Stefan H E Kaufmann

Max Planck Institute for Infection Biology, Berlín, Berlin, Germany

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Publications (503)3268.14 Total impact

  • Anca Dorhoi · Stefan H.E. Kaufmann
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    ABSTRACT: Heightened morbidity and mortality in pulmonary tuberculosis (TB) are consequences of complex disease processes triggered by the causative agent, Mycobacterium tuberculosis (Mtb). Mtb modulates inflammation at distinct stages of its intracellular life. Recognition and phagocytosis, replication in phagosomes and cytosol escape induce tightly regulated release of cytokines [including interleukin (IL)-1, tumor necrosis factor (TNF), IL-10], chemokines, lipid mediators, and type I interferons (IFN-I). Mtb occupies various lung lesions at sites of pathology. Bacteria are barely detectable at foci of lipid pneumonia or in perivascular/bronchiolar cuffs. However, abundant organisms are evident in caseating granulomas and at the cavity wall. Such lesions follow polar trajectories towards fibrosis, encapsulation and mineralization or liquefaction, extensive matrix destruction, and tissue injury. The outcome is determined by immune factors acting in concert. Gradients of cytokines and chemokines (CCR2, CXCR2, CXCR3/CXCR5 agonists; TNF/IL-10, IL-1/IFN-I), expression of activation/death markers on immune cells (TNF receptor 1, PD-1, IL-27 receptor) or abundance of enzymes [arginase-1, matrix metalloprotease (MMP)-1, MMP-8, MMP-9] drive genesis and progression of lesions. Distinct lesions coexist such that inflammation in TB encompasses a spectrum of tissue changes. A better understanding of the multidimensionality of immunopathology in TB will inform novel therapies against this pulmonary disease.
    Seminars in Immunopathology 10/2015; DOI:10.1007/s00281-015-0531-3 · 7.75 Impact Factor
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    ABSTRACT: Unlabelled: An estimated one-third of the world's population is currently latently infected with Mycobacterium tuberculosis. Latent M. tuberculosis infection (LTBI) progresses into active tuberculosis (TB) disease in ~5 to 10% of infected individuals. Diagnostic and prognostic biomarkers to monitor disease progression are urgently needed to ensure better care for TB patients and to decrease the spread of TB. Biomarker development is primarily based on transcriptomics. Our understanding of biology combined with evolving technical advances in high-throughput techniques led us to investigate the possibility of additional platforms (epigenetics and proteomics) in the quest to (i) understand the biology of the TB host response and (ii) search for multiplatform biosignatures in TB. We engaged in a pilot study to interrogate the DNA methylome, transcriptome, and proteome in selected monocytes and granulocytes from TB patients and healthy LTBI participants. Our study provides first insights into the levels and sources of diversity in the epigenome and proteome among TB patients and LTBI controls, despite limitations due to small sample size. Functionally the differences between the infection phenotypes (LTBI versus active TB) observed in the different platforms were congruent, thereby suggesting regulation of function not only at the transcriptional level but also by DNA methylation and microRNA. Thus, our data argue for the development of a large-scale study of the DNA methylome, with particular attention to study design in accounting for variation based on gender, age, and cell type. Importance: DNA methylation modifies the transcriptional program of cells. We have focused on two major populations of leukocytes involved in immune response to infectious diseases, granulocytes and monocytes, both of which are professional phagocytes that engulf and kill bacteria. We have interrogated how DNA methylation, gene expression, and protein translation differ in these two cell populations between healthy individuals and patients suffering from TB. To better understand the underlying biologic mechanisms, we harnessed a statistical enrichment analysis, taking advantage of predefined and well-characterized gene sets. Not only were there clear differences on various levels between the two populations, but there were also differences between TB patients and healthy controls in the transcriptome, proteome, and, for the first time, DNA methylome in these cells. Our pilot study emphasizes the value of a large-scale study of the DNA methylome taking into account our findings.
    mBio 09/2015; 6(5). DOI:10.1128/mBio.01187-15 · 6.79 Impact Factor
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    ABSTRACT: The treatment of tuberculosis is based on combinations of drugs that directly target Mycobacterium tuberculosis. A new global initiative is now focusing on a complementary approach of developing adjunct host-directed therapies.
