Publications by authors named "Birgit Baumgarten"

11 Publications

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The RESOLUTE consortium: unlocking SLC transporters for drug discovery.

Authors:
Giulio Superti-Furga Daniel Lackner Tabea Wiedmer Alvaro Ingles-Prieto Barbara Barbosa Enrico Girardi Ulrich Goldmann Bettina Gürtl Kristaps Klavins Christoph Klimek Sabrina Lindinger Eva Liñeiro-Retes André C Müller Svenja Onstein Gregor Redinger Daniela Reil Vitaly Sedlyarov Gernot Wolf Matthew Crawford Robert Everley David Hepworth Shenping Liu Stephen Noell Mary Piotrowski Robert Stanton Hui Zhang Salvatore Corallino Andrea Faedo Maria Insidioso Giovanna Maresca Loredana Redaelli Francesca Sassone Lia Scarabottolo Michela Stucchi Paola Tarroni Sara Tremolada Helena Batoulis Andreas Becker Eckhard Bender Yung-Ning Chang Alexander Ehrmann Anke Müller-Fahrnow Vera Pütter Diana Zindel Bradford Hamilton Martin Lenter Diana Santacruz Coralie Viollet Charles Whitehurst Kai Johnsson Philipp Leippe Birgit Baumgarten Lena Chang Yvonne Ibig Martin Pfeifer Jürgen Reinhardt Julian Schönbett Paul Selzer Klaus Seuwen Charles Bettembourg Bruno Biton Jörg Czech Hélène de Foucauld Michel Didier Thomas Licher Vincent Mikol Antje Pommereau Frédéric Puech Veeranagouda Yaligara Aled Edwards Brandon J Bongers Laura H Heitman Ad P IJzerman Huub J Sijben Gerard J P van Westen Justine Grixti Douglas B Kell Farah Mughal Neil Swainston Marina Wright-Muelas Tina Bohstedt Nicola Burgess-Brown Liz Carpenter Katharina Dürr Jesper Hansen Andreea Scacioc Giulia Banci Claire Colas Daniela Digles Gerhard Ecker Barbara Füzi Viktoria Gamsjäger Melanie Grandits Riccardo Martini Florentina Troger Patrick Altermatt Cédric Doucerain Franz Dürrenberger Vania Manolova Anna-Lena Steck Hanna Sundström Maria Wilhelm Claire M Steppan

Nat Rev Drug Discov 2020 07;19(7):429-430

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http://dx.doi.org/10.1038/d41573-020-00056-6DOI Listing
July 2020

Glucocorticoid-loaded liposomes induce a pro-resolution phenotype in human primary macrophages to support chronic wound healing.

Biomaterials 2018 09 5;178:481-495. Epub 2018 Apr 5.

Chemical Biology and Therapeutics, Novartis Institutes for BioMedical Research, Basel, Switzerland. Electronic address:

Glucocorticoids are well established anti-inflammatory agents, however, their use to treat chronic inflammatory diseases is limited due to a number of serious side effects. For example, long-term local treatment of chronic wounds with glucocorticoids is prohibited by dysregulation of keratinocyte and fibroblast function, leading to skin thinning. Here, we developed and tested liposome formulations for local delivery of dexamethasone to primary human macrophages, to drive an anti-inflammatory/pro-resolution phenotype appropriate for tissue repair. The liposomes were loaded with the pro-drug dexamethasone-phosphate and surface-modified with either polyethylene glycol or phosphatidylserine. The latter was used to mimic phosphatidylserine-harboring apoptotic cells, which are substrates for efferocytosis, an essential pro-resolution function. Both formulations induced a dexamethasone-like gene expression signature in macrophages, decreased IL6 and TNFα release, increased secretion of thrombospondin 1 and increased efferocytosis activity. Phosphatidylserine-modified liposomes exhibited a faster uptake, a higher potency and a more robust phenotype induction than polyethylene glycol-modified liposomes. Fibroblast and keratinocyte cell cultures as well as a 3D skin equivalent model showed that liposomes applied locally to wounds are preferentially phagocytosed by macrophages. These findings indicate that liposomes, in particular upon shell modification with phosphatidylserine, promote dexamethasone delivery to macrophages and induce a phenotype suitable to support chronic wound healing.
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http://dx.doi.org/10.1016/j.biomaterials.2018.04.006DOI Listing
September 2018

A natural ligand for the orphan receptor GPR15 modulates lymphocyte recruitment to epithelia.

