Peter Staeheli

Universitätsklinikum Freiburg, Freiburg an der Elbe, Lower Saxony, Germany

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Publications (255)1372.18 Total impact

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    ABSTRACT: As the tissue macrophages of the CNS, microglia are critically involved in diseases of the CNS. However, it remains unknown what controls their maturation and activation under homeostatic conditions. We observed substantial contributions of the host microbiota to microglia homeostasis, as germ-free (GF) mice displayed global defects in microglia with altered cell proportions and an immature phenotype, leading to impaired innate immune responses. Temporal eradication of host microbiota severely changed microglia properties. Limited microbiota complexity also resulted in defective microglia. In contrast, recolonization with a complex microbiota partially restored microglia features. We determined that short-chain fatty acids (SCFA), microbiota-derived bacterial fermentation products, regulated microglia homeostasis. Accordingly, mice deficient for the SCFA receptor FFAR2 mirrored microglia defects found under GF conditions. These findings suggest that host bacteria vitally regulate microglia maturation and function, whereas microglia impairment can be rectified to some extent by complex microbiota.
    Nature Neuroscience 06/2015; DOI:10.1038/nn.4030 · 14.98 Impact Factor
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    ABSTRACT: The epithelium is the main entry point for many viruses, but the processes that protect barrier surfaces against viral infections are incompletely understood. Here we identified interleukin 22 (IL-22) produced by innate lymphoid cell group 3 (ILC3) as an amplifier of signaling via interferon-λ (IFN-λ), a synergism needed to curtail the replication of rotavirus, the leading cause of childhood gastroenteritis. Cooperation between the receptor for IL-22 and the receptor for IFN-λ, both of which were 'preferentially' expressed by intestinal epithelial cells (IECs), was required for optimal activation of the transcription factor STAT1 and expression of interferon-stimulated genes (ISGs). These data suggested that epithelial cells are protected against viral replication by co-option of two evolutionarily related cytokine networks. These data may inform the design of novel immunotherapy for viral infections that are sensitive to interferons.
    Nature Immunology 05/2015; DOI:10.1038/ni.3180 · 24.97 Impact Factor
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    ABSTRACT: Unrelenting environmental challenges to the gut epithelium place particular demands on the local immune system. In this context, intestinal intraepithelial lymphocytes (IEL) compose a large, highly conserved T cell compartment, hypothesized to provide a first line of defence via cytolysis of dysregulated intestinal epithelial cells (IEC) and cytokine-mediated re-growth of healthy IEC. Here we show that one of the most conspicuous impacts of activated IEL on IEC is the functional upregulation of antiviral interferon (IFN)-responsive genes, mediated by the collective actions of IFNs with other cytokines. Indeed, IEL activation in vivo rapidly provoked type I/III IFN receptor-dependent upregulation of IFN-responsive genes in the villus epithelium. Consistent with this, activated IEL mediators protected cells against virus infection in vitro, and pre-activation of IEL in vivo profoundly limited norovirus infection. Hence, intraepithelial T cell activation offers an overt means to promote the innate antiviral potential of the intestinal epithelium.
    Nature Communications 05/2015; 6. DOI:10.1038/ncomms8090 · 10.74 Impact Factor
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    ABSTRACT: Epithelial cells are a major port of entry for many viruses, but the molecular networks which protect barrier surfaces against viral infections are incompletely understood. Viral infections induce simultaneous production of type I (IFN-α/β) and type III (IFN-λ) interferons. All nucleated cells are believed to respond to IFN-α/β, whereas IFN-λ responses are largely confined to epithelial cells. We observed that intestinal epithelial cells, unlike hematopoietic cells of this organ, express only very low levels of functional IFN-α/β receptors. Accordingly, after oral infection of IFN-α/β receptor-deficient mice, human reovirus type 3 specifically infected cells in the lamina propria but, strikingly, did not productively replicate in gut epithelial cells. By contrast, reovirus replicated almost exclusively in gut epithelial cells of IFN-λ receptor-deficient mice, suggesting that the gut mucosa is equipped with a compartmentalized IFN system in which epithelial cells mainly respond to IFN-λ that they produce after viral infection, whereas other cells of the gut mostly rely on IFN-α/β for antiviral defense. In suckling mice with IFN-λ receptor deficiency, reovirus replicated in the gut epithelium and additionally infected epithelial cells lining the bile ducts, indicating that infants may use IFN-λ for the control of virus infections in various epithelia-rich tissues. Thus, IFN-λ should be regarded as an autonomous virus defense system of the gut mucosa and other epithelial barriers that may have evolved to avoid unnecessarily frequent triggering of the IFN-α/β system which would induce exacerbated inflammation.