    Nature Reviews Drug Discovery 07/2015; 14(8). DOI:10.1038/nrd4696 · 41.91 Impact Factor
  • Anca Dorhoi · Stefan H E Kaufmann
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    ABSTRACT: Tuberculosis (TB), a chronic bacterial infectious disease caused by Mycobacterium tuberculosis (Mtb), typically affects the lung and causes profound morbidity and mortality rates worldwide. Recent advances in cellular immunology emphasize the complexity of myeloid cell subsets controlling TB inflammation. The specialization of myeloid cell subsets for particular immune processes has tailored their roles in protection and pathology. Among myeloid cells, dendritic cells (DCs) are essential for the induction of adaptive immunity, macrophages predominantly harbor Mtb within TB granulomas and polymorphonuclear neutrophils (PMNs) orchestrate lung damage. However, within each myeloid cell population, diverse phenotypes with unique functions are currently recognized, differentially influencing TB pneumonia and granuloma functionality. More recently, myeloid-derived suppressor cells (MDSCs) have been identified at the site of Mtb infection. Along with PMNs, MDSCs accumulate within the inflamed lung, interact with granuloma-residing cells and contribute to exuberant inflammation. In this review, we discuss the contribution of different myeloid cell subsets to inflammation in TB by highlighting their interactions with Mtb and their role in lung pathology. Uncovering the manifold nature of myeloid cells in TB pathogenesis will inform the development of future immune therapies aimed at tipping the inflammation balance to the benefit of the host. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 07/2015; 45(8). DOI:10.1002/eji.201545493 · 4.03 Impact Factor
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    ABSTRACT: Mycobacterium tuberculosis remains a health concern due to its ability to enter a non-replicative dormant state linked to drug resistance. Understanding transitions into and out of dormancy will inform therapeutic strategies. We implemented a universally applicable, label-free approach to estimate absolute cellular protein concentrations on a proteome-wide scale based on SWATH mass spectrometry. We applied this approach to examine proteomic reorganization of M. tuberculosis during exponential growth, hypoxia-induced dormancy, and resuscitation. The resulting data set covering >2,000 proteins reveals how protein biomass is distributed among cellular functions during these states. The stress-induced DosR regulon contributes 20% to cellular protein content during dormancy, whereas ribosomal proteins remain largely unchanged at 5%-7%. Absolute protein concentrations furthermore allow protein alterations to be translated into changes in maximal enzymatic reaction velocities, enhancing understanding of metabolic adaptations. Thus, global absolute protein measurements provide a quantitative description of microbial states, which can support the development of therapeutic interventions. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell host & microbe 06/2015; 18(1). DOI:10.1016/j.chom.2015.06.001 · 12.33 Impact Factor
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    January Weiner · Stefan H E Kaufmann · Jeroen Maertzdorf
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    ABSTRACT: Rational vaccine development can benefit from biomarker studies, which help to predict, optimize and evaluate the immunogenicity of vaccines and ultimately provide surrogate endpoints for vaccine trials. Systems biology approaches facilitate acquisition of both simple biomarkers and complex biosignatures. Yet, evaluation of high-throughput (HT) data requires a plethora of tools for data integration and analysis. In this review, we present an overview of methods towards evaluation and integration of large amounts of data collected in vaccine trials from similar and divergent molecular HT techniques, such as transcriptomic, proteomic and metabolic profiling. We will describe a selection of relevant statistical and bioinformatic approaches that are frequently associated with "systems biology." We will present data dimension reduction techniques, functional analysis approaches and methods of integrating heterogeneous HT data. Finally, we will provide a few examples of applications of these techniques in vaccine research and development. Copyright © 2015. Published by Elsevier Ltd.