Sci Signal 2017 Sep 12;10(496). Epub 2017 Sep 12.

Novartis Institutes for BioMedical Research, CH-4056 Basel, Switzerland.

GPR15 is an orphan G protein-coupled receptor (GPCR) that is found in lymphocytes. It functions as a co-receptor of simian immunodeficiency virus and HIV-2 and plays a role in the trafficking of T cells to the lamina propria in the colon and to the skin. We describe the purification from porcine colonic tissue extracts of an agonistic ligand for GPR15 and its functional characterization. In humans, this ligand, which we named GPR15L, is encoded by the gene and has some features similar to the CC family of chemokines. was found in some human and mouse epithelia exposed to the environment, such as the colon and skin. In humans, was also abundant in the cervix. In skin, was readily detected after immunologic challenge and in human disease, for example, in psoriatic lesions. Allotransplantation of skin from -deficient mice onto wild-type mice resulted in substantial graft protection, suggesting nonredundant roles for GPR15 and GPR15L in the generation of effector T cell responses. Together, these data identify a receptor-ligand pair that is required for immune homeostasis at epithelia and whose modulation may represent an alternative approach to treating conditions affecting the skin such as psoriasis.
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http://dx.doi.org/10.1126/scisignal.aal0180DOI Listing
September 2017

Multidimensional pooled shRNA screens in human THP-1 cells identify candidate modulators of macrophage polarization.

PLoS One 2017 24;12(8):e0183679. Epub 2017 Aug 24.

Novartis Institutes for Biomedical Research, Basel, Switzerland.

Macrophages are key cell types of the innate immune system regulating host defense, inflammation, tissue homeostasis and cancer. Within this functional spectrum diverse and often opposing phenotypes are displayed which are dictated by environmental clues and depend on highly plastic transcriptional programs. Among these the 'classical' (M1) and 'alternative' (M2) macrophage polarization phenotypes are the best characterized. Understanding macrophage polarization in humans may reveal novel therapeutic intervention possibilities for chronic inflammation, wound healing and cancer. Systematic loss of function screening in human primary macrophages is limited due to lack of robust gene delivery methods and limited sample availability. To overcome these hurdles we developed cell-autonomous assays using the THP-1 cell line allowing genetic screens for human macrophage phenotypes. We screened 648 chromatin and signaling regulators with a pooled shRNA library for M1 and M2 polarization modulators. Validation experiments confirmed the primary screening results and identified OGT (O-linked N-acetylglucosamine (GlcNAc) transferase) as a novel mediator of M2 polarization in human macrophages. Our approach offers a possible avenue to utilize comprehensive genetic tools to identify novel candidate genes regulating macrophage polarization in humans.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0183679PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5570424PMC
October 2017

Progressive histoplasmosis with hemophagocytic lymphohistiocytosis and epithelioid cell granulomatosis: A case report and review of the literature.

Eur J Haematol 2017 Jul 11;99(1):91-100. Epub 2017 May 11.

Department of Medicine A, University Hospital Muenster, Muenster, Germany.

Histoplasmosis in central Europe is a rare fungal disease with diverse clinical presentations. Apart from acute pulmonary histoplasmosis and involvement of the central nervous system, the most serious clinical presentation is progressive disseminated histoplasmosis which is generally associated with severe immunodeficiency and, in particular, advanced human immunodeficiency virus infection. Here, we report on an immunocompetent female residing in a non-endemic area, presenting with progressive disseminated histoplasmosis after a remote travel history to Thailand and Costa Rica. Diagnosis was delayed by several months due to misinterpretation of epithelioid cell granulomatosis of the intestine as Crohn's disease and of similar lung lesions as acute sarcoidosis. Prompted by clinical deterioration with signs and symptoms consistent with hemophagocytic lymphohistiocytosis, a bone marrow aspiration was performed that documented hemophagocytosis and intracellular organisms interpreted as Leishmania sp., but later identified by molecular methods as Histoplasma capsulatum. Treatment with liposomal amphotericin B followed by posaconazole led to prompt clinical improvement and ultimately cure.
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http://dx.doi.org/10.1111/ejh.12886DOI Listing
July 2017

Transcriptional regulation and functional characterization of the oxysterol/EBI2 system in primary human macrophages.