    PLoS Pathogens 04/2015; 11(4):e1004782. DOI:10.1371/journal.ppat.1004782 · 8.06 Impact Factor
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    ABSTRACT: The H2N2/1957 and H3N2/1968 pandemic influenza viruses emerged via the exchange of genomic RNA segments between human and avian viruses. The avian hemagglutinin (HA) allowed the hybrid viruses to escape pre-existing immunity in the human population. Both pandemic viruses further received the PB1 gene segment from the avian parent (Y.Kawaoka, S.Krauss and R.G.Webster, J Virol 63:4603-4608, 1989), but the biological significance of this observation was not understood. To assess whether the avian-origin PB1 segment provided pandemic viruses with some selective advantage, either on its own or via cooperation with the homologous HA segment, we modeled by reverse genetics the reassortment event that led to the emergence of the H3N2/1968 pandemic virus. Using seasonal H2N2 virus A/California/1/66 (Cal) as a surrogate precursor human virus and pandemic virus A/Hong Kong/1/68 (H3N2) (HK) as a source of avian-derived PB1 and HA gene segments, we generated four reassortant recombinant viruses and compared pairs of viruses which differed solely by the origin of PB1. Substitution of the PB1 segment of Cal by PB1 of HK facilitated viral polymerase activity, replication efficiency in human cells and contact transmission in guinea pigs. A combination of PB1 and HA segments of HK did not enhance replicative fitness of the reassortant virus in comparison with the single-gene PB1 reassortant. Our data suggest that the avian PB1 segment of the 1968 pandemic virus served to enhance viral growth and transmissibility, likely, by enhancing activity of the viral polymerase complex. Despite the high impact of influenza pandemics on human health, some mechanisms underlying the emergence of pandemic influenza viruses are still poorly understood. Thus, it was unclear why both H2N2/1957 and H3N2/1968 reassortant pandemic viruses contained, in addition to the avian HA, the PB1 gene segment of the avian parent. Here we addressed this long-standing question by modeling the emergence of the H3N2/1968 virus from its putative human and avian precursors. We show that the avian PB1 segment increased activity of the viral polymerase and facilitated viral replication. Our results suggest that in addition to acquisition of antigenically novel HA ("antigenic shift") enhanced viral polymerase activity may be required for the emergence of pandemic influenza viruses from their seasonal human precursors. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Journal of Virology 01/2015; 89(8). DOI:10.1128/JVI.03194-14 · 4.65 Impact Factor
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    ABSTRACT: Hepatitis C virus (HCV) efficiently infects only humans and chimpanzees. Although the detailed mechanisms responsible for this narrow species tropism remain elusive, recent evidence has shown that murine innate immune responses efficiently suppress HCV replication. Therefore, poor adaptation of HCV to evade and/or counteract innate immune responses may prevent HCV replication in mice. The HCV NS3-4A protease cleaves human MAVS, a key cellular adaptor protein required for RIG-I like receptor (RLRs) dependent innate immune signalling. However, it is unclear if HCV interferes with mouse MAVS function equally well. Moreover, MAVS-dependent signalling events that restrict HCV replication in mouse cells were incompletely defined. Thus, we quantified the ability of HCV NS3-4A to counteract mouse and human MAVS. HCV NS3-4A similarly diminished both human and mouse MAVS-dependent signalling in human and mouse cells. Moreover, replicon-encoded protease cleaved a similar fraction of both MAVS variants. Finally, FLAG-tagged MAVS proteins repressed HCV replication to similar degree. Depending on MAVS expression, HCV replication in mouse liver cells triggered not only type-I but also type-III IFNs, which cooperatively repressed HCV replication. Mouse liver cells lacking both type-I and -III IFN receptors were refractory to MAVS-dependent antiviral effects indicating that the HCV-induced MAVS-dependent antiviral state depends on both type-I and -III IFN-receptor signalling. Here we found that HCV NS3-4A similarly diminished both human and mouse MAVS-dependent signalling in human and mouse cells. Therefore, it is unlikely that ineffective cleavage of mouse MAVS per se precludes HCV propagation in immune competent mouse liver cells. Hence, approaches to reinforce HCV replication in mouse liver cells (e.g. by expression of essential human replication co-factors) should not be thwarted by the poor ability of HCV to counteract MAVS-dependent antiviral signalling. In addition we show that that mouse MAVS induces both type-I and type-III IFNs, which together control HCV replication. Characterization of type-I or type-III-dependent interferon stimulated genes in these cells should help to identify key murine restriction factors that preclude HCV propagation in immune competent mouse liver cells. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Journal of Virology 01/2015; 89:3833-3845. DOI:10.1128/JVI.03129-14 · 4.65 Impact Factor
