytes turned out to be an important target of Yop injection by Ye, it was unclear which Ye adhesins and which leukocyte receptors are required for Yop injection. To explain this, we investigated the role of YadA, Inv and β1 integrins for Yop injection into leukocytes and their impact on the course of systemic Ye infection in mice. Ex vivo infection experiments revealed that adhesion of Ye via Inv or YadA is sufficient to promote Yop injection into leukocytes as revealed by a β-lactamase reporter assay. Serum factors inhibit YadA- but not Inv-mediated Yop injection into B and T cells, shifting YadA-mediated Yop injection in the direction of neutrophils and other myeloid cells. Systemic Ye mouse infection experiments demonstrated that YadA is essential for Ye virulence and Yop injection into leukocytes, while Inv is dispensable for virulence and plays only a transient and minor role for Yop injection in the early phase of infection. Ye infection of mice with β1 integrin-depleted leukocytes demonstrated that β1 integrins are dispensable for YadA-mediated Yop injection into leukocytes, but contribute to Inv-mediated Yop injection. Despite reduced Yop injection into leukocytes, β1 integrin-deficient mice exhibited an increased susceptibility for Ye infection, suggesting an important role of β1 integrins in immune defense against Ye. This study demonstrates that Yop injection into leukocytes by Ye is largely mediated by YadA exploiting, as yet unknown, leukocyte receptors.
    No preview · Article · Dec 2015 · International journal of medical microbiology: IJMM
  • Article: ID: 173

    No preview · Article · Nov 2015 · Cytokine
  • Article: ID: 178

    No preview · Article · Nov 2015 · Cytokine
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    ABSTRACT: The human gut forms a dynamic reservoir of antibiotic resistance genes (ARGs). Treatment with antimicrobial agents has a significant impact on the intestinal resistome, and leads to enhanced horizontal transfer and selection of resistance. We have followed the development of intestinal ARGs over a six-days course of ciprofloxacin (Cp) treatment in two healthy individuals by using sequenced-based metagenomics and different ARG quantification methods. Fixed- and random-effects models were applied to determine the change in ARG abundance per defined daily dose of Cp as an expression of the respective selection pressure. Among various shifts in the composition of the intestinal resistome we found in one individual a strong positive selection for class D beta-lactamases which were partly located on a mobile genetic element. Furthermore, a trend to a negative selection has been observed with class A beta-lactamases (-2.66 hits per million sample reads/defined daily dose; p = 0.06). By 4 weeks after the end of treatment, the composition of ARGs returned toward their initial state but to a different degree in both subjects. We present here a novel analysis algorithm for the determination of antibiotic selection pressure which can be applied in clinical settings to compare therapeutic regimes regarding their effect on the intestinal resistome. This information is of critical importance for clinicians to choose antimicrobial agents with a low selective force on their patients' intestinal ARGs, likely resulting in a diminished spread of resistance and a reduced burden of hospital-acquired infections with multidrug resistant pathogens.
