Peter Staeheli

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

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Publications (261)1339.2 Total impact

  • Article: ID: 213

    Cytokine 11/2015; 76(1):103. DOI:10.1016/j.cyto.2015.08.217 · 2.66 Impact Factor
  • Article: ID: 158

    Cytokine 11/2015; 76(1):95. DOI:10.1016/j.cyto.2015.08.178 · 2.66 Impact Factor
  • Article: ID: 52

    Cytokine 11/2015; 76(1):74. DOI:10.1016/j.cyto.2015.08.082 · 2.66 Impact Factor
  • Article: ID: 208

    Cytokine 11/2015; 76(1):102. DOI:10.1016/j.cyto.2015.08.212 · 2.66 Impact Factor
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    ABSTRACT: The interferon-induced Mx1 gene is an important part of the mammalian defense against influenza viruses. Mus musculus Mx1 inhibits influenza A virus replication and transcription by suppressing the polymerase activity of viral ribonucleoproteins (vRNPs). Here, we compared the anti-influenza activity of Mx1 from Mus musculus A2G with its ortholog from Mus spretus. We found that the antiviral activity of M. spretus Mx1 was less potent than that of M. musculus Mx1. Sequence comparison of M. musculus with M. spretus Mx1 revealed 25 amino acid differences, over half of which are present in the GTPase domain and two in loop L4. However, the in vitro GTPase activity of Mx1 from the two mouse species was similar. Replacing one of the residues in loop L4 in M. spretus Mx1 by the corresponding residue of A2G Mx1 increased its antiviral activity. We also show that deletion of loop L4 prevented binding of Mx1 to influenza A virus nucleoprotein and hence abolished antiviral activity of mouse Mx1. These results indicate that loop L4 of mouse Mx1 is a determinant of antiviral activity. Our findings suggest that Mx proteins from different mammals use a common mechanism to inhibit influenza A viruses. Mx proteins are evolutionary conserved in vertebrates and inhibit a wide range of viruses. Still, the exact details of their antiviral mechanisms remain largely unknown. Functional comparison of Mx genes from two species, that diverged relatively recently in evolution, can provide novel insight into these mechanisms. We show that both Mus musculus A2G Mx1 and Mus spretus Mx1 target influenza nucleoprotein. We also found that loop L4 in mouse Mx1 is crucial for its antiviral activity, as was reported recently for primate MxA. This indicates that human and mouse Mx proteins, which diverged by 75 million years of evolution, recognize and inhibit influenza A viruses by a common mechanism. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Journal of Virology 08/2015; DOI:10.1128/JVI.01744-15 · 4.44 Impact Factor
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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; 18(7). DOI:10.1038/nn.4030 · 16.10 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; 16(7). DOI:10.1038/ni.3180 · 20.00 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 · 11.47 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 · 7.56 Impact Factor
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    ABSTRACT: Unlabelled: 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 preexisting 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. Replacement 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 compared 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. Importance: Despite the high impact of influenza pandemics on human health, some mechanisms underlying the emergence of pandemic influenza viruses still are 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 the acquisition of antigenically novel HA (i.e., antigenic shift), enhanced viral polymerase activity is required for the emergence of pandemic influenza viruses from their seasonal human precursors.
    Journal of Virology 01/2015; 89(8). DOI:10.1128/JVI.03194-14 · 4.44 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 (RLR)-dependent innate immune signaling. However, it is unclear if HCV interferes with mouse MAVS function equally well. Moreover, MAVS-dependent signaling 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 signaling 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 degrees. 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 signaling.
    Journal of Virology 01/2015; 89:3833-3845. DOI:10.1128/JVI.03129-14 · 4.44 Impact Factor
  • Otto Haller · Peter Staeheli · Martin Schwemmle · Georg Kochs ·
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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 · 9.19 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 · 11.47 Impact Factor

  • Immunology; 12/2014
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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-α, IFN-γ, 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-α 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-α-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.
    PLoS ONE 11/2014; 9(11). DOI:10.1371/journal.pone.0112469 · 3.23 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

Publication Stats

11k Citations
1,339.20 Total Impact Points


  • 2013-2015
    • Universitätsklinikum Freiburg
      • Institute of Virology
      Freiburg an der Elbe, Lower Saxony, Germany
  • 1991-2014
    • University of Freiburg
      • • Department of Virology
      • • Institute of Psychology
      Freiburg, Baden-Württemberg, Germany
  • 2009-2012
    • Helmholtz Centre for Infection Research
      • • Department of Molecular Immunology (MOLI)
      • • Department of Gene Regulation and Differentiation
      Brunswyck, Lower Saxony, Germany
    • Sunnybrook Health Sciences Centre
      Toronto, Ontario, Canada
  • 2011
    • Munich University of Applied Sciences
      München, Bavaria, Germany
  • 2010
    • Max Planck Institute of Molecular Cell Biology and Genetics
      Dresden, Saxony, Germany
  • 1983-2008
    • University of Zurich
      • • Psychiatry Research
      • • Institut für Molekulare Biologie
      • • Institute of Virology
      Zürich, Zurich, Switzerland
  • 2001
    • University of Connecticut
      • Department of Molecular and Cell Biology
      Сторс, Connecticut, United States
  • 2000
    • Technische Universität Bergakademie Freiberg
      Freiburg, Saxony, Germany
  • 1995
    • Evangelische Hochschule Freiburg, Germany
      Freiburg, Baden-Württemberg, Germany
  • 1992
    • Icahn School of Medicine at Mount Sinai
      • Department of Microbiology
      Borough of Manhattan, New York, United States
  • 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
      لا هویا, California, United States
  • 1984
    • The Rockefeller University
      New York, New York, United States