@article{GrummtWeinmannDorschSchneiderSchauliesetal.1986, author = {Grummt, F. and Weinmann-Dorsch, C. and Schneider-Schaulies, J{\"u}rgen and Lux, A.}, title = {Zinc as a second messenger of mitogenic induction}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-54799}, year = {1986}, abstract = {DNA synthesis and adenosine(S')tetraphosphate(S ')adenosine (Ap.A) levels decrease in cells treated with EDTA. The inhibitory effect of EDTA can be reversed with micro molar amounts of ZnCI2• ZnCh in micromolar concentrations also inhibits Ap.A hydrolase and stimulates amino acid-dependent Ap.A synthesis, suggesting that Zn2+ is modulating intracellular Ap.A pools. Serum addition to GI-arrested cells enhances uptake of Zn, whereas serum depletion leads to a fivefold decrease of the rates of zinc uptake. These results are discussed by regarding Zn2+ as a putative 'second messenger' of mitogenic induction and Ap.A as a possible 'third messenger' and trigger of DNA synthesis.}, subject = {Immunologie}, language = {en} } @article{RutkowskiErhardL'Hernaultetal.2015, author = {Rutkowski, Andrzej J. and Erhard, Florian and L'Hernault, Anne and Bonfert, Thomas and Schilhabel, Markus and Crump, Colin and Rosenstiel, Philip and Efstathiou, Stacey and Zimmer, Ralf and Friedel, Caroline C. and D{\"o}lken, Lars}, title = {Widespread disruption of host transcription termination in HSV-1 infection}, series = {Nature Communications}, volume = {6}, journal = {Nature Communications}, number = {7126}, doi = {10.1038/ncomms8126}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-148643}, year = {2015}, abstract = {Herpes simplex virus 1 (HSV-1) is an important human pathogen and a paradigm for virus-induced host shut-off. Here we show that global changes in transcription and RNA processing and their impact on translation can be analysed in a single experimental setting by applying 4sU-tagging of newly transcribed RNA and ribosome profiling to lytic HSV-1 infection. Unexpectedly, we find that HSV-1 triggers the disruption of transcription termination of cellular, but not viral, genes. This results in extensive transcription for tens of thousands of nucleotides beyond poly(A) sites and into downstream genes, leading to novel intergenic splicing between exons of neighbouring cellular genes. As a consequence, hundreds of cellular genes seem to be transcriptionally induced but are not translated. In contrast to previous reports, we show that HSV-1 does not inhibit co-transcriptional splicing. Our approach thus substantially advances our understanding of HSV-1 biology and establishes HSV-1 as a model system for studying transcription termination.}, language = {en} } @article{WylerMenegattiFrankeetal.2017, author = {Wyler, Emanuel and Menegatti, Jennifer and Franke, Vedran and Kocks, Christine and Boltengagen, Anastasiya and Hennig, Thomas and Theil, Kathrin and Rutkowski, Andrzej and Ferrai, Carmelo and Baer, Laura and Kermas, Lisa and Friedel, Caroline and Rajewsky, Nikolaus and Akalin, Altuna and D{\"o}lken, Lars and Gr{\"a}sser, Friedrich and Landthaler, Markus}, title = {Widespread activation of antisense transcription of the host genome during herpes simplex virus 1 infection}, series = {Genome Biology}, volume = {18}, journal = {Genome Biology}, doi = {10.1186/s13059-017-1329-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173381}, year = {2017}, abstract = {Background Herpesviruses can infect a wide range of animal species. Herpes simplex virus 1 (HSV-1) is one of the eight herpesviruses that can infect humans and is prevalent worldwide. Herpesviruses have evolved multiple ways to adapt the infected cells to their needs, but knowledge about these transcriptional and post-transcriptional modifications is sparse. Results Here, we show that HSV-1 induces the expression of about 1000 antisense transcripts from the human host cell genome. A subset of these is also activated by the closely related varicella zoster virus. Antisense transcripts originate either at gene promoters or within the gene body, and they show different susceptibility to the inhibition of early and immediate early viral gene expression. Overexpression of the major viral transcription factor ICP4 is sufficient to turn on a subset of antisense transcripts. Histone marks around transcription start sites of HSV-1-induced and constitutively transcribed antisense transcripts are highly similar, indicating that the genetic loci are already poised to transcribe these novel RNAs. Furthermore, an antisense transcript overlapping with the BBC3 gene (also known as PUMA) transcriptionally silences this potent inducer of apoptosis in cis. Conclusions We show for the first time that a virus induces widespread antisense transcription of the host cell genome. We provide evidence that HSV-1 uses this to downregulate a strong inducer of apoptosis. Our findings open new perspectives on global and specific alterations of host cell transcription by viruses.}, language = {en} } @article{SiwkaSchwinnBaczkoetal.1994, author = {Siwka, Wieslaw and Schwinn, Andreas and Baczko, Knut and Pardowitz, Iancu and Mhalu, Fred and Shao, John and Rethwilm, Axel and ter Meulen, Volker}, title = {vpu and env sequence variability of HIV-1 isolates from Tanzania}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-61355}, year = {1994}, abstract = {No abstract available}, subject = {Virologie}, language = {en} } @article{EckertRibechiniJaricketal.2021, author = {Eckert, Ina N. and Ribechini, Eliana and Jarick, Katja J. and Strozniak, Sandra and Potter, Sarah J. and Beilhack, Andreas and Lutz, Manfred B.