    Vaccine 05/2015; DOI:10.1016/j.vaccine.2015.04.096 · 3.62 Impact Factor
  • Stefan H E Kaufmann · Helen Fletcher · Carlos A Guzman · Tom H Ottenhoff
    Vaccine 05/2015; DOI:10.1016/j.vaccine.2015.04.078 · 3.62 Impact Factor
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    ABSTRACT: Background: A major barrier to effective tuberculosis control is our limited understanding of risk factors for tuberculosis disease progression. This study examined the role of apoptosis in immunity to tuberculosis. Methods: Cell subsets from tuberculosis cases and tuberculin skin test-positive (TST(+)) and TST-negative (TST(-)) household contacts (HHCs) were analyzed for expression of annexin-V and propidium iodide by flow cytometry. RNA microarrays were used to determine differences in apoptotic gene expression levels and multiplex ligation-dependent probe amplification was used to analyze gene expression in HHCs who progressed to active tuberculosis. Results: T cells from TST(+)HHC exhibited higher levels of apoptosis than tuberculosis cases; however, tuberculosis cases had a higher proportion of late apoptotic cells within the CD3(+)PD-1(+) subset. Tuberculosis cases had reduced levels of antiapoptotic genes compared to HHCs with a significant reduction in BCL2 associated with disease progression at least 1 year prior to progression. Conclusions: While T cells are clearly able to mount a robust immune response to Mycobacterium tuberculosis, there are increased levels of apoptosis seen in effector T cells from tuberculosis patients. Dysregulation of several apoptotic genes suggest that apoptosis is a major functional pathway that could be targeted for future host-directed therapeutics.
    The Journal of Infectious Diseases 04/2015; DOI:10.1093/infdis/jiv238 · 6.00 Impact Factor
  • Stefan H E Kaufmann
    Vaccine 04/2015; 33(26). DOI:10.1016/j.vaccine.2015.04.001 · 3.62 Impact Factor
  • Anca Dorhoi · Yonghong Feng · Stefan H E Kaufmann
    The Journal of Infectious Diseases 03/2015; 212(7). DOI:10.1093/infdis/jiv156 · 6.00 Impact Factor
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    ABSTRACT: The immune response upon infection with the pathogen Mycobacterium tuberculosis is poorly understood, hampering the discovery of new treatments and the improvements in diagnosis. In the last years, a blood transcriptional signature in tuberculosis has provided knowledge on the immune response occurring during active tuberculosis disease. This signature was absent in the majority of asymptomatic individuals who are latently infected with M. tuberculosis (referred to as latent). Using modular and pathway analyses of the complex data has shown, now in multiple studies, that the signature of active tuberculosis is dominated by overexpression of interferon-inducible genes (consisting of both type I and type II interferon signaling), myeloid genes, and inflammatory genes. There is also downregulation of genes encoding B and T-cell function. The blood signature of tuberculosis correlates with the extent of radiographic disease and is diminished upon effective treatment suggesting the possibility of new improved strategies to support diagnostic assays and methods for drug treatment monitoring. The signature suggested a previously under-appreciated role for type I interferons in development of active tuberculosis disease, and numerous mechanisms have now been uncovered to explain how type I interferon impedes the protective response to M. tuberculosis infection. © 2015 The Medical Research Council. Immunological Reviews published by John Wiley & Sons Ltd.
    Immunological Reviews 03/2015; 264(1). DOI:10.1111/imr.12269 · 10.12 Impact Factor
  • Stefan H E Kaufmann · Thomas G Evans · Willem A Hanekom
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    ABSTRACT: We need a global strategy for the development of better tuberculosis vaccines. Copyright © 2015, American Association for the Advancement of Science.
    Science translational medicine 02/2015; 7(276):276fs8. DOI:10.1126/scitranslmed.aaa4730 · 15.84 Impact Factor
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    ABSTRACT: TRANSVAC was a collaborative infrastructure project aimed at enhancing European translational vaccine research and training. The objective of this four year project (2009-2013), funded under the European Commission's (EC) seventh framework programme (FP7), was to support European collaboration in the vaccine field, principally through the provision of transnational access (TNA) to critical vaccine research and development (R&D) infrastructures, as well as by improving and harmonising the services provided by these infrastructures through joint research activities (JRA). The project successfully provided all available services to advance 29 projects and, through engaging all vaccine stakeholders, successfully laid down the blueprint for the implementation of a permanent research infrastructure for early vaccine R&D in Europe. Copyright © 2015. Published by Elsevier Ltd.
