Stefan H E Kaufmann

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

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Publications (478)3166.71 Total impact

  • The Journal of Infectious Diseases 04/2015; DOI:10.1093/infdis/jiv238 · 5.78 Impact Factor
  • Stefan H E Kaufmann
    Vaccine 04/2015; DOI:10.1016/j.vaccine.2015.04.001 · 3.49 Impact Factor
  • Anca Dorhoi, Yonghong Feng, Stefan H E Kaufmann
    The Journal of Infectious Diseases 03/2015; DOI:10.1093/infdis/jiv156 · 5.78 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 · 12.91 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 · 14.41 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 · 3.49 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 · 19.75 Impact Factor
  • The Journal of Infectious Diseases 12/2014; DOI:10.1093/infdis/jiu675 · 5.78 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; DOI:10.1016/j.jinf.2014.05.014 · 4.02 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 · 6.12 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 · 7.56 Impact Factor
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    ABSTRACT: Tuberculosis (TB) diagnosis in low-income countries is mainly done by microscopy. Hence, little is known about the diversity of Mycobacterium spp. in TB infections. Different genotypes or lineages of Mycobacterium tuberculosis vary in virulence and induce different inflammatory and immune responses. Trained Cricetomys rats show a potential for rapid diagnosis of TB. They detect over 28 % of smear-negative, culture-positive TB. However, it is unknown whether these rats can equally detect sputa from patients infected with different genotypes of M. tuberculosis. A 4-month prospective study on diversity of Mycobacterium spp. was conducted in Dar es Salaam, Tanzania. 252 sputa from 161 subjects were cultured on Lowenstein-Jensen medium and thereafter tested by rats. Mycobacterial isolates were subjected to molecular identification and multispacer sequence typing (MST) to determine species and genotypes. A total of 34 Mycobacterium spp. isolates consisting of 32 M. tuberculosis, 1 M. avium subsp. hominissuis and 1 M. intracellulare were obtained. MST analyses of 26 M. tuberculosis isolates yielded 10 distinct MST genotypes, including 3 new genotypes with two clusters of related patterns not grouped by geographic areas. Genotype MST-67, shared by one-third of M. tuberculosis isolates, was associated with the Mwananyamala clinic. This study shows that diverse M. tuberculosis genotypes (n = 10) occur in Dar es Salaam and trained rats detect 80 % of the genotypes. Sputa with two M. tuberculosis genotypes (20 %), M. avium hominissuis and M. intracellulare were not detected. Therefore, rats detect sputa with different M. tuberculosis genotypes and can be used to detect TB in resource-poor countries.
    Current Microbiology 10/2014; 70(2). DOI:10.1007/s00284-014-0705-6 · 1.36 Impact Factor
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    ABSTRACT: Lung granulomas develop upon Mycobacterium tuberculosis (Mtb) infection as a hallmark of human tuberculosis (TB). They are structured aggregates consisting mainly of Mtb-infected and -uninfected macrophages and Mtb-specific T cells. The production of NO by granuloma macrophages expressing nitric oxide synthase-2 (NOS2) via l-arginine and oxygen is a key protective mechanism against mycobacteria. Despite this protection, TB granulomas are often hypoxic, and bacterial killing via NOS2 in these conditions is likely suboptimal. Arginase-1 (Arg1) also metabolizes l-arginine but does not require oxygen as a substrate and has been shown to regulate NOS2 via substrate competition. However, in other infectious diseases in which granulomas occur, such as leishmaniasis and schistosomiasis, Arg1 plays additional roles such as T-cell regulation and tissue repair that are independent of NOS2 suppression. To address whether Arg1 could perform similar functions in hypoxic regions of TB granulomas, we used a TB murine granuloma model in which NOS2 is absent. Abrogation of Arg1 expression in macrophages in this setting resulted in exacerbated lung granuloma pathology and bacterial burden. Arg1 expression in hypoxic granuloma regions correlated with decreased T-cell proliferation, suggesting that Arg1 regulation of T-cell immunity is involved in disease control. Our data argue that Arg1 plays a central role in the control of TB when NOS2 is rendered ineffective by hypoxia.
    Proceedings of the National Academy of Sciences 09/2014; 111(38). DOI:10.1073/pnas.1408839111 · 9.81 Impact Factor
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    ABSTRACT: The aryl hydrocarbon receptor (AhR) is a highly conserved ligand-dependent transcription factor that senses environmental toxins and endogenous ligands, thereby inducing detoxifying enzymes and modulating immune cell differentiation and responses. We hypothesized that AhR evolved to sense not only environmental pollutants but also microbial insults. We characterized bacterial pigmented virulence factors, namely the phenazines from Pseudomonas aeruginosa and the naphthoquinone phthiocol from Mycobacterium tuberculosis, as ligands of AhR. Upon ligand binding, AhR activation leads to virulence factor degradation and regulated cytokine and chemokine production. The relevance of AhR to host defence is underlined by heightened susceptibility of AhR-deficient mice to both P. aeruginosa and M. tuberculosis. Thus, we demonstrate that AhR senses distinct bacterial virulence factors and controls antibacterial responses, supporting a previously unidentified role for AhR as an intracellular pattern recognition receptor, and identify bacterial pigments as a new class of pathogen-associated molecular patterns.
    Nature 08/2014; 512(7515). DOI:10.1038/nature13684 · 42.35 Impact Factor
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    ABSTRACT: General interest in the biological functions of IFN type I in Mycobacterium tuberculosis (Mtb) infection increased after the recent identification of a distinct IFN gene expression signature in tuberculosis (TB) patients. Here we demonstrate that TB-susceptible mice lacking the receptor for IFN I (IFNAR1) were protected from death upon aerogenic infection with Mtb. Using this experimental model to mimic primary progressive pulmonary TB we dissected the immune processes affected by IFN I. IFNAR1 signaling did not affect T-cell responses, but markedly altered migration of inflammatory monocytes and neutrophils to the lung. This process was orchestrated by IFNAR1 expressed on both immune and tissue-resident radioresistant cells. IFNAR1-driven TB susceptibility was initiated by augmented Mtb replication and in situ death events, along with CXCL5/CXCL1-driven accumulation of neutrophils in alveoli, followed by the discrete compartmentalization of Mtb in lung phagocytes. Early depletion of neutrophils rescued TB-susceptible mice to levels observed in mice lacking IFNAR1. We conclude that IFN I alters early innate events at the site of Mtb invasion leading to fatal immunopathology. These data furnish a mechanistic explanation for the detrimental role of IFN I in pulmonary TB and form a basis for understanding the complex roles of IFN I in chronic inflammation.This article is protected by copyright. All rights reserved