}, title = {VLA-1 Binding to Collagen IV Controls Effector T Cell Suppression by Myeloid-Derived Suppressor Cells in the Splenic Red Pulp}, series = {Frontiers in Immunology}, volume = {11}, journal = {Frontiers in Immunology}, issn = {1664-3224}, doi = {10.3389/fimmu.2020.616531}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-222671}, year = {2021}, abstract = {Myeloid-derived suppressor cells (MDSCs) represent a major population controlling T cell immune responses. However, little is known about their molecular requirements for homing and T cell interaction to mediate suppression. Here, we investigated the functional role of the homing and collagen IV receptor VLA-1 (α1β1-integrin) on in vitro GM-CSF generated murine MDSCs from wild-type (WT) and CD49a/α1-integrin (Itga1\(^{-/-}\)) gene-deficient mice. Here, we found that effector (Teff) but not naive (Tn) CD4\(^+\) T cells express VLA-1 and monocytes further up-regulated their expression after culture in GM-CSF when they differentiated into the monocytic subset of resting MDSCs (R-MDSCs). Subsequent activation of R-MDSCs by LPS+IFN-γ (A-MDSCs) showed increased in vitro suppressor potential, which was independent of VLA-1. Surprisingly, VLA-1 deficiency did not influence A-MDSC motility or migration on collagen IV in vitro. However, interaction times of Itga1\(^{-/-}\) A-MDSCs with Teff were shorter than with WT A-MDSCs on collagen IV but not on fibronectin substrate in vitro. After injection, A-MDSCs homed to the splenic red pulp where they co-localized with Teff and showed immediate suppression already after 6 h as shown by inhibition of T cell proliferation and induction of apoptosis. Injection of A-MDSCs from Itga1\(^{-/-}\) mice showed equivalent homing into the spleen but a reduced suppressive effect. Interaction studies of A-MDSCs with Teff in the subcapsular red pulp with intravital two-photon microscopy revealed also here that MDSC motility and migration parameters were not altered by VLA-1 deficiency, but the interaction times with Teff were reduced. Together, our data point to a new role of VLA-1 adhesion to collagen IV as a prerequisite for extended contact times with Teff required for suppression.}, language = {en} } @article{GrafenSchumacherChithelenetal.2019, author = {Grafen, Anika and Schumacher, Fabian and Chithelen, Janice and Kleuser, Burkhard and Beyersdorf, Niklas and Schneider-Schaulies, J{\"u}rgen}, title = {Use of acid ceramidase and sphingosine kinase inhibitors as antiviral compounds against measles virus infection of lymphocytes in vitro}, series = {Frontiers in Cell and Developmental Biology}, volume = {7}, journal = {Frontiers in Cell and Developmental Biology}, number = {218}, issn = {2296-634X}, doi = {10.3389/fcell.2019.00218}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196099}, year = {2019}, abstract = {As structural membrane components and signaling effector molecules sphingolipids influence a plethora of host cell functions, and by doing so also the replication of viruses. Investigating the effects of various inhibitors of sphingolipid metabolism in primary human peripheral blood lymphocytes (PBL) and the human B cell line BJAB we found that not only the sphingosine kinase (SphK) inhibitor SKI-II, but also the acid ceramidase inhibitor ceranib-2 efficiently inhibited measles virus (MV) replication. Virus uptake into the target cells was not grossly altered by the two inhibitors, while titers of newly synthesized MV were reduced by approximately 1 log (90\%) in PBL and 70-80\% in BJAB cells. Lipidomic analyses revealed that in PBL SKI-II led to increased ceramide levels, whereas in BJAB cells ceranib-2 increased ceramides. SKI-II treatment decreased sphingosine-1-phosphate (S1P) levels in PBL and BJAB cells. Furthermore, we found that MV infection of lymphocytes induced a transient (0.5-6 h) increase in S1P, which was prevented by SKI-II. Investigating the effect of the inhibitors on the metabolic (mTORC1) activity we found that ceranib-2 reduced the phosphorylation of p70 S6K in PBL, and that both inhibitors, ceranib-2 and SKI-II, reduced the phosphorylation of p70 S6K in BJAB cells. As mTORC1 activity is required for efficient MV replication, this effect of the inhibitors is one possible antiviral mechanism. In addition, reduced intracellular S1P levels affect a number of signaling pathways and functions including Hsp90 activity, which was reported to be required for MV replication. Accordingly, we found that pharmacological inhibition of Hsp90 with the inhibitor 17-AAG strongly impaired MV replication in primary PBL. Thus, our data suggest that treatment of lymphocytes with both, acid ceramidase and SphK inhibitors, impair MV replication by affecting a number of cellular activities including mTORC1 and Hsp90, which alter the metabolic state of the cells causing a hostile environment for the virus.}, language = {en} } @article{BodemSchromMoschalletal.2013, author = {Bodem, Jochen and Schrom, Eva-Maria and Moschall, Rebecca and Hartl, Maximilian J. and Weitner, Helena and Fecher, David and Langemeier, J{\"o}rg and W{\"o}hrl, Brigitta M.