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    ABSTRACT: The Mx dynamin-like GTPases are key antiviral effector proteins of the type I and type III interferon (IFN) systems. They inhibit several different viruses by blocking early steps of the viral replication cycle. We focus on new structural and functional insights and discuss recent data revealing that human MxA (MX1) provides a safeguard against introduction of avian influenza A viruses (FLUAV) into the human population. The related human MxB (MX2) serves as restriction factor for HIV-1 and other primate lentiviruses. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Trends in Microbiology 01/2015; 23(3). DOI:10.1016/j.tim.2014.12.003 · 9.81 Impact Factor
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    ABSTRACT: The type I interferon (IFN) response represents the first line of defence to invading pathogens. Internalized viral ribonucleoproteins (vRNPs) of negative-strand RNA viruses induce an early IFN response by interacting with retinoic acid inducible gene I (RIG-I) and its recruitment to mitochondria. Here we employ three-dimensional stochastic optical reconstruction microscopy (STORM) to visualize incoming influenza A virus (IAV) vRNPs as helical-like structures associated with mitochondria. Unexpectedly, an early IFN induction in response to vRNPs is not detected. A distinct amino-acid motif in the viral polymerases, PB1/PA, suppresses early IFN induction. Mutation of this motif leads to reduced pathogenicity in vivo, whereas restoration increases it. Evolutionary dynamics in these sequences suggest that completion of the motif, combined with viral reassortment can contribute to pandemic risks. In summary, inhibition of the immediate anti-viral response is 'pre-packaged' in IAV in the sequences of vRNP-associated polymerase proteins.
    Nature Communications 12/2014; 5:5645. DOI:10.1038/ncomms6645 · 10.74 Impact Factor
  • Immunology 12/2014; 143:103-103. · 3.74 Impact Factor
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    ABSTRACT: The human intestinal parasite Schistosoma mansoni causes a chronic disease, schistosomiasis or bilharzia. According to the current literature, the parasite induces vigorous immune responses that are controlled by Th2 helper cells at the expense of Th1 helper cells. The latter cell type is, however, indispensable for anti-viral immune responses. Remarkably, there is no reliable literature among 230 million patients worldwide describing defective anti-viral immune responses in the upper respiratory tract, for instance against influenza A virus or against respiratory syncitial virus (RSV). We therefore re-examined the immune response to a human isolate of S. mansoni and challenged mice in the chronic phase of schistosomiasis with influenza A virus, or with pneumonia virus of mice (PVM), a mouse virus to model RSV infections. We found that mice with chronic schistosomiasis had significant, systemic immune responses induced by Th1, Th2, and Th17 helper cells. High serum levels of TNF-a, IFN-c, IL-5, IL-13, IL-2, IL-17, and GM-CSF were found after mating and oviposition. The lungs of diseased mice showed low-grade inflammation, with goblet cell hyperplasia and excessive mucus secretion, which was alleviated by treatment with an anti-TNF-a agent (Etanercept). Mice with chronic schistosomiasis were to a relative, but significant extent protected from a secondary viral respiratory challenge. The protection correlated with the onset of oviposition and TNF-a-mediated goblet cell hyperplasia and mucus secretion, suggesting that these mechanisms are involved in enhanced immune protection to respiratory viruses during chronic murine schistosomiasis. Indeed, also in a model of allergic airway inflammation mice were protected from a viral respiratory challenge with PVM. Copyright: ß 2014 Scheer et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files. Funding: SS was supported by the Fonds National de la Recherche, Luxembourg (http://www.fnr.lu) (PHD-08-045-RE). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist.