    European Journal of Immunology 08/2014; 44(8). DOI:10.1002/eji.201344219 · 4.52 Impact Factor
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    ABSTRACT: Human primary dendritic cells (DCs) are heterogeneous by phenotype, function, and tissue localization and distinct from inflammatory monocyte-derived DCs. Current information regarding the susceptibility and functional role of primary human DC subsets to Mycobacterium tuberculosis (Mtb) infection is limited. Here, we dissect the response of different primary DC subsets to Mtb infection. Myeloid CD11c(+) cells and pDCs (C-type lectin 4C(+) cells) were located in human lymph nodes (LNs) of tuberculosis (TB) patients by histochemistry. Rare CD141(hi) DCs (C-type lectin 9A(+) cells) were also identified. Infection with live Mtb revealed a higher responsiveness of myeloid CD1c(+) DCs compared to CD141(hi) DCs and pDCs. CD1c(+) DCs produced interleukin (IL)-6, tumor necrosis factor α, and IL-1β but not IL-12p70, a cytokine important for Th1 activation and host defenses against Mtb. Yet, CD1c(+) DCs were able to activate autologous naïve CD4(+) T cells. By combining cell purification with fluorescence-activated cell sorting and gene expression profiling on rare cell populations, we detected in responding CD4(+) T cells, genes related to effector-cytolytic functions and transcription factors associated with Th1, Th17, and Treg polarization, suggesting multifunctional properties in our experimental conditions. Finally, immunohistologic analyses revealed contact between CD11c(+) cells and pDCs in LNs of TB patients and in vitro data suggest that cooperation between Mtb-infected CD1c(+) DCs and pDCs favors stimulation of CD4(+) T cells.
    Frontiers in Immunology 07/2014; 5:324. DOI:10.3389/fimmu.2014.00324
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    ABSTRACT: Epithelioid, foam and multinucleated giant cells (MNGCs) are characteristics of tuberculosis (TB) granulomas, yet the precise genesis and functions of these transformed macrophages are unclear. We evaluated the role of platelets as drivers of macrophage transformation in mycobacterial infection.
    The Journal of Infectious Diseases 07/2014; DOI:10.1093/infdis/jiu355 · 5.78 Impact Factor
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    ABSTRACT: Protective immunity against preerythrocytic malaria parasite infection is difficult to achieve. Intracellular Plasmodium parasites likely minimize antigen presentation by surface-expressed major histocompatibility complex class I (MHC-I) molecules on infected cells, yet they actively remodel their host cells by export of parasite factors. Whether exported liver-stage proteins constitute better candidates for MHC-I antigen presentation to CD8(+) T lymphocytes remains unknown. Here, we systematically characterized the contribution of protein export to the magnitude of antigen-specific T-cell responses against Plasmodium berghei liver-stage parasites in C57BL/6 mice. We generated transgenic sporozoites that secrete a truncated ovalbumin (OVA) surrogate antigen only in the presence of an amino-terminal protein export element. Immunization with live attenuated transgenic sporozoites revealed that antigen export was not critical for CD8(+) T-cell priming but enhanced CD8(+) T-cell proliferation in the liver. Upon transfer of antigen-specific CD8(+) T cells, liver-stage parasites secreting the target protein were eliminated more efficiently. We conclude that Plasmodium parasites strictly control protein export during liver infection to minimize immune recognition. Strategies that enhance the discharge of parasite proteins into infected hepatocytes could improve the efficacy of candidate preerythrocytic malaria vaccines.
    mBio 07/2014; 5(4). DOI:10.1128/mBio.01321-14 · 6.88 Impact Factor
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    ABSTRACT: High-throughput analyses of RNA and protein expression are increasingly used for better understanding of vaccine-induced immunity and protection against infectious disease. With an increasing number of vaccine candidates in clinical development, it is timely to consider standardisation and harmonisation of sample collection, storage and analysis to ensure results of highest quality from these precious samples. These challenges were discussed by a group of international experts during a workshop organised by TRANSVAC, a European Commission-funded Research Infrastructure project. The main conclusions were: Platforms are rarely standardised for use in preclinical and clinical studies. Coordinated efforts should continue to harmonise the experimental set up of these studies, as well as the establishment of internal standards and controls. This will ensure comparability, efficiency and feasibility of the global analyses performed on preclinical and clinical data sets.
    Vaccine 07/2014; 32(35). DOI:10.1016/j.vaccine.2014.06.014 · 3.49 Impact Factor
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    ABSTRACT: Bacillus Calmette-Guérin (BCG) has been used for vaccination against tuberculosis (TB) for nearly a century. Here we analyse immunity induced by a live TB vaccine candidate, recombinant BCG ΔureC::hly (rBCG), with proven pre-clinical and clinical safety and immunogenicity. We pursue in-depth analysis of the endogenous mycobacteria-specific CD4 T cell population, comparing the more efficacious rBCG with canonical BCG to determine which T memory responses are prerequisite for superior protection against TB. rBCG induced higher numbers and proportions of antigen-specific memory CD4 T cells than BCG, with a CXCR5(+)CCR7(+) phenotype and low expression of the effector transcription factors T-bet and Bcl-6. We find that superior protection of rBCG over BCG correlated with higher proportions and numbers of these central memory T cells, and increased T follicular helper cells associated with specific antibody responses. Adoptive transfer of mycobacteria-specific central memory T cells validated their critical role in protection against pulmonary TB.
    The Journal of Infectious Diseases 06/2014; 210(12). DOI:10.1093/infdis/jiu347 · 5.78 Impact Factor