}, title = {U1snRNP-mediated suppression of polyadenylation in conjunction with the RNA structure controls poly (A) site selection in foamy viruses}, series = {Retrovirology}, journal = {Retrovirology}, doi = {10.1186/1742-4690-10-55}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-96085}, year = {2013}, abstract = {Background During reverse transcription, retroviruses duplicate the long terminal repeats (LTRs). These identical LTRs carry both promoter regions and functional polyadenylation sites. To express full-length transcripts, retroviruses have to suppress polyadenylation in the 5′LTR and activate polyadenylation in the 3′LTR. Foamy viruses have a unique LTR structure with respect to the location of the major splice donor (MSD), which is located upstream of the polyadenylation signal. Results Here, we describe the mechanisms of foamy viruses regulating polyadenylation. We show that binding of the U1 small nuclear ribonucleoprotein (U1snRNP) to the MSD suppresses polyadenylation at the 5′LTR. In contrast, polyadenylation at the 3′LTR is achieved by adoption of a different RNA structure at the MSD region, which blocks U1snRNP binding and furthers RNA cleavage and subsequent polyadenylation. Conclusion Recently, it was shown that U1snRNP is able to suppress the usage of intronic cryptic polyadenylation sites in the cellular genome. Foamy viruses take advantage of this surveillance mechanism to suppress premature polyadenylation at the 5'end of their RNA. At the 3'end, Foamy viruses use a secondary structure to presumably block access of U1snRNP and thereby activate polyadenylation at the end of the genome. Our data reveal a contribution of U1snRNP to cellular polyadenylation site selection and to the regulation of gene expression.}, subject = {Polyadenylierung}, language = {en} } @article{HaakeHaackSchaeferetal.2023, author = {Haake, Markus and Haack, Beatrice and Sch{\"a}fer, Tina and Harter, Patrick N. and Mattavelli, Greta and Eiring, Patrick and Vashist, Neha and Wedekink, Florian and Genssler, Sabrina and Fischer, Birgitt and Dahlhoff, Julia and Mokhtari, Fatemeh and Kuzkina, Anastasia and Welters, Marij J. P. and Benz, Tamara M. and Sorger, Lena and Thiemann, Vincent and Almanzar, Giovanni and Selle, Martina and Thein, Klara and Sp{\"a}th, Jacob and Gonzalez, Maria Cecilia and Reitinger, Carmen and Ipsen-Escobedo, Andrea and Wistuba-Hamprecht, Kilian and Eichler, Kristin and Filipski, Katharina and Zeiner, Pia S. and Beschorner, Rudi and Goedemans, Renske and Gogolla, Falk Hagen and Hackl, Hubert and Rooswinkel, Rogier W. and Thiem, Alexander and Romer Roche, Paula and Joshi, Hemant and P{\"u}hringer, Dirk and W{\"o}ckel, Achim and Diessner, Joachim E. and R{\"u}diger, Manfred and Leo, Eugen and Cheng, Phil F. and Levesque, Mitchell P. and Goebeler, Matthias and Sauer, Markus and Nimmerjahn, Falk and Schuberth-Wagner, Christine and Felten, Stefanie von and Mittelbronn, Michel and Mehling, Matthias and Beilhack, Andreas and van der Burg, Sjoerd H. and Riedel, Angela and Weide, Benjamin and Dummer, Reinhard and Wischhusen, J{\"o}rg}, title = {Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment}, series = {Nature Communications}, volume = {14}, journal = {Nature Communications}, doi = {10.1038/s41467-023-39817-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357333}, year = {2023}, abstract = {Immune checkpoint blockade therapy is beneficial and even curative for some cancer patients. However, the majority don't respond to immune therapy. Across different tumor types, pre-existing T cell infiltrates predict response to checkpoint-based immunotherapy. Based on in vitro pharmacological studies, mouse models and analyses of human melanoma patients, we show that the cytokine GDF-15 impairs LFA-1/β2-integrin-mediated adhesion of T cells to activated endothelial cells, which is a pre-requisite of T cell extravasation. In melanoma patients, GDF-15 serum levels strongly correlate with failure of PD-1-based immune checkpoint blockade therapy. Neutralization of GDF-15 improves both T cell trafficking and therapy efficiency in murine tumor models. Thus GDF-15, beside its known role in cancer-related anorexia and cachexia, emerges as a regulator of T cell extravasation into the tumor microenvironment, which provides an even stronger rationale for therapeutic anti-GDF-15 antibody development.}, language = {en} } @article{HollmannWieseDennstaedtetal.2019, author = {Hollmann, Claudia and Wiese, Teresa and Dennst{\"a}dt, Fabio and Fink, Julian and Schneider-Schaulies, J{\"u}rgen and Beyersdorf, Niklas}, title = {Translational approaches targeting ceramide generation from sphingomyelin in T cells to modulate immunity in humans}, series = {Frontiers in Immunology}, volume = {10}, journal = {Frontiers in Immunology}, number = {2363}, issn = {1664-3224}, doi = {10.3389/fimmu.2019.02363}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-198806}, year = {2019}, abstract = {In T cells, as in all other cells of the body, sphingolipids form important structural components of membranes. Due to metabolic modifications, sphingolipids additionally play an active part in the signaling of cell surface receptors of T cells like the T cell receptor or the co-stimulatory molecule CD28. Moreover, the sphingolipid composition of their membranes crucially affects the integrity and function of subcellular compartments such as the lysosome. Previously, studying sphingolipid metabolism has been severely hampered by the limited number of analytical methods/model systems available. Besides well-established high resolution mass spectrometry new tools are now available like novel minimally modified sphingolipid subspecies for click chemistry as well as recently generated mouse mutants with deficiencies/overexpression of sphingolipid-modifying enzymes. Making use of these tools we and others discovered that the sphingolipid sphingomyelin is metabolized to ceramide to different degrees in distinct T cell subpopulations of mice and humans. This knowledge has already been translated into novel immunomodulatory approaches in mice and will in the future hopefully also be applicable to humans. In this paper we are, thus, summarizing the most recent findings on the impact of sphingolipid metabolism on T cell activation, differentiation, and effector functions. Moreover, we are discussing the therapeutic concepts arising from these insights and drugs or drug candidates which are already in clinical use or could be developed for clinical use in patients with diseases as distant as major depression and chronic viral infection.