Biochem Biophys Res Commun 2014 Apr 27;446(3):663-8. Epub 2014 Jan 27.

Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Basel, Switzerland. Electronic address:

Oxysterols such as 7 alpha, 25-dihydroxycholesterol (7α,25-OHC) are natural ligands for the Epstein-Barr virus (EBV)-induced gene 2 (EBI2, aka GPR183), a G protein-coupled receptor (GPCR) highly expressed in immune cells and required for adaptive immune responses. Activation of EBI2 by specific oxysterols leads to chemotaxis of B cells in lymphoid tissues. While the ligand gradient necessary for this critical process of the adaptive immune response is established by a stromal cells subset here we investigate the involvement of the oxysterol/EBI2 system in the innate immune response. First, we show that primary human macrophages express EBI2 and the enzymes needed for ligand production such as cholesterol 25-hydroxylase (CH25H), sterol 27-hydroxylase (CYP27A1), and oxysterol 7α-hydroxylase (CYP7B1). Furthermore, challenge of monocyte-derived macrophages with lipopolysaccharides (LPS) triggers a strong up-regulation of CH25H and CYP7B1 in comparison to a transient increase in EBI2 expression. Stimulation of EBI2 expressed on macrophages leads to calcium mobilization and to directed cell migration. Supernatants of LPS-stimulated macrophages are able to stimulate EBI2 signaling indicating that an induction of CH25H, CYP27A1, and CYP7B1 results in an enhanced production and release of oxysterols into the cellular environment. This is a study characterizing the oxysterol/EBI2 pathway in primary monocyte-derived macrophages. Given the crucial functional role of macrophages in the innate immune response these results encourage further exploration of a possible link to systemic autoimmunity.
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http://dx.doi.org/10.1016/j.bbrc.2014.01.069DOI Listing
April 2014

Reduced pathological angiogenesis and tumor growth in mice lacking GPR4, a proton sensing receptor.

Angiogenesis 2011 Dec 2;14(4):533-44. Epub 2011 Nov 2.

Novartis Institutes for Biomedical Research, Forum 1 Novartis Campus, CH-4056, Basel, Switzerland.

The G protein-coupled receptor GPR4 is activated by acidic pH and recent evidence indicates that it is expressed in endothelial cells. In agreement with these reports, we observe a high correlation of GPR4 mRNA expression with endothelial marker genes, and we confirm expression and acidic pH dependent function of GPR4 in primary human vascular endothelial cells. GPR4-deficient mice were generated; these are viable and fertile and show no gross abnormalities. However, these animals show a significantly reduced angiogenic response to VEGF (vascular endothelial growth factor), but not to bFGF (basic fibroblast growth factor), in a growth factor implant model. Accordingly, in two different orthotopic models, tumor growth is strongly reduced in mice lacking GPR4. Histological analysis of tumors indicates reduced tumor cell proliferation as well as altered vessel morphology, length and density. Moreover, GPR4 deficiency results in reduced VEGFR2 (VEGF Receptor 2) levels in endothelial cells, accounting, at least in part, for the observed phenotype. Our data suggest that endothelial cells sense local tissue acidosis via GPR4 and that this signal is required to generate a full angiogenic response to VEGF.
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http://dx.doi.org/10.1007/s10456-011-9238-9DOI Listing
December 2011

Oxysterols direct immune cell migration via EBI2.

Nature 2011 Jul 27;475(7357):524-7. Epub 2011 Jul 27.

Euroscreen S.A., 6041 Gosselies, Belgium.