Publication Stats

18k Citations
3,166.71 Total Impact Points

Institutions

  • 1998–2015
    • Max Planck Institute for Infection Biology
      • Department of Immunology
      Berlín, Berlin, Germany
  • 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
  • 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
    • University of Lille Nord de France
      Lille, Nord-Pas-de-Calais, France
    • 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
  • 2006
    • European Federation of Immunological Societies
      Berlín, Berlin, Germany
    • National Institute of Infectious Diseases, Tokyo
      Edo, Tōkyō, Japan
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 2005
    • Cornell University
      Итак, New York, United States
  • 2002
    • Humboldt-Universität zu Berlin
      Berlín, Berlin, Germany
  • 1988–2002
    • Universität Ulm
      • • Institute of Microbiology and Biotechnology
      • • Institute of Medical Microbiology and Hygiene
      Ulm, Baden-Wuerttemberg, Germany
  • 1998–2001
    • University of Wuerzburg
      • Department of Microbiology
      Würzburg, Bavaria, Germany
  • 1995
    • Tokyo Metropolitan Institute of Public Health
      • Department of Veterinary Public Health
      Edo, Tōkyō, Japan
  • 1984–1988
    • Max Planck Institute of Immunobiology and Epigenetics
      Freiburg, Baden-Württemberg, Germany
  • 1981–1983
    • Freie Universität Berlin
      Berlín, Berlin, Germany