}, language = {en} } @article{DahlhoffManzSteinfattetal.2022, author = {Dahlhoff, Julia and Manz, Hannah and Steinfatt, Tim and Delgado-Tascon, Julia and Seebacher, Elena and Schneider, Theresa and Wilnit, Amy and Mokhtari, Zeinab and Tabares, Paula and B{\"o}ckle, David and Rasche, Leo and Martin Kort{\"u}m, K. and Lutz, Manfred B. and Einsele, Hermann and Brandl, Andreas and Beilhack, Andreas}, title = {Transient regulatory T-cell targeting triggers immune control of multiple myeloma and prevents disease progression}, series = {Leukemia}, volume = {36}, journal = {Leukemia}, number = {3}, issn = {1476-5551}, doi = {10.1038/s41375-021-01422-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-271787}, pages = {790-800}, year = {2022}, abstract = {Multiple myeloma remains a largely incurable disease of clonally expanding malignant plasma cells. The bone marrow microenvironment harbors treatment-resistant myeloma cells, which eventually lead to disease relapse in patients. In the bone marrow, CD4\(^{+}\)FoxP3\(^{+}\) regulatory T cells (Tregs) are highly abundant amongst CD4\(^{+}\) T cells providing an immune protective niche for different long-living cell populations, e.g., hematopoietic stem cells. Here, we addressed the functional role of Tregs in multiple myeloma dissemination to bone marrow compartments and disease progression. To investigate the immune regulation of multiple myeloma, we utilized syngeneic immunocompetent murine multiple myeloma models in two different genetic backgrounds. Analyzing the spatial immune architecture of multiple myeloma revealed that the bone marrow Tregs accumulated in the vicinity of malignant plasma cells and displayed an activated phenotype. In vivo Treg depletion prevented multiple myeloma dissemination in both models. Importantly, short-term in vivo depletion of Tregs in mice with established multiple myeloma evoked a potent CD8 T cell- and NK cell-mediated immune response resulting in complete and stable remission. Conclusively, this preclinical in-vivo study suggests that Tregs are an attractive target for the treatment of multiple myeloma.}, language = {en} } @article{BrabletzPfeufferSchorretal.1993, author = {Brabletz, Thomas and Pfeuffer, Isolde and Schorr, Elke and Siebelt, Friederike and Wirth, Thomas and Serfling, Edgar}, title = {Transforming growth factor \(\beta\) and cyclosporin A inhibit the inducible activity of the interleukin-2 gene in T cells through a noncanonical octamer-binding site}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-31199}, year = {1993}, abstract = {Transforming growth factor \(\beta\) (TGF-\(\beta\)) has a growth-inhibitory effect on numerous different cell types of the immune system, including T lymphocytes. We show in this study that the inhibitory action of TGF-\(\beta\) on T lymphocytes is accompanied by a block of interleukin 2 (IL-2) gene expression which is mediated, at least in part, by inhibition of IL-2 promoter/enhancer activity. The functional analysis of cis-regulatory (protoenhancer) elements of the IL-2 enhancer/promoter region showed that the most TGF-\(\beta\)-responsive element maps to its so-called upstream promoter site. The proto-enhancer activity of the upstream promoter site element is also inhibited by cyclosporin A. The upstream promoter site DNA harbors two noncanonical, closely linked binding sequences for octamer and AP-1-like factors. Both sites are involved in the establishment of IL-2 enhancer activity. Since the activity of genuine octamer sites but not that of AP-1-binding sites is also impaired by TGF-\(\beta\) and cyclosporin A in E14 T lymphoma cells, we conclude that both immunosuppressives interfere with the activity but not the DNA binding of octamer factors in T lymphocytes.}, language = {en} } @article{BugaMargaritescuScholzetal.2014, author = {Buga, Ana Maria and Margaritescu, Claudiu and Scholz, Claus J{\"u}rgen and Radu, Eugen and Zelenak, Christine and Popa-Wagner, Aurel}, title = {Transcriptomics of Post-Stroke Angiogenesis in the Aged Brain}, series = {Frontiers in Aging Neuroscience}, volume = {6}, journal = {Frontiers in Aging Neuroscience}, number = {44}, doi = {10.3389/fnagi.2014.00044}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-120700}, year = {2014}, abstract = {Despite the obvious clinical significance of post-stroke angiogenesis in aged subjects, a detailed transcriptomic analysis of post-stroke angiogenesis has not yet been undertaken in an aged experimental model. In this study, by combining stroke transcriptomics with immunohistochemistry in aged rats and post-stroke patients, we sought to identify an age-specific gene expression pattern that may characterize the angiogenic process after stroke. We found that both young and old infarcted rats initiated vigorous angiogenesis. However, the young rats