    PLoS ONE 11/2014; DOI:10.1371/journal.pone.0112469 · 3.53 Impact Factor
  • 2nd Annual Meeting of the International-Cytokine-and-Interferon-Society; 11/2014
  • 2nd Annual Meeting of the International-Cytokine-and-Interferon-Society; 11/2014
  • 2nd Annual Meeting of the International-Cytokine-and-Interferon-Society; 11/2014
  • Julia Spanier, Peter Staeheli, Ulrich Kalinke
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    ABSTRACT: Many pathogens trigger type I interferon (IFN-I) responses early after infection that confer protection until adaptive immunity is induced. Upon infection with vesicular stomatitis virus (VSV) Toll-like receptor (TLR) and RIG-I-like helicase (RLH) signaling platforms are indispensable for the induction of protective IFN-I. Hence, TLR- and RLH-ablated MyTrCa−/− mice challenged with VSV do not mount IFN-I responses and are inevitably susceptible to lethal VSV infection. To study the impact of the kinetics of IFN-I responses on the induction of adaptive immunity, we infected MyTrCa−/− mice with VSV and treated them 4, 8, 16, and 24 h after infection with recombinant IFN-αα (rIFN-α)α). Interestingly, under such conditions MyTrCa−/− mice mounted normal adaptive immune responses and approximately 76% of the mice survived. On the contrary, initiation of the rIFN-αα treatment scheme 4 h before VSV infection significantly prolonged survival, whereas reduced VSV-specific cytotoxic T-lymphocytes and basically no VSV neutralizing antibody responses were induced and 100% of the mice finally died. Long-term rIFN-α treatment for 9 days initiated 4 h after VSV infection promoted 100% survival of MyTrCa−/− mice and protective immunity was induced normally as verified by 100% of the animals surviving even a VSV re-challenge 3 weeks after discontinuation of the rIFN-α treatment. Initiation of the 9 days rIFN-α regimen 4 h prior to infection also rescued 100% of the mice, however, no adaptive immunity developed and 100% of the animals succumbed to re-challenge. In conclusion, long-term rIFN-α treatment initiated before virus infection prevented induction of protective adaptive immunity, whereas initiation of rIFN-α treatment hours after infection supported development of normal adaptive immunity and protective memory response. These observations have implications for immunotherapies and vaccination strategies, in particular for patients under long-term IFN-I therapy who are treated with live attenuated vaccines.
    Cytokines Down Under 2014: From Bench To Beyond, Melbourne; 10/2014
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    ABSTRACT: Avian bornaviruses (ABVs) are a group of genetically diverse viruses within the Bornaviridae family that can infect numerous avian species and represent the causative agents of proventricular dilatation disease, an often fatal disease that is widely distributed in captive populations of parrots and related species. The current study was designed to assess the antigenic variability of the family Bornaviridae and to determine its impact on ABV diagnosis by employing fluorescent antibody assays. It was shown that polyclonal rabbit sera directed against recombinant bornavirus nucleoprotein, X protein, phosphoprotein, and matrix protein provided sufficient cross-reactivity for the detection of viral antigen from a broad range of bornavirus genotypes grown in cell culture. In contrast, a rabbit anti-glycoprotein serum and 2 monoclonal antibodies directed against nucleoprotein and phosphoprotein proteins reacted more specifically. Antibodies were readily detected in sera from avian patients infected with known ABV genotypes if cells persistently infected with a variety of different bornavirus genotypes were used for analysis. For all sera, calculated antibody titers were highest when the homologous or a closely related target virus was used for the assay. Cross-reactivity with more distantly related genotypes of other phylogenetic groups was usually reduced, resulting in titer reduction of up to 3 log units. The presented results contribute to a better understanding of the antigenic diversity of family Bornaviridae and further emphasize the importance of choosing appropriate diagnostic tools for sensitive detection of ABV infections.