    No preview · Article · Sep 2015 · Antimicrobial Agents and Chemotherapy

  • No preview · Article · Aug 2015 · Zeitschrift für Gastroenterologie
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    ABSTRACT: Dendritic cells (DCs) are professional antigen-presenting cells playing a crucial role in the initiation of T-cell responses to combat infection. However, systemic bacterial infection with various pathogens leads to DC-depletion in humans and mice. The mechanisms of pathogen-induced DC-depletion remain poorly understood. Previously, we showed that mice infected with Yersinia enterocolitica (Ye) had impaired de novo DC-development, one reason for DC-depletion. Here, we extend these studies to gain insight into the molecular mechanisms of DC-depletion and the impact of different bacteria on DC-development. We show that the number of BM hematopoietic progenitors committed to the DC lineage is reduced following systemic infection with different Gram-positive and Gram-negative bacteria. This is associated with a TLR4- and IFN-γ-signaling dependent increase of committed monocyte progenitors in the BM and mature monocytes in the spleen upon Ye-infection. Adoptive transfer experiments revealed that infection-induced monopoiesis occurs at the expense of DC-development. Our data provide evidence for a general response of hematopoietic progenitors upon systemic bacterial infections to enhance monocyte production, thereby increasing the availability of innate immune cells for pathogen control, whereas impaired DC-development leads to DC-depletion, possibly driving transient immunosuppression in bacterial sepsis. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Full-text · Article · Jul 2015 · European Journal of Immunology
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    ABSTRACT: Diagnosis of Pneumocystis jirovecii pneumonia (PjP) is challenging. Therefore highly-sensitive and time-efficient new diagnostic tools are needed for early antibiotic treatment start and optimized patient outcome. We evaluated a prototype of a new molecular diagnostic tool using PCR/microarray hybridization for P. jirovecii detection in respiratory samples of hospitalized patients suffering from pneumonia. Prototype results were first compared to established routine PCR results and were set in the context of patients' immune status and clinical presentation in an overall assessment (true positive, false negative or false positive). In our study population, P. jirovecii was assayed with both detection methods in eleven patients out of 739 evaluable study patients; of these, six cases were detected only with the prototype system, two cases only with site-established PCR and three cases with both methods. From these eleven positive cases, we found that six prototype positive cases were true false positives, three prototype positive cases were confirmed as true positives and two prototype negative cases were true false negatives. Overall prevalence for P. jirovecii was low in this study population. Although more positive cases were found using the prototype system, these cases seemed not to be of any clinical significance which might have led to an antibiotic overtreatment of patients under real conditions. However, the correct detection of three positive cases within a few hours might render the prototype a valuable diagnostic tool in the future.
    Full-text · Article · May 2015 · Mycoses
  • Thomas Ulrich · Philipp Oberhettinger · Ingo B. Autenrieth · Doron Rapaport
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    ABSTRACT: Beta-barrel proteins are found in the outer membrane of Gram-negative bacteria, mitochondria, and chloroplasts. The evolutionary conservation in the biogenesis of these proteins allows mitochondria to assemble bacterial β-barrel proteins in their functional form. In this chapter, we describe exemplarily how the capacity of yeast mitochondria to process the trimeric autotransporter YadA can be used to study the role of bacterial periplasmic chaperones in this process.
    No preview · Article · Apr 2015
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    ABSTRACT: The current paradigm suggests that Yersinia entercolitica (Ye) adheres to host cells via the outer membrane proteins YadA or invasin (Inv) to facilitate injection of Yops by the type III secretion system; in this process Inv binds directly to β1 integrins of host cells while YadA may bind indirectly via extracellular matrix proteins to β1 integrins. Here we challenged this paradigm and investigated the requirements for Yop injection. We demonstrate that Inv-, but not YadA-mediated adhesion depends on β1 integrin binding and activation, and that tight adhesion is a prerequisite for Yop injection. By means of novel transgenic cell lines, shRNA approaches and RGD peptides we found that YadA, in contrast to Inv, may use a broad host cell receptor repertoire for host cell adhesion. In the absence of β1 integrins, YadA mediates Yop injection by interaction with αV integrins in cooperation with yet unknown cofactors expressed by epithelial cells, but not fibroblasts. Electron microscopic and flow chamber studies revealed that a defined intimate contact area between Ye and host cells resulting in adhesion forces resisting shear stress is required for Yop injection. Thus, the indirect binding of YadA to a broad ECM binding host cell receptor repertoire of different cell types makes YadA a versatile tool to ensure Yop injection. In conclusion, given the differential expression of the outer membrane proteins Inv and YadA in the course of Ye infection and differential expression of integrins by various host cell populations, the data demonstrate that Ye is flexibly armed to accomplish Yop injection in different host cell types, a central event in its immune evasion strategy. This article is protected by copyright. All rights reserved.