had a higher vascular density by day 14 post-stroke. "New-for-stroke" genes that were linked to the increased vasculature density in young animals included Angpt2, Angptl2, Angptl4, Cib1, Ccr2, Col4a2, Cxcl1, Lef1, Hhex, Lamc1, Nid2, Pcam1, Plod2, Runx3, Scpep1, S100a4, Tgfbi, and Wnt4, which are required for sprouting angiogenesis, reconstruction of the basal lamina (BL), and the resolution phase. The vast majority of genes involved in sprouting angiogenesis (Angpt2, Angptl4, Cib1, Col8a1, Nrp1, Pcam1, Pttg1ip, Rac2, Runx1, Tnp4, Wnt4); reconstruction of a new BL (Col4a2, Lamc1, Plod2); or tube formation and maturation (Angpt1, Gpc3, Igfbp7, Sparc, Tie2, Tnfsf10), had however, a delayed upregulation in the aged rats. The angiogenic response in aged rats was further diminished by the persistent upregulation of "inflammatory" genes (Cxcl12, Mmp8, Mmp12, Mmp14, Mpeg1, Tnfrsf1a, Tnfrsf1b) and vigorous expression of genes required for the buildup of the fibrotic scar (Cthrc1, Il6ra, Il13ar1, Il18, Mmp2, Rassf4, Tgfb1, Tgfbr2, Timp1). Beyond this barrier, angiogenesis in the aged brains was similar to that in young brains. We also found that the aged human brain is capable of mounting a vigorous angiogenic response after stroke, which most likely reflects the remaining brain plasticity of the aged brain.}, language = {en} } @article{HerpinBraaschKraeusslingetal.2010, author = {Herpin, Amaury and Braasch, Ingo and Kraeussling, Michael and Schmidt, Cornelia and Thoma, Eva C. and Nakamura, Shuhei and Tanaka, Minoru and Schartl, Manfred}, title = {Transcriptional Rewiring of the Sex Determining dmrt1 Gene Duplicate by Transposable Elements}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-68437}, year = {2010}, abstract = {Control and coordination of eukaryotic gene expression rely on transcriptional and posttranscriptional regulatory networks. Evolutionary innovations and adaptations often require rapid changes of such networks. It has long been hypothesized that transposable elements (TE) might contribute to the rewiring of regulatory interactions. More recently it emerged that TEs might bring in ready-to-use transcription factor binding sites to create alterations to the promoters by which they were captured. A process where the gene regulatory architecture is of remarkable plasticity is sex determination. While the more downstream components of the sex determination cascades are evolutionary conserved, the master regulators can switch between groups of organisms even on the interspecies level or between populations. In the medaka fish (Oryzias latipes) a duplicated copy of dmrt1, designated dmrt1bY or DMY, on the Y chromosome was shown to be the master regulator of male development, similar to Sry in mammals. We found that the dmrt1bY gene has acquired a new feedback downregulation of its expression. Additionally, the autosomal dmrt1a gene is also able to regulate transcription of its duplicated paralog by binding to a unique target Dmrt1 site nested within the dmrt1bY proximal promoter region. We could trace back this novel regulatory element to a highly conserved sequence within a new type of TE that inserted into the upstream region of dmrt1bY shortly after the duplication event. Our data provide functional evidence for a role of TEs in transcriptional network rewiring for sub- and/or neo-functionalization of duplicated genes. In the particular case of dmrt1bY, this contributed to create new hierarchies of sex-determining genes.}, subject = {Gen}, language = {en} } @article{MaurerSerflingterMeulenetal.1991, author = {Maurer, Bernd and Serfling, Edgar and ter Meulen, Volker and Rethwilm, Axel}, title = {Transcription factor AP-1 modulates the activity of the human foamy virus long terminal repeat}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-61444}, year = {1991}, abstract = {The human foamy virus (HFV) contains within the UJ region of its long terminal repeat (L TR) three perfect consensus sequences for the binding of the inducible transcription factor AP-1. Results of DNase I footprint protection and gel retardation assays demonstrated that proteins in extracts of HeLa and BHK-21 cells as weil as bacterially expressed Jun and Fos proteins bind to these AP-1 sites. By conducting transient expression assays using chloramphenicol acetyltransferase plasmids carrying LTR sequences with point-mutated AP-1 sites it was found that the three AP-1 sites contribute to the optimal activity ofthe HFV promoter. It is shown that lnduction of the HFV L TR by 12-O-tetradecanoylphorbol-13-acetate (TPA) and serum factors is mediated through the AP-1 sites.}, subject = {Virologie}, language = {en} } @article{RethwilmMoriMaureretal.1990, author = {Rethwilm, Axel and Mori, Kazuyasu and Maurer, Bernd and ter Meulen, Volker}, title = {Transacting transcriptional activation of human spumaretrovirus LTR in infected cells}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-61488}, year = {1990}, abstract = {The long terminal repeat (LTR) of the human spumaretrovirus (HSRV) was examined with respect to its ability to function as transcriptional promotor in virus-infected and uninfected cells. Transient transfections using a plasmid in which the 3' L TR of HSRV was coupled to the bacterial chloramphenicol cetyltransferase (cat) gene revealed that the Ievei of HSRV LTR-directed cat gene expression was markedly increased in HSRV-infected cells compared to uninfected cells. Northern blot analysis of cat mRNA from transfected cultures suggests that transactivation of HSRVdirected gene expression occurs at the transcriptionallevel.