    Vaccine 02/2015; DOI:10.1016/j.vaccine.2015.01.079 · 3.62 Impact Factor
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    ABSTRACT: The probabilistic expression of cytokine genes in differentiated T helper (Th) cell populations remains ill defined. By single-cell analyses and mathematical modeling, we show that one stimulation featured stable cytokine nonproducers as well as stable producers with wide cell-to-cell variability in the magnitude of expression. Focusing on interferon-γ (IFN-γ) expression by Th1 cells, mathematical modeling predicted that this behavior reflected different cell-intrinsic capacities and not mere gene-expression noise. In vivo, Th1 cells sort purified by secreted IFN-γ amounts preserved a quantitative memory for both probability and magnitude of IFN-γ re-expression for at least 1 month. Mechanistically, this memory resulted from quantitatively distinct transcription of individual alleles and was controlled by stable expression differences of the Th1 cell lineage-specifying transcription factor T-bet. Functionally, Th1 cells with graded IFN-γ production competence differentially activated Salmonella-infected macrophages for bacterial killing. Thus, individual Th cells commit to produce distinct amounts of a given cytokine, thereby generating functional intrapopulation heterogeneity. Copyright © 2015 Elsevier Inc. All rights reserved.
    Immunity 12/2014; 42(1). DOI:10.1016/j.immuni.2014.12.018 · 21.56 Impact Factor
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    ABSTRACT: Background: The recombinant BCG ΔureC::hly (rBCG) vaccine candidate induces improved protection against tuberculosis over parental BCG (pBCG) in preclinical studies and has successfully completed a phase 2a clinical trial. However, the mechanisms responsible for the superior vaccine efficacy of rBCG are still incompletely understood. Here, we investigated the underlying biological mechanisms elicited by the rBCG vaccine candidate relevant to its protective efficacy. Methods: THP-1 macrophages were infected with pBCG or rBCG, and inflammasome activation and autophagy were evaluated. In addition, mice were vaccinated with pBCG or rBCG, and gene expression in the draining lymph nodes was analyzed by microarray at day 1 after vaccination. Results: BCG-derived DNA was detected in the cytosol of rBCG-infected macrophages. rBCG infection was associated with enhanced absent in melanoma 2 (AIM2) inflammasome activation, increased activation of caspases and production of interleukin (IL)-1β and IL-18, as well as induction of AIM2-dependent and stimulator of interferon genes (STING)-dependent autophagy. Similarly, mice vaccinated with rBCG showed early increased expression of Il-1β, Il-18, and Tmem173 (transmembrane protein 173; also known as STING). Conclusions: rBCG stimulates AIM2 inflammasome activation and autophagy, suggesting that these cell-autonomous functions should be exploited for improved vaccine design.
    The Journal of Infectious Diseases 12/2014; DOI:10.1093/infdis/jiu675 · 6.00 Impact Factor
  • Stefan H. E. Kaufmann
    Seminars in Immunology 12/2014; 26(6):429-430. DOI:10.1016/j.smim.2014.09.007 · 5.17 Impact Factor
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    ABSTRACT: Introduction Accurate, simple and cost-effective diagnostic tests are needed for diagnosis of active tuberculosis (TB). Serodiagnosis is attractive as it can be harnessed for point-of-care tests. Methods We evaluated, in a blinded fashion, the sensitivity and specificity of serologic IgG, IgA and/or IgM responses to Apa, HSP16.3, HSP20, PE35, Tpx and LAM in 42 HIV-negative South African pulmonary TB patients and 67 control individuals. The status of latent Mycobacterium tuberculosis infection (LTBI) among controls was defined through the TST and IFN-γ release assays. We evaluated 47 definite LTBI (IGRA+/LTBI), 8 putative LTBI (IGRA–/TST+) and 12 TB-uninfected (non-LTBI) subjects. Results In contrast to anti-PE35 IgA, anti-PE35 IgG and particularly anti-Apa IgA, performances of anti-LAM IgG and selected anti-protein antibodies were less affected by inclusion of LTBI participants into the analysis. Anti-LAM IgG showed with a sensitivity/specificity of 71.4%/86.6% (p<0.001) the best discrimination between TB and non-TB subjects. Selected five-antibody-combinations (including anti-LAM IgG, anti-LAM IgA and anti-Tpx IgG) further improved this performance to an accuracy exceeding 86%. Conclusions Antibody responses to some M. tuberculosis antigens often also reflect latent infection explaining the poor performance of antibody-based tests for active TB in TB endemic settings. Our results suggest that rather a combination of serological responses against selected protein and non-protein antigens and different Ig classes should be investigated for TB serodiagnostics.
    Journal of Infection 12/2014; 69(6). DOI:10.1016/j.jinf.2014.05.014 · 4.44 Impact Factor
  • Anca Dorhoi · Stefan H.E. Kaufmann
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    ABSTRACT: Pro- and anti-inflammatory mechanisms contribute equally to establishment and progression of tuberculosis.•Inflammatory mediators exhibit distinct roles at various stages of tuberculosis. Therefore in-depth temporal characterization of inflammation can provide guidelines for future interventions.•Inflammatory events are conditioned by distinct inflammatory microenvironments and depend on lung anatomy and physiological imprints.•Granuloma caseation, tissue liquefaction and lung cavitation form the basis for disease transmission.
    Seminars in Immunology 10/2014; 26(6). DOI:10.1016/j.smim.2014.10.002 · 5.17 Impact Factor
  • Jeroen Maertzdorf · Stefan H E Kaufmann · January Weiner
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    ABSTRACT: Accurate and rapid diagnosis of active tuberculosis (TB) disease is still hampered by inadequate tools. Although current assays relying on single-marker readouts mostly display inadequate sensitivity and/or specificity, host-related multimarker signatures are especially poorly developed. As a consequence, research programs have been initiated to search for combinations of markers-so-called biosignatures with superior performance. Many such investigations harness high-throughput platforms to analyze the host response during infection and disease. A major challenge for these activities is the analysis of vast amounts of data produced. Specialized bioinformatic tools are being applied to identify the most robust biosignatures for classification of exposed and diseased individuals and prognosis of risk of disease in endemic areas. Validation of the most promising biosignatures in ongoing multicohort studies will bring us a step closer to the identification of an accurate unified signature.
    Cold Spring Harbor Perspectives in Medicine 10/2014; 5(1). DOI:10.1101/cshperspect.a018531 · 9.47 Impact Factor

Publication Stats

20k Citations
3,268.14 Total Impact Points


  • 1998–2015
    • Max Planck Institute for Infection Biology
      • Department of Immunology
      Berlín, Berlin, Germany
    • University of Wuerzburg
      • Department of Microbiology
      Würzburg, Bavaria, Germany
  • 2013
    • University of Melbourne
      Melbourne, Victoria, Australia
  • 2012
    • French National Centre for Scientific Research
      • Institute of Pharmacology and Structural Biology
      Lutetia Parisorum, Île-de-France, France
  • 2011
    • Technische Universität München
      München, Bavaria, Germany
    • Charité Universitätsmedizin Berlin
      Berlín, Berlin, Germany
  • 2009
    • Makerere University
      • School of Medicine
      Kampala, Central Region, Uganda
  • 1990–2008
    • Universität Heidelberg
      • Institute of Immunology and Serology
      Heidelburg, Baden-Württemberg, Germany
  • 2007
    • Vanderbilt University
      Nashville, Michigan, United States
    • London School of Hygiene and Tropical Medicine
      • Department of Immunology and Infection
      London, ENG, United Kingdom
    • University of Greifswald
      • Institute for Microbiology
      Greifswald, Mecklenburg-Vorpommern, Germany
    • University of Lille Nord de France
      Lille, Nord-Pas-de-Calais, France
  • 2006
    • European Federation of Immunological Societies
      Berlín, Berlin, Germany
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 2005
    • Cornell University
      Итак, New York, United States
  • 1988–2002
    • Universität Ulm
      • • Institute of Microbiology and Biotechnology
      • • Institute of Medical Microbiology and Hygiene
      Ulm, Baden-Wuerttemberg, Germany
  • 2000
    • Statens Serum Institut
      København, Capital Region, Denmark
  • 1999
    • Humboldt-Universität zu Berlin
      Berlín, Berlin, Germany
  • 1984–1988
    • Max Planck Institute of Immunobiology and Epigenetics
      Freiburg, Baden-Württemberg, Germany
  • 1981–1983
    • Freie Universität Berlin
      Berlín, Berlin, Germany