    Journal of veterinary diagnostic investigation: official publication of the American Association of Veterinary Laboratory Diagnosticians, Inc 08/2014; 26(6). DOI:10.1177/1040638714547258 · 1.23 Impact Factor
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    ABSTRACT: Several studies indicated that TLR as well as retinoic acid-inducible gene I-like helicase (RLH) signaling contribute to vesicular stomatitis virus (VSV)-mediated triggering of type I IFN (IFN-I) responses. Nevertheless, TLR-deficient MyD88(-/-)Trif(-/-) mice and RLH-deficient caspase activation and recruitment domain adaptor inducing IFN-β (Cardif)(-/-) mice showed only marginally enhanced susceptibility to lethal VSV i.v. infection. Therefore, we addressed whether concomitant TLR and RLH signaling, or some other additional mechanism, played a role. To this end, we generated MyD88(-/-)Trif(-/-)Cardif(-/-) (MyTrCa(-/-)) mice that succumbed to low-dose i.v. VSV infection with similar kinetics as IFN-I receptor-deficient mice. Three independent approaches (i.e., analysis of IFN-α/β serum levels, experiments with IFN-β reporter mice, and investigation of local IFN-stimulated gene induction) revealed that MyTrCa(-/-) mice did not mount IFN-I responses following VSV infection. Of note, treatment with rIFN-α protected the animals, qualifying MyTrCa(-/-) mice as a model to study the contribution of different immune cell subsets to the production of antiviral IFN-I. Upon adoptive transfer of wild-type plasmacytoid dendritic cells and subsequent VSV infection, MyTrCa(-/-) mice displayed significantly reduced viral loads in peripheral organs and showed prolonged survival. On the contrary, adoptive transfer of wild-type myeloid dendritic cells did not have such effects. Analysis of bone marrow chimeric mice revealed that TLR and RLH signaling of radioresistant and radiosensitive cells was required for efficient protection. Thus, upon VSV infection, plasmacytoid dendritic cell-derived IFN-I primarily protects peripheral organs, whereas concomitant TLR and RLH signaling of radioresistant stroma cells as well as of radiosensitive immune cells is needed to effectively protect against lethal disease.
    The Journal of Immunology 08/2014; DOI:10.4049/jimmunol.1400959 · 5.36 Impact Factor
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    ABSTRACT: Avian bornaviruses (ABV) are the causative agents of proventricular dilatation disease (PDD), a widely distributed disease of parrots. Distinct ABV lineages were also found in various non-psittacine avian species, such as canaries, but the pathogenic role of ABV in these species is less clear. Despite the wide distribution of ABV in captive parrots and canaries, its mode of transmission is poorly understood: both horizontal transmission via the urofaecal-oral route and vertical transmission are discussed to play a role. In this study we investigated pathology and horizontal transmission of ABV in domestic canaries (Serinus canaria forma domestica) and cockatiels (Nymphicus hollandicus), two natural host species commonly used for experimental ABV infections. ABV inoculation resulted in persistent infection of all inoculated animals from both species. ABV-infected cockatiels exhibited PDD-like symptoms, such as neurologic signs or shedding of undigested seeds. In contrast, infected domestic canaries did not develop clinical disease. Interestingly, we did not detect viral RNA in cloacal swabs and organ samples or ABV-specific antibodies in serum samples of contact-exposed sentinel birds from either species at any time during a four months observation period. Our results strongly indicate that horizontal transmission of ABV by direct contact is inefficient in immunocompetent fully fledged domestic canaries and cockatiels.
    Veterinary Microbiology 05/2014; 172(1-2). DOI:10.1016/j.vetmic.2014.05.011 · 2.73 Impact Factor
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    ABSTRACT: The transcription factor STAT1 is essential for interferon- (IFN) mediated immunity in humans and mice. STAT1 function is tightly regulated and both loss- and gain-of function mutations result in severe immune diseases. The two alternatively spliced isoforms, STAT1α and STAT1β, differ with regard to a C-terminal transactivation domain, which is absent in STAT1β. STAT1β is considered to be transcriptionally inactive and to be a competitive inhibitor of STAT1α. To investigate the functions of the STAT1 isoforms in vivo we generated mice deficient for either STAT1α or STAT1β. As expected, the functions of STAT1α and STAT1β in IFNα/β- and IFNλ-dependent antiviral activity are largely redundant. In contrast to the current dogma, however, we found that STAT1β is transcriptionally active in response to IFNγ. In the absence of STAT1α, STAT1β shows more prolonged IFNγ-induced phosphorylation and promoter binding. Both isoforms mediate protective, IFNγ-dependent immunity against the bacterium Listeria monocytogenes, although with remarkably different efficiencies. Our data shed new light on the potential contribution of the individual STAT1 isoforms to STAT1-dependent immune responses. The knowledge of STAT1β's function will help fine-tune diagnostic approaches and design more specific strategies to interfere with STAT1 activity.
    Molecular and Cellular Biology 04/2014; 34(12). DOI:10.1128/MCB.00295-14 · 5.04 Impact Factor
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    ABSTRACT: The type III interferon (IFN) receptor is preferentially expressed by epithelial cells. It is made of two subunits: IFNLR1, which is specific to IFN-lambda (IFN-λ) and IL10RB, which is shared by other cytokine receptors. Human hepatocytes express IFNLR1 and respond to IFN-λ. In contrast, the IFN-λ response of the mouse liver is very weak and IFNLR1 expression is hardly detectable in this organ. Here we investigated the IFN-λ response at the cellular level in the mouse liver and we tested whether human and mouse hepatocytes truly differ in responsiveness to IFN-λ. When monitoring expression of the IFN-responsive Mx genes by immunohistofluorescence, we observed that the IFN-λ response in mouse livers was restricted to cholangiocytes, which form the bile ducts, and that mouse hepatocytes were indeed not responsive to IFN-λ. The lack of mouse hepatocyte response to IFN-λ was observed in different experimental settings, including the infection with a hepatotropic strain of influenza A virus which triggered a strong local production of IFN-λ. With the help of chimeric mice containing transplanted human hepatocytes, we show that hepatocytes of human origin readily responded to IFN-λ in a murine environment. Thus, our data suggest that human but not mouse hepatocytes are responsive to IFN-λ in vivo. The non-responsiveness is an intrinsic property of mouse hepatocytes and is not due to the mouse liver micro-environment.
    PLoS ONE 01/2014; 9(1):e87906. DOI:10.1371/journal.pone.0087906 · 3.53 Impact Factor

Publication Stats

10k Citations
1,372.18 Total Impact Points

Institutions

  • 2013–2015
    • Universitätsklinikum Freiburg
      • Institute of Virology
      Freiburg an der Elbe, Lower Saxony, Germany
  • 1993–2015
    • University of Freiburg
      • • Department of Virology
      • • Institute of Psychology
      Freiburg, Baden-Württemberg, Germany
  • 2012
    • Helmholtz Centre for Infection Research
      • Department of Molecular Immunology (MOLI)
      Brunswyck, Lower Saxony, Germany
  • 2011
    • Munich University of Applied Sciences
      München, Bavaria, Germany
  • 2010
    • University of Rochester
      • School of Medicine and Dentistry
      Rochester, New York, United States
    • Max Planck Institute of Molecular Cell Biology and Genetics
      Dresden, Saxony, Germany
  • 2009
    • Justus-Liebig-Universität Gießen
      • Institute for Veterinary Physiology
      Gieben, Hesse, Germany
    • Sunnybrook Health Sciences Centre
      Toronto, Ontario, Canada
  • 1983–2008
    • University of Zurich
      • • Psychiatry Research
      • • Institut für Molekulare Biologie
      • • Institute of Virology
      Zürich, Zurich, Switzerland
  • 2007
    • Centers for Disease Control and Prevention
      • Influenza Division
      Druid Hills, GA, United States
    • Catholic University of Louvain
      Walloon Region, Belgium
    • Paul-Ehrlich-Institut
      Langen, Hesse, Germany
  • 2005
    • Bavarian Nordic Research Institute
      Espergjærde, Capital Region, Denmark
  • 2003
    • Bielefeld University
      Bielefeld, North Rhine-Westphalia, Germany
  • 2000
    • Technische Universität Bergakademie Freiberg
      Freiburg, Saxony, Germany
  • 1995
    • Evangelische Hochschule Freiburg, Germany
      Freiburg, Baden-Württemberg, Germany
  • 1988
    • Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
      Torrance, California, United States
  • 1987
    • The Scripps Research Institute
      • Department of Cell and Molecular Biology
      La Jolla, California, United States
  • 1984
    • The Rockefeller University
      New York, New York, United States