}, subject = {Virologie}, language = {en} } @article{VendelovaAshourBlanketal.2018, author = {Vendelova, Emilia and Ashour, Diyaaeldin and Blank, Patrick and Erhard, Florian and Saliba, Antoine-Emmanuel and Kalinke, Ulrich and Lutz, Manfred B.}, title = {Tolerogenic transcriptional signatures of steady-state and pathogen-induced dendritic cells}, series = {Frontiers in Immunology}, volume = {9}, journal = {Frontiers in Immunology}, number = {333}, doi = {10.3389/fimmu.2018.00333}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-175636}, year = {2018}, abstract = {Dendritic cells (DCs) are key directors of tolerogenic and immunogenic immune responses. During the steady state, DCs maintain T cell tolerance to self-antigens by multiple mechanisms including inducing anergy, deletion, and Treg activity. All of these mechanisms help to prevent autoimmune diseases or other hyperreactivities. Different DC subsets contribute to pathogen recognition by expression of different subsets of pattern recognition receptors, including Toll-like receptors or C-type lectins. In addition to the triggering of immune responses in infected hosts, most pathogens have evolved mechanisms for evasion of targeted responses. One such strategy is characterized by adopting the host's T cell tolerance mechanisms. Understanding these tolerogenic mechanisms is of utmost importance for therapeutic approaches to treat immune pathologies, tumors and infections. Transcriptional profiling has developed into a potent tool for DC subset identification. Here, we review and compile pathogen-induced tolerogenic transcriptional signatures from mRNA profiling data of currently available bacterial- or helminth-induced transcriptional signatures. We compare them with signatures of tolerogenic steady-state DC subtypes to identify common and divergent strategies of pathogen induced immune evasion. Candidate molecules are discussed in detail. Our analysis provides further insights into tolerogenic DC signatures and their exploitation by different pathogens.}, language = {en} } @article{SchleicherPaduchDebusetal.2016, author = {Schleicher, Ulrike and Paduch, Katrin and Debus, Andrea and Obermeyer, Stephanie and K{\"o}nig, Till and Kling, Jessica C. and Ribechini, Eliana and Dudziak, Diana and Mougiakakos, Dimitrios and Murray, Peter J. and Ostuni, Renato and K{\"o}rner, Heinrich and Bogdan, Christian}, title = {TNF-Mediated Restriction of Arginase 1 Expression in Myeloid Cells Triggers Type 2 NO Synthase Activity at the Site of Infection}, series = {Cell Reports}, volume = {15}, journal = {Cell Reports}, number = {5}, doi = {10.1016/j.celrep.2016.04.001}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-164897}, pages = {1062-1075}, year = {2016}, abstract = {Neutralization or deletion of tumor necrosis factor (TNF) causes loss of control of intracellular pathogens in mice and humans, but the underlying mechanisms are incompletely understood. Here, we found that TNF antagonized alternative activation of macrophages and dendritic cells by IL-4. TNF inhibited IL-4-induced arginase 1 (Arg1) expression by decreasing histone acetylation, without affecting STAT6 phosphorylation and nuclear translocation. In Leishmania major-infected C57BL/6 wild-type mice, type 2 nitric oxide (NO) synthase (NOS2) was detected in inflammatory dendritic cells or macrophages, some of which co-expressed Arg1. In TNF-deficient mice, Arg1 was hyperexpressed, causing an impaired production of NO in situ. A similar phenotype was seen in L. major-infected BALB/c mice. Arg1 deletion in hematopoietic cells protected these mice from an otherwise lethal disease, although their disease-mediating T cell response (Th2, Treg) was maintained. Thus, deletion or TNF-mediated restriction of Arg1 unleashes the production of NO by NOS2, which is critical for pathogen control.}, language = {en} } @article{KasimirToomeyLiuetal.2022, author = {Kasimir, Francesca and Toomey, Danny and Liu, Zheng and Kaiping, Agnes C. and Ariza, Maria Eugenia and Prusty, Bhupesh K.}, title = {Tissue specific signature of HHV-6 infection in ME/CFS}, series = {Frontiers in Molecular Biosciences}, volume = {9}, journal = {Frontiers in Molecular Biosciences}, issn = {2296-889X}, doi = {10.3389/fmolb.2022.1044964}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-299433}, year = {2022}, abstract = {First exposure to various human herpesviruses (HHVs) including HHV-6, HCMV and EBV does not cause a life-threatening disease. In fact, most individuals are frequently unaware of their first exposure to such pathogens. These herpesviruses acquire lifelong latency in the human body where they show minimal genomic activity required for their survival. We hypothesized that it is not the latency itself but a timely, regionally restricted viral reactivation in a sub-set of host cells that plays a key role in disease development. HHV-6 (HHV-6A and HHV-6B) and HHV-7 are unique HHVs that acquire latency by integration of the viral genome into sub-telomeric region of human chromosomes. HHV-6 reactivation has been linked to Alzheimer's Disease, Chronic Fatigue Syndrome, and many other diseases. However, lack of viral activity in commonly tested biological materials including blood or serum strongly suggests tissue specific localization of active HHV-6 genome. Here in this paper, we attempted to analyze active HHV-6 transcripts in postmortem tissue biopsies from a small cohort of ME/CFS patients and matched controls by fluorescence in situ hybridization using a probe against HHV-6 microRNA (miRNA), miR-aU14. Our results show abundant viral miRNA in various regions of the human brain and associated neuronal tissues including the spinal cord that is only detected in ME/CFS patients and not in controls. Our findings provide evidence of tissue-specific active HHV-6 and EBV infection in ME/CFS, which along with recent work demonstrating a possible relationship between herpesvirus infection and ME/CFS, provide grounds for renewed discussion on the role of herpesviruses in ME/CFS.