Epstein-Barr virus-induced gene 2 (EBI2, also known as GPR183) is a G-protein-coupled receptor that is required for humoral immune responses; polymorphisms in the receptor have been associated with inflammatory autoimmune diseases. The natural ligand for EBI2 has been unknown. Here we describe the identification of 7α,25-dihydroxycholesterol (also called 7α,25-OHC or 5-cholesten-3β,7α,25-triol) as a potent and selective agonist of EBI2. Functional activation of human EBI2 by 7α,25-OHC and closely related oxysterols was verified by monitoring second messenger readouts and saturable, high-affinity radioligand binding. Furthermore, we find that 7α,25-OHC and closely related oxysterols act as chemoattractants for immune cells expressing EBI2 by directing cell migration in vitro and in vivo. A critical enzyme required for the generation of 7α,25-OHC is cholesterol 25-hydroxylase (CH25H). Similar to EBI2 receptor knockout mice, mice deficient in CH25H fail to position activated B cells within the spleen to the outer follicle and mount a reduced plasma cell response after an immune challenge. This demonstrates that CH25H generates EBI2 biological activity in vivo and indicates that the EBI2-oxysterol signalling pathway has an important role in the adaptive immune response.
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http://dx.doi.org/10.1038/nature10280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297623PMC
July 2011

Bioinformatics prediction of overlapping frameshifted translation products in mammalian transcripts.

BMC Genomics 2008 Mar 6;9:122. Epub 2008 Mar 6.

Genedata AG, Maulbeerstrasse 46, CH-4016 Basel, Switzerland.

Background: Exceptionally, a single nucleotide sequence can be translated in vivo in two different frames to yield distinct proteins. In the case of the G-protein alpha subunit XL-alpha-s transcript, a frameshifted open reading frame (ORF) in exon 1 is translated to yield a structurally distinct protein called Alex, which plays a role in platelet aggregation and neurological processes. We carried out a novel bioinformatics screen for other possible dual-frame translated sequences, based on comparative genomics.

Results: Our method searched human, mouse and rat transcripts in frames +1 and -1 for ORFs which are unusually well conserved at the amino acid level. We name these conserved frameshifted overlapping ORFs 'matreshkas' to reflect their nested character. Select findings of our analysis revealed that the G-protein coupled receptor GPR27 is entirely contained within a frame -1 matreshka, thrombopoietin contains a matreshka which spans ~70% of its length, platelet glycoprotein IIIa (ITGB3) contains a matreshka with the predicted characteristics of a secreted peptide hormone, while the potassium channel KCNK12 contains a matreshka spanning >400 amino acids.

Conclusion: Although the in vivo existence of translated matreshkas has not been experimentally verified, this genome-wide analysis provides strong evidence that substantial overlapping coding sequences exist in a number of human and rodent transcripts.
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http://dx.doi.org/10.1186/1471-2164-9-122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2329644PMC
March 2008

High diversity of ankA sequences of Anaplasma phagocytophilum among Ixodes ricinus ticks in Germany.

J Clin Microbiol 2003 Nov;41(11):5033-40

Institute of Clinical Microbiology, Immunology and Hygiene, University of Erlangen, Erlangen, Germany.

In Germany humans with acute granulocytic ehrlichiosis have not yet been described. Here, we characterized three different genes of Anaplasma phagocytophilum strains infecting German Ixodes ricinus ticks in order to test whether they differ from strains in other European countries and the United States. A total of 1,022 I. ricinus ticks were investigated for infection with A. phagocytophilum by nested PCR and sequence analysis. Forty-two (4.1%) ticks were infected. For all positive ticks, parts of the 16S rRNA and groESL genes were sequenced. The complete coding sequence of the ankA gene could be determined in 24 samples. The 16S rRNA and groESL gene sequences were as much as 100% identical to known sequences. Fifteen ankA sequences were >/=99.37% identical to sequences derived from humans with granulocytic ehrlichiosis in Europe and from a horse with granulocytic ehrlichiosis in Germany. Thus, German I. ricinus ticks most likely harbor A. phagocytophilum strains that can cause disease in humans. Nine additional sequences were clearly different from known ankA sequences. Because these newly described sequences have never been obtained from diseased humans or animals, their biological significance is currently unknown. Based on this unexpected sequence heterogeneity, we propose to use the ankA gene for further phylogenetic analyses of A. phagocytophilum and to investigate the biology and pathogenicity of strains that differ in the ankA gene.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC262509PMC
http://dx.doi.org/10.1128/jcm.41.11.5033-5040.2003DOI Listing
November 2003