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  1. Artikel ; Online: Computational prediction and experimental validation of Salmonella Typhimurium SopE-mediated fine-tuning of autophagy in intestinal epithelial cells

    Amanda Demeter / Anne-Claire Jacomin / Lejla Gul / Ashleigh Lister / James Lipscombe / Rachele Invernizzi / Priscilla Branchu / Iain Macaulay / Ioannis P. Nezis / Robert A. Kingsley / Tamas Korcsmaros / Isabelle Hautefort

    Frontiers in Cellular and Infection Microbiology, Vol

    2022  Band 12

    Abstract: Macroautophagy is a ubiquitous homeostasis and health-promoting recycling process of eukaryotic cells, targeting misfolded proteins, damaged organelles and intracellular infectious agents. Some intracellular pathogens such as Salmonella enterica serovar ... ...

    Abstract Macroautophagy is a ubiquitous homeostasis and health-promoting recycling process of eukaryotic cells, targeting misfolded proteins, damaged organelles and intracellular infectious agents. Some intracellular pathogens such as Salmonella enterica serovar Typhimurium hijack this process during pathogenesis. Here we investigate potential protein-protein interactions between host transcription factors and secreted effector proteins of Salmonella and their effect on host gene transcription. A systems-level analysis identified Salmonella effector proteins that had the potential to affect core autophagy gene regulation. The effect of a SPI-1 effector protein, SopE, that was predicted to interact with regulatory proteins of the autophagy process, was investigated to validate our approach. We then confirmed experimentally that SopE can directly bind to SP1, a host transcription factor, which modulates the expression of the autophagy gene MAP1LC3B. We also revealed that SopE might have a double role in the modulation of autophagy: Following initial increase of MAP1LC3B transcription triggered by Salmonella infection, subsequent decrease in MAP1LC3B transcription at 6h post-infection was SopE-dependent. SopE also played a role in modulation of the autophagy flux machinery, in particular MAP1LC3B and p62 autophagy proteins, depending on the level of autophagy already taking place. Upon typical infection of epithelial cells, the autophagic flux is increased. However, when autophagy was chemically induced prior to infection, SopE dampened the autophagic flux. The same was also observed when most of the intracellular Salmonella cells were not associated with the SCV (strain lacking sifA) regardless of the autophagy induction status before infection. We demonstrated how regulatory network analysis can be used to better characterise the impact of pathogenic effector proteins, in this case, Salmonella. This study complements previous work in which we had demonstrated that specific pathogen effectors can affect the autophagy ...
    Schlagwörter Salmonella Typhimurium ; autophagy ; SopE ; network biology ; MAP1LC3B ; Host-microbe interactions ; Microbiology ; QR1-502
    Thema/Rubrik (Code) 570
    Sprache Englisch
    Erscheinungsdatum 2022-08-01T00:00:00Z
    Verlag Frontiers Media S.A.
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  2. Artikel ; Online: CytokineLink

    Marton Olbei / John P. Thomas / Isabelle Hautefort / Agatha Treveil / Balazs Bohar / Matthew Madgwick / Lejla Gul / Luca Csabai / Dezso Modos / Tamas Korcsmaros

    Cells, Vol 10, Iss 2242, p

    A Cytokine Communication Map to Analyse Immune Responses—Case Studies in Inflammatory Bowel Disease and COVID-19

    2021  Band 2242

    Abstract: Intercellular communication mediated by cytokines is critical to the development of immune responses, particularly in the context of infectious and inflammatory diseases. By releasing these small molecular weight peptides, the source cells can influence ... ...

    Abstract Intercellular communication mediated by cytokines is critical to the development of immune responses, particularly in the context of infectious and inflammatory diseases. By releasing these small molecular weight peptides, the source cells can influence numerous intracellular processes in the target cells, including the secretion of other cytokines downstream. However, there are no readily available bioinformatic resources that can model cytokine–cytokine interactions. In this effort, we built a communication map between major tissues and blood cells that reveals how cytokine-mediated intercellular networks form during homeostatic conditions. We collated the most prevalent cytokines from the literature and assigned the proteins and their corresponding receptors to source tissue and blood cell types based on enriched consensus RNA-Seq data from the Human Protein Atlas database. To assign more confidence to the interactions, we integrated the literature information on cell–cytokine interactions from two systems of immunology databases, immuneXpresso and ImmunoGlobe. From the collated information, we defined two metanetworks: a cell–cell communication network connected by cytokines; and a cytokine–cytokine interaction network depicting the potential ways in which cytokines can affect the activity of each other. Using expression data from disease states, we then applied this resource to reveal perturbations in cytokine-mediated intercellular signalling in inflammatory and infectious diseases (ulcerative colitis and COVID-19, respectively). For ulcerative colitis, with CytokineLink, we demonstrated a significant rewiring of cytokine-mediated intercellular communication between non-inflamed and inflamed colonic tissues. For COVID-19, we were able to identify cell types and cytokine interactions following SARS-CoV-2 infection, highlighting important cytokine interactions that might contribute to severe illness in a subgroup of patients. Such findings have the potential to inform the development of novel, ...
    Schlagwörter cytokine ; network ; resource ; Cytoscape ; NDEx ; COVID-19 ; Biology (General) ; QH301-705.5
    Thema/Rubrik (Code) 610
    Sprache Englisch
    Erscheinungsdatum 2021-08-01T00:00:00Z
    Verlag MDPI AG
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  3. Artikel ; Online: ViralLink

    Agatha Treveil / Balazs Bohar / Padhmanand Sudhakar / Lejla Gul / Luca Csabai / Marton Olbei / Martina Poletti / Matthew Madgwick / Tahila Andrighetti / Isabelle Hautefort / Dezso Modos / Tamas Korcsmaros

    PLoS Computational Biology, Vol 17, Iss 2, p e

    An integrated workflow to investigate the effect of SARS-CoV-2 on intracellular signalling and regulatory pathways.

    2021  Band 1008685

    Abstract: The SARS-CoV-2 pandemic of 2020 has mobilised scientists around the globe to research all aspects of the coronavirus virus and its infection. For fruitful and rapid investigation of viral pathomechanisms, a collaborative and interdisciplinary approach is ...

    Abstract The SARS-CoV-2 pandemic of 2020 has mobilised scientists around the globe to research all aspects of the coronavirus virus and its infection. For fruitful and rapid investigation of viral pathomechanisms, a collaborative and interdisciplinary approach is required. Therefore, we have developed ViralLink: a systems biology workflow which reconstructs and analyses networks representing the effect of viruses on intracellular signalling. These networks trace the flow of signal from intracellular viral proteins through their human binding proteins and downstream signalling pathways, ending with transcription factors regulating genes differentially expressed upon viral exposure. In this way, the workflow provides a mechanistic insight from previously identified knowledge of virally infected cells. By default, the workflow is set up to analyse the intracellular effects of SARS-CoV-2, requiring only transcriptomics counts data as input from the user: thus, encouraging and enabling rapid multidisciplinary research. However, the wide-ranging applicability and modularity of the workflow facilitates customisation of viral context, a priori interactions and analysis methods. Through a case study of SARS-CoV-2 infected bronchial/tracheal epithelial cells, we evidence the functionality of the workflow and its ability to identify key pathways and proteins in the cellular response to infection. The application of ViralLink to different viral infections in a context specific manner using different available transcriptomics datasets will uncover key mechanisms in viral pathogenesis.
    Schlagwörter Biology (General) ; QH301-705.5
    Thema/Rubrik (Code) 570
    Sprache Englisch
    Erscheinungsdatum 2021-02-01T00:00:00Z
    Verlag Public Library of Science (PLoS)
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  4. Artikel ; Online: Integrative analysis of Paneth cell proteomic and transcriptomic data from intestinal organoids reveals functional processes dependent on autophagy

    Emily J. Jones / Zoe J. Matthews / Lejla Gul / Padhmanand Sudhakar / Agatha Treveil / Devina Divekar / Jasmine Buck / Tomasz Wrzesinski / Matthew Jefferson / Stuart D. Armstrong / Lindsay J. Hall / Alastair J. M. Watson / Simon R. Carding / Wilfried Haerty / Federica Di Palma / Ulrike Mayer / Penny P. Powell / Isabelle Hautefort / Tom Wileman /
    Tamas Korcsmaros

    Disease Models & Mechanisms, Vol 12, Iss

    2019  Band 3

    Abstract: Paneth cells are key epithelial cells that provide an antimicrobial barrier and maintain integrity of the small-intestinal stem cell niche. Paneth cell abnormalities are unfortunately detrimental to gut health and are often associated with digestive ... ...

    Abstract Paneth cells are key epithelial cells that provide an antimicrobial barrier and maintain integrity of the small-intestinal stem cell niche. Paneth cell abnormalities are unfortunately detrimental to gut health and are often associated with digestive pathologies such as Crohn's disease or infections. Similar alterations are observed in individuals with impaired autophagy, a process that recycles cellular components. The direct effect of autophagy impairment on Paneth cells has not been analysed. To investigate this, we generated a mouse model lacking Atg16l1 specifically in intestinal epithelial cells, making these cells impaired in autophagy. Using three-dimensional intestinal organoids enriched for Paneth cells, we compared the proteomic profiles of wild-type and autophagy-impaired organoids. We used an integrated computational approach combining protein-protein interaction networks, autophagy-targeted proteins and functional information to identify the mechanistic link between autophagy impairment and disrupted pathways. Of the 284 altered proteins, 198 (70%) were more abundant in autophagy-impaired organoids, suggesting reduced protein degradation. Interestingly, these differentially abundant proteins comprised 116 proteins (41%) that are predicted targets of the selective autophagy proteins p62, LC3 and ATG16L1. Our integrative analysis revealed autophagy-mediated mechanisms that degrade key proteins in Paneth cell functions, such as exocytosis, apoptosis and DNA damage repair. Transcriptomic profiling of additional organoids confirmed that 90% of the observed changes upon autophagy alteration have effects at the protein level, not on gene expression. We performed further validation experiments showing differential lysozyme secretion, confirming our computationally inferred downregulation of exocytosis. Our observations could explain how protein-level alterations affect Paneth cell homeostatic functions upon autophagy impairment. This article has an associated First Person interview with the joint first ...
    Schlagwörter Paneth cells ; Atg16l1 ; Intestinal organoids ; Quantitative proteomics ; Selective autophagy ; Medicine ; R ; Pathology ; RB1-214
    Thema/Rubrik (Code) 612
    Sprache Englisch
    Erscheinungsdatum 2019-03-01T00:00:00Z
    Verlag The Company of Biologists
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  5. Artikel ; Online: A Bacterial Homolog of a Eukaryotic Inositol Phosphate Signaling Enzyme Mediates Cross-kingdom Dialog in the Mammalian Gut

    Régis Stentz / Samantha Osborne / Nikki Horn / Arthur W.H. Li / Isabelle Hautefort / Roy Bongaerts / Marine Rouyer / Paul Bailey / Stephen B. Shears / Andrew M. Hemmings / Charles A. Brearley / Simon R. Carding

    Cell Reports, Vol 6, Iss 4, Pp 646-

    2014  Band 656

    Abstract: Dietary InsP6 can modulate eukaryotic cell proliferation and has complex nutritive consequences, but its metabolism in the mammalian gastrointestinal tract is poorly understood. Therefore, we performed phylogenetic analyses of the gastrointestinal ... ...

    Abstract Dietary InsP6 can modulate eukaryotic cell proliferation and has complex nutritive consequences, but its metabolism in the mammalian gastrointestinal tract is poorly understood. Therefore, we performed phylogenetic analyses of the gastrointestinal microbiome in order to search for candidate InsP6 phosphatases. We determined that prominent gut bacteria express homologs of the mammalian InsP6 phosphatase (MINPP) and characterized the enzyme from Bacteroides thetaiotaomicron (BtMinpp). We show that BtMinpp has exceptionally high catalytic activity, which we rationalize on the basis of mutagenesis studies and by determining its crystal structure at 1.9 Å resolution. We demonstrate that BtMinpp is packaged inside outer membrane vesicles (OMVs) protecting the enzyme from degradation by gastrointestinal proteases. Moreover, we uncover an example of cross-kingdom cell-to-cell signaling, showing that the BtMinpp-OMVs interact with intestinal epithelial cells to promote intracellular Ca2+ signaling. Our characterization of BtMinpp offers several directions for understanding how the microbiome serves human gastrointestinal physiology.
    Schlagwörter Biology (General) ; QH301-705.5
    Thema/Rubrik (Code) 572
    Sprache Englisch
    Erscheinungsdatum 2014-02-01T00:00:00Z
    Verlag Elsevier
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  6. Artikel ; Online: Intestinal intraepithelial lymphocyte-enterocyte crosstalk regulates production of bactericidal angiogenin 4 by Paneth cells upon microbial challenge.

    Catherine R Walker / Isabelle Hautefort / Jane E Dalton / Karin Overweg / Charlotte E Egan / Roy J Bongaerts / Darren J Newton / Sheena M Cruickshank / Elizabeth M Andrew / Simon R Carding

    PLoS ONE, Vol 8, Iss 12, p e

    2013  Band 84553

    Abstract: Antimicrobial proteins influence intestinal microbial ecology and limit proliferation of pathogens, yet the regulation of their expression has only been partially elucidated. Here, we have identified a putative pathway involving epithelial cells and ... ...

    Abstract Antimicrobial proteins influence intestinal microbial ecology and limit proliferation of pathogens, yet the regulation of their expression has only been partially elucidated. Here, we have identified a putative pathway involving epithelial cells and intestinal intraepithelial lymphocytes (iIELs) that leads to antimicrobial protein (AMP) production by Paneth cells. Mice lacking γδ iIELs (TCRδ(-/-)) express significantly reduced levels of the AMP angiogenin 4 (Ang4). These mice were also unable to up-regulate Ang4 production following oral challenge by Salmonella, leading to higher levels of mucosal invasion compared to their wild type counterparts during the first 2 hours post-challenge. The transfer of γδ iIELs from wild type (WT) mice to TCRδ(-/-) mice restored Ang4 production and Salmonella invasion levels were reduced to those obtained in WT mice. The ability to restore Ang4 production in TCRδ(-/-) mice was shown to be restricted to γδ iIELs expressing Vγ7-encoded TCRs. Using a novel intestinal crypt co-culture system we identified a putative pathway of Ang4 production initiated by exposure to Salmonella, intestinal commensals or microbial antigens that induced intestinal epithelial cells to produce cytokines including IL‑23 in a TLR-mediated manner. Exposure of TCR-Vγ7(+) γδ iIELs to IL-23 promoted IL‑22 production, which triggered Paneth cells to secrete Ang4. These findings identify a novel role for γδ iIELs in mucosal defence through sensing immediate epithelial cell cytokine responses and influencing AMP production. This in turn can contribute to the maintenance of intestinal microbial homeostasis and epithelial barrier function, and limit pathogen invasion.
    Schlagwörter Medicine ; R ; Science ; Q
    Thema/Rubrik (Code) 570
    Sprache Englisch
    Erscheinungsdatum 2013-01-01T00:00:00Z
    Verlag Public Library of Science (PLoS)
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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