    Full-text · Article · Feb 2015 · Cellular Microbiology
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    ABSTRACT: Toll-like receptor (TLR) expression in patients with inflammatory bowel disease is increased when compared with healthy controls. However, the impact of TLR signaling during inflammatory bowel disease is not fully understood. In this study, we used a murine model of acute phase inflammation in bone marrow chimeric mice to investigate in which cell type TLR2/4 signal induction is important in preventing intestinal inflammation and how intestinal dendritic cells are influenced. Mice were either fed with wild-type bacteria, able to initiate the TLR2/4 signaling cascade, or with mutant strains with impaired signal induction capacity. The induction of the TLR2/4 signal cascade in epithelial cells resulted in inflammation in bone marrow chimeric mice, whereas induction in hematopoietic cells had an opposed function. Furthermore, feeding of wild-type bacteria prevented disease; however, differing signal induction of bacteria had no effect on lamina propria dendritic cell activation. In contrast, functional TLR2/4 signals resulted in increased frequencies of CD103-expressing lamina propria and mesenteric lymph node dendritic cells, which were able to ameliorate disease. The TLR-mediated amelioration of disease, the increase in CD103-expressing cells, and the beneficial function of TLR signal induction in hematopoietic cells indicate that the increased expression of TLRs in patients with inflammatory bowel disease might result in counterregulation of the host and serve in preventing disease.
    Full-text · Article · Feb 2015 · Inflammatory Bowel Diseases
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    ABSTRACT: Here we report on a long-term outbreak from 2009 to 2012 with an XDR Pseudomonas aeruginosa on two wards at a university hospital in southern Germany. Whole-genome sequencing was performed on the outbreak isolates and a core genome was constructed for molecular epidemiological analysis. We applied a time-place-sequence algorithm to improve estimation of transmission probabilities. By using conventional infection control methods we identified 49 P. aeruginosa strains, including eight environmental isolates that belonged to ST308 (by MLST) and carried the metallo-β-lactamase IMP-8. Phylogenetic analysis on the basis of a non-recombinant core genome that contained 22 outbreak-specific SNPs revealed a pattern of four dominant clades with a strong phylogeographic structure and allowed us to determine the potential temporal origin of the outbreak to July 2008, 1 year before the index case was diagnosed. Superspreaders at the root of clades exhibited a high number of probable and predicted transmissions, indicating their exceptional position in the outbreak. Our results suggest that the initial expansion of dominant sublineages was driven by a few superspreaders, while environmental contamination seemed to sustain the outbreak for a long period despite regular environmental control measures. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
    No preview · Article · Jan 2015 · Journal of Antimicrobial Chemotherapy
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    ABSTRACT: Background This study aimed to investigate risk factors for colonisation with extensively drug-resistant P. aeruginosa (XDR-PA) in immunocompromised patients and to build a clinical risk score (CRS) based on these results.Methods We conducted a matched case¿control study with 31 cases and 93 controls (1:3). Cases were colonised with XDR-PA during hospitalisation. Independent risk factors were determined using a three step conditional logistic regression procedure. A CRS was built with respect to the corresponding risk fraction of each risk factor, and its discriminatory power was estimated by receiver operating characteristic (ROC) analysis.ResultsThe presence of a central venous catheter (OR 7.41, P¿=¿0.0008), the presence of a urinary catheter (OR 21.04, P¿<¿0.0001), CRP¿>¿10 mg/dl (OR 7.36, P¿=¿0.0015), and ciprofloxacin administration (OR 5.53, P¿=¿0.025) were independent risk factors. The CRS exhibited a high discriminatory power, defining a high risk population with an approximately fourteen times greater risk for XDR-PA colonisation.Conclusions Unnecessary use of antibiotics, particularly ciprofloxacin should be avoided, and a high standard of infection control measures must be achieved when using medical devices. A CRS can be used for adaptation of the active screening culture policy to the local setting.
    Full-text · Article · Dec 2014 · BMC Infectious Diseases
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    ABSTRACT: Autotransporter proteins comprise a large family of virulence factors which consist of a β-barrel translocation unit and an extracellular effector or passenger domain. The β-barrel anchors the protein to the outer membrane of Gram-negative bacteria and facilitates the transport of the passenger domain onto the cell surface. By inserting an epitope tag into the N-terminus of the passenger domain of the inverse autotransporter Intimin, we generated a mutant defective in autotransport. Using this stalled mutant we could show that (I) at the timepoint of stalling the β-barrel appears folded, (II) the stalled autotransporter is associated with BamA and SurA, (III) the stalled Intimin is decorated with large amounts of SurA, (IV) the stalled autotransporter is not degraded by periplasmic proteases, and that (V) inverse autotransporter passenger domains are translocated by a hairpin mechanism. Our results suggest a function for the BAM complex not only in insertion and folding of the β-barrel but also for passenger translocation. Copyright © 2014, The American Society for Biochemistry and Molecular Biology.
    No preview · Article · Dec 2014 · Journal of Biological Chemistry
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    ABSTRACT: Severe pneumonia remains an important cause of morbidity and mortality. Polymerase chain reaction (PCR) has been shown to be more sensitive than current standard microbiological methods – particularly in patients with prior antibiotic treatment – and therefore, may improve the accuracy of microbiological diagnosis for hospitalized patients with pneumonia. Conventional detection techniques and multiplex PCR for 14 typical bacterial pneumonia-associated pathogens were performed on respiratory samples collected from adult hospitalized patients enrolled in a prospective multi-center study. Patients were enrolled from March until September 2012. A total of 739 fresh, native samples were eligible for analysis, of which 75 were sputa, 421 aspirates, and 234 bronchial lavages. 276 pathogens were detected by microbiology for which a valid PCR result was generated (positive or negative detection result by Curetis prototype system). Among these, 120 were identified by the prototype assay, 50 pathogens were not detected. Overall performance of the prototype for pathogen identification was 70.6% sensitivity (95% confidence interval (CI) lower bound: 63.3%, upper bound: 76.9%) and 95.2% specificity (95% CI lower bound: 94.6%, upper bound: 95.7%). Based on the study results, device cut-off settings were adjusted for future series production. The overall performance with the settings of the CE series production devices was 78.7% sensitivity (95% CI lower bound: 72.1%) and 96.6% specificity (95% CI lower bound: 96.1%). Time to result was 5.2 hours (median) for the prototype test and 43.5 h for standard-of-care. The Pneumonia Application provides a rapid and moderately sensitive assay for the detection of pneumonia-causing pathogens with minimal hands-on time. Trial Registration Deutsches Register Klinischer Studien (DRKS) DRKS00005684
    Full-text · Article · Nov 2014 · PLoS ONE
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    ABSTRACT: Intimin and Invasin are prototypical inverse (Type Ve) autotransporters and important virulence factors of enteropathogenic Escherichia coli and Yersinia spp., respectively. In addition to a C-terminal extracellular domain and a β-barrel transmembrane domain, both proteins also contain a short N-terminal periplasmic domain that, in Intimin, includes a lysin motif (LysM), which is thought to mediate binding to peptidoglycan. We show that the periplasmic domain of Intimin does bind to peptidoglycan both in vitro and in vivo, but only under acidic conditions. We were able to determine a dissociation constant of 0.8 μM for this interaction, whereas the Invasin periplasmic domain, which lacks a LysM, bound only weakly in vitro and failed to bind peptidoglycan in vivo. We present the solution structure of the Intimin LysM, which has an additional α-helix conserved within inverse autotransporter LysMs but lacking in others. In contrast to previous reports, we demonstrate that the periplasmic domain of Intimin mediates dimerisation. We further show that dimerisation and peptidoglycan binding are general features of LysM-containing inverse autotransporters. Peptidoglycan binding by the periplasmic domain in the infection process may aid in resisting mechanical and chemical stress during transit through the gastrointestinal tract.
    Full-text · Article · Oct 2014 · Molecular Microbiology
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    ABSTRACT: Yersinia adhesin A (YadA) belongs to a class of bacterial adhesins that form trimeric structures. Their mature form contains a passenger domain and a C-terminal β-domain that anchors the protein in the outer membrane (OM). Little is known about how precursors of such proteins cross the periplasm and assemble into the OM. In the present study we took advantage of the evolutionary conservation in the biogenesis of β-barrel proteins between bacteria and mitochondria. We previously observed that upon expression in yeast cells, bacterial β-barrel proteins including the transmembrane domain of YadA assemble into the mitochondrial OM. In the current study we found that when expressed in yeast cells both the monomeric and trimeric forms of full-length YadA were detected in mitochondria but only the trimeric species was fully integrated into the OM. The oligomeric form was exposed on the surface of the organelle in its native conformation and maintained its capacity to adhere to host cells. The co-expression of YadA with a mitochondria-targeted form of the bacterial periplasmic chaperone Skp, but not with SurA or SecB, resulted in enhanced levels of both forms of YadA. Taken together, these results indicate that the proper assembly of trimeric autotransporter can occur also in a system lacking the lipoproteins of the BAM machinery and is specifically enhanced by the chaperone Skp.
    Full-text · Article · Sep 2014 · Journal of Biological Chemistry
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    ABSTRACT: Mutations in the nucleotide-binding oligomerization domain-containing protein 2 (NOD2) play an important role in the pathogenesis of Crohn's disease. NOD2 is an intracellular pattern recognition receptor (PRR) that senses bacterial peptidoglycan (PGN) structures, e.g., muramyl dipeptide (MDP). Here we focused on the effect of more-cross-linked, polymeric PGN fragments (PGNpol) in the activation of the innate immune system. In this study, the effect of combined NOD2 and Toll-like receptor 2 (TLR2) stimulation was examined compared to single stimulation of the NOD2 receptor alone. PGNpol species derived from a lipoprotein-containing Staphylococcus aureus strain (SA113) and a lipoprotein-deficient strain (SA113 Δlgt) were isolated. While PGNpol constitutes a combined NOD2 and TLR2 ligand, lipoprotein-deficient PGNpolΔlgt leads to activation of the immune system only via the NOD2 receptor. Murine bone marrow-derived dendritic cells (BMDCs), J774 cells, and Mono Mac 6 (MM6) cells were stimulated with these ligands. Cytokines (interleukin-6 [IL-6], IL-12p40, and tumor necrosis factor alpha [TNF-α]) as well as DC activation and maturation parameters were measured. Stimulation with PGNpolΔlgt did not lead to enhanced cytokine secretion or DC activation and maturation. However, stimulation with PGNpol led to strong cytokine secretion and subsequent DC maturation. These results were confirmed in MM6 and J774 cells. We showed that the NOD2-mediated activation of DCs with PGNpol was dependent on TLR2 costimulation. Therefore, signaling via both receptors leads to a more potent activation of the immune system than that with stimulation via each receptor alone.
    Full-text · Article · Aug 2014 · Infection and immunity
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    Evelina Tacconelli · Andreas Peschel · Ingo B Autenrieth
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    ABSTRACT: Translation research strategy in infectious diseases, combining the results from basic research with patient-orientated research, aims to bridge the gap between laboratory findings and clinical infectious disease practice to improve disease management. In an era of increasing antimicrobial resistance, there are four main areas of clinical and scientific uncertainty that need to be urgently addressed by translational research: (i) early diagnosis of antibiotic-resistant infections and the appropriateness of empirical antibiotic therapy; (ii) the identification of reservoirs of antibiotic-resistant pathogens; (iii) the development of new antibiotics with lower propensities to evoke resistance; and (iv) the development of new non-antibiotic drugs to be used in the prevention of the spread of resistant bacterial strains. Strict European collaboration among major stakeholders is therefore essential. Appropriate educational tools to train a new generation of scientists with regard to a multifaceted approach to antimicrobial resistance research should be developed. Key areas include the support and implementation of European networks focused on translational research and related education activities, making potential therapeutics more attractive to investors and helping academic investigators to determine whether new molecules can be developed with clinical applicability.
    Preview · Article · Jul 2014 · Journal of Antimicrobial Chemotherapy
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    ABSTRACT: Nasal colonization is a major risk factor for S. aureus infections. The mechanisms responsible for colonization are still not well understood and involve several factors on the host and the bacterial side. One key factor is the cell wall teichoic acid (WTA) of S. aureus, which governs direct interactions with nasal epithelial surfaces. We report here the first receptor for the cell wall glycopolymer WTA on nasal epithelial cells. In several assay systems this type F-scavenger receptor, termed SREC-I, bound WTA in a charge dependent manner and mediated adhesion to nasal epithelial cells in vitro. The impact of WTA and SREC-I interaction on epithelial adhesion was especially pronounced under shear stress, which resembles the conditions found in the nasal cavity. Most importantly, we demonstrate here a key role of the WTA-receptor interaction in a cotton rat model of nasal colonization. When we inhibited WTA mediated adhesion with a SREC-I antibody, nasal colonization in the animal model was strongly reduced at the early onset of colonization. More importantly, colonization stayed low over an extended period of 6 days. Therefore we propose targeting of this glycopolymer-receptor interaction as a novel strategy to prevent or control S. aureus nasal colonization.
    Full-text · Article · May 2014 · PLoS Pathogens
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    ABSTRACT: Author Summary About 20% of the human population is colonized by Staphylococcus aureus . The reservoir of S. aureus is mainly the human nose. Usually, colonization does not lead to infection and is therefore without symptoms. However, when hospitalized patients exhibit a suppressed immune system, they are at risk of getting infected by their own nasal S. aureus strain. Therefore, it is important to understand the events and mechanisms underlying colonization. Until now S. aureus nasal colonization is only partially understood. One bacterial key factor is a sugar polymer of S. aureus , termed cell wall teichoic acid (WTA), which is involved in S. aureus adhesion to cellular surfaces in the inner part of the nasal cavity. We show here that a receptor-protein, which is expressed on such cells, binds WTA and is thereby involved in adhesion of S. aureus to nasal cells. This
    No preview · Article · May 2014

Publication Stats

7k Citations
974.61 Total Impact Points

Institutions

  • 2003-2015
    • Universitätsklinikum Tübingen
      • Institute of Medical Microbiology and Hygiene
      Tübingen, Baden-Württemberg, Germany
  • 2000-2015
    • University of Tuebingen
      • • Institute of Medical Microbiology and Hygiene
      • • Interfaculty Institute of Microbiology and Infection Medicine Tübingen (IMIT)
      Tübingen, Baden-Württemberg, Germany
  • 2013
    • Deutsches Zentrum für Infektionsforschung DZIF
      Brunswyck, Lower Saxony, Germany
  • 2012
    • Friedrich-Schiller-University Jena
      • Faculty of Biology and Pharmacy
      Jena, Thuringia, Germany
  • 2010
    • Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute
      Jena, Thuringia, Germany
  • 1992-2010
    • University of Wuerzburg
      • • Institute for Molecular Infection Biology
      • • Institute for Hygiene and Microbiology
      Würzburg, Bavaria, Germany
  • 2008
    • Max Planck Institute for Developmental Biology
      • Department of Protein Evolution
      Tübingen, Baden-Württemberg, Germany
  • 1997-2004
    • Ludwig-Maximilians-University of Munich
      • • Clinic and Polyclinic for Obstetrics and Gynecology
      • • Max-von-Pettenkofer Institute for Hygiene and Medical Microbiology
      München, Bavaria, Germany
  • 1998-2000
    • Max von Pettenkofer-Institut
      München, Bavaria, Germany
    • Technische Universität München
      München, Bavaria, Germany
  • 1996
    • Cornell University
      Ithaca, New York, United States