}, language = {en} } @article{RiquelmeHaarerKammleretal.2018, author = {Riquelme, Paloma and Haarer, Jan and Kammler, Anja and Walter, Lisa and Tomiuk, Stefan and Ahrens, Norbert and Wege, Anja K. and Goecze, Ivan and Zecher, Daniel and Banas, Bernhard and Spang, Rainer and F{\"a}ndrich, Fred and Lutz, Manfred B. and Sawitzki, Birgit and Schlitt, Hans J. and Ochando, Jordi and Geissler, Edward K. and Hutchinson, James A.}, title = {TIGIT\(^+\) iTregs elicited by human regulatory macrophages control T cell immunity}, series = {Nature Communications}, volume = {9}, journal = {Nature Communications}, number = {9}, doi = {10.1038/s41467-018-05167-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226321}, pages = {2858, 1-18}, year = {2018}, abstract = {Human regulatory macrophages (Mreg) have shown early clinical promise as a cell-based adjunct immunosuppressive therapy in solid organ transplantation. It is hypothesised that recipient CD4(+) T cell responses are actively regulated through direct allorecognition of donor-derived Mregs. Here we show that human Mregs convert allogeneic CD4(+) T cells to IL-10-producing, TIGIT(+) FoxP3(+)-induced regulatory T cells that non-specifically suppress bystander T cells and inhibit dendritic cell maturation. Differentiation of Mreg-induced Tregs relies on multiple non-redundant mechanisms that are not exclusive to interaction of Mregs and T cells, including signals mediated by indoleamine 2,3-dioxygenase, TGF-beta, retinoic acid, Notch and progestagen-associated endometrial protein. Preoperative administration of donor-derived Mregs to living-donor kidney transplant recipients results in an acute increase in circulating TIGIT(+) Tregs. These results suggest a feed-forward mechanism by which Mreg treatment promotes allograft acceptance through rapid induction of direct-pathway Tregs.}, language = {en} } @article{Lutz2012, author = {Lutz, Manfred B.}, title = {Therapeutic Potential of Semi-Mature Dendritic Cells for Tolerance Induction}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75535}, year = {2012}, abstract = {Dendritic cells (DCs) are major players in the control of adaptive tolerance and immunity. Therefore, their specific generation and adoptive transfer into patients or their in vivo targeting is attractive for clinical applications. While injections of mature immunogenic DCs are tested in clinical trials, tolerogenic DCs still are awaiting this step. Besides the tolerogenic potential of immature DCs, also semi-mature DCs can show tolerogenic activity but both types also bear unfavorable features. Optimal tolerogenic DCs, their molecular tool bar, and their use for specific diseases still have to be defined. Here, the usefulness of in vitro generated and adoptively transferred semi-mature DCs for tolerance induction is outlined. The in vivo targeting of semi-mature DCs as represented by steady state migratory DCs are discussed for treatment of autoimmune diseases and allergies. First clinical trials with transcutaneous allergen application may point to their therapeutic use in the future.}, subject = {Medizin}, language = {en} } @article{HerrmannKarunakaran2014, author = {Herrmann, Thomas and Karunakaran, Mohindar M.}, title = {The Vγ9Vδ2 T cell antigen receptor and butyrophilin-3 A1: models of interaction, the possibility of co-evolution, and the case of dendritic epidermal T cells}, doi = {10.3389/fimmu.2014.00648}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-111141}, year = {2014}, abstract = {Most circulating human gamma delta T cells are Vγ9Vδ2 T cells. Their hallmark is the expression of T cell antigen receptors (TCR) whose γ-chains show a Vγ9-JP (Vγ2-Jγ1.2) rearrangement and are paired with Vδ2-containing δ-chains, a dominantTCR configuration, which until recently seemed to occur in primates only. Vγ9Vδ2 T cells respond to phosphoantigens (PAg) such as (E)-4-Hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), which is produced by many pathogens and isopentenyl pyrophosphate (IPP), which accumulates in certain tumors or cells treated with aminobisphosphonates such as zoledronate. A prerequisite for PAg-induced activation is the contact of Vγ9Vδ2 T cells with cells expressing butyrophilin-3 A1 (BTN3A1). We will first critically review models of how BTN3 might act in PAg-mediated Vγ9Vδ2 T cell activation and then address putative co-evolution of Vγ9, Vδ2, and BTN3 genes. In those rodent and lagomorphs used as animal models, all three genes are lost but a data-base analysis showed that they emerged together with placental mammals. A strong concomitant conservation of functional Vγ9, Vδ2, and BTN3 genes in other species suggests co-evolution of these three genes. A detailed analysis was performed for the new world camelid alpaca (Vicugna pacos). It provides an excellent candidate for a non-primate species with presumably functional Vγ9Vδ2 T cells since TCR rearrangements share features characteristic for PAg-reactive primate Vγ9Vδ2 TCR and proposed PAg-binding sites of BTN3A1 have been conserved. Finally, we analyze the possible functional relationship between the butyrophilin-family member Skint1 and the γδTCR-V genes used by murine dendritic epithelialT cells (DETC). Among placental mammals, we identify five rodents, the cow, a bat, and the cape golden mole as the only species concomitantly possessing potentially functional homologs of murineVγ3,Vδ4 genes, and Skint1 gene and suggest to search for DETC like cells in these species.}, language = {en} } @article{RethwilmErlweinBaunachetal.1991, author = {Rethwilm, Axel and Erlwein, Otto and Baunach, Gerald and Mauerer, Bernd and ter Meulen, Volker}, title = {The transcriptional transactivator of human foamy virus maps to the bel 1 genomic region}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-47342}, year = {1991}, abstract = {The human foamy virus (HFV) genome possesses three open reading frames (bel I, 2, and 3) located between env and the 3' long terminal repeat. By analogy to other human retroviruses this region was selected as the most Iikely candidate to encode the viral transactivator. ResuIts presented here confirmed this and showed further that a deletion introduced only into the bell open reading frame of a plasmid derived from an infectious molecular clone of HFV abolished transactivation. In contrast, deletions in bel 2 and bel 3 had only minor effects on the ability to transactivate. The role of the bel I genomic region as a transactivator was further investigated by eukaryotic expression of a genome fragment of HFV spanning the bel I open reading frame. A construct expressing bell under control of a heterologous promoter was found to transactivate the HFV long terminal repeat in a dose-dependent fashion. Furthermore, it is shown that the U3 region of the HFV long terminal repeat is sufficient to respond to the HFV transactivator.}, subject = {Virologie}, language = {en} } @article{MuellerKrennCzubetal.1993, author = {M{\"u}ller, J. and Krenn, V. and Czub, S. and Schindler, C. and Kneitz, C. and Kerkau, T. and Stahl-Henning, C. and Coulibaly, C. and Hunsmann, G. and Rethwilm, Axel and ter Meulen, Volker and M{\"u}ller-Hermelink, H. K.}, title = {The thymus in SIV infection}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-80265}, year = {1993}, abstract = {no abstract available}, subject = {HIV-Infektion}, language = {en} } @article{ChithelenFrankeLaenderetal.2022, author = {Chithelen, Janice and Franke, Hannah and L{\"a}nder, Nora and Grafen, Anika and Schneider-Schaulies, J{\"u}rgen}, title = {The sphingolipid inhibitors ceranib-2 and SKI-II reduce measles virus replication in primary human lymphocytes: effects on mTORC1 downstream signaling}, series = {Frontiers in Physiology}, volume = {13}, journal = {Frontiers in Physiology}, issn = {1664-042X}, doi = {10.3389/fphys.2022.856143}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265988}, year = {2022}, abstract = {The bioactive sphingolipids ceramide and sphingosine-1-phosphate (S1P) are involved in the regulation of cell homeostasis and activity ranging from apoptosis to proliferation. We recently described that the two compounds ceranib-2 (inhibiting acid ceramidase) and SKI-II [inhibiting the sphingosine kinases 1 and - 2 (SphK1/2)] reduce mTORC1 activity and measles virus (MV) replication in human primary peripheral blood lymphocytes (PBL) by about one log step. We now further investigated whether mTORC1 downstream signaling and viral protein expression may be affected by ceranib-2 and/or SKI-II. Western blot analyses showed that in uninfected cells the phosphorylation of the eukaryotic initiation factor 4E (eIF4E) was reduced by both inhibitors. Interestingly, MV infection led to an increase of rpS6 protein levels and phosphorylation of eIF4E. Treatment with both inhibitors reduced the rpS6 protein expression, and in addition, SKI-II reduced rpS6 phosphorylation. The phosphorylation of eIF4E was slightly reduced by both inhibitors. In addition, SKI-II led to reduced levels of IKK in MV-infected cells. Both inhibitors reduced the expression of viral proteins and the titers of newly synthesized MV by approximately one log step. As expected, SKI-II and rapamycin reduced also the virally encoded GFP expression; however, ceranib-2 astonishingly led to increased levels of GFP fluorescence. Our findings suggest that the inhibitors ceranib-2 and SKI-II act via differential mechanisms on MV replication. The observed effects on mTORC1 downstream signaling, predominantly the reduction of rpS6 levels by both inhibitors, may affect the translational capacity of the cells and contribute to the antiviral effect in human primary PBL.}, language = {en} } @article{ZimniakKirschnerHilpertetal.2021, author = {Zimniak, Melissa and Kirschner, Luisa and Hilpert, Helen and Geiger, Nina and Danov, Olga and Oberwinkler, Heike and Steinke, Maria and Sewald, Katherina and Seibel, J{\"u}rgen and Bodem, Jochen}, title = {The serotonin reuptake inhibitor Fluoxetine inhibits SARS-CoV-2 in human lung tissue}, series = {Scientific Reports}, volume = {11}, journal = {Scientific Reports}, doi = {10.1038/s41598-021-85049-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259820}, pages = {5890}, year = {2021}, abstract = {To circumvent time-consuming clinical trials, testing whether existing drugs are effective inhibitors of SARS-CoV-2, has led to the discovery of Remdesivir. We decided to follow this path and screened approved medications "off-label" against SARS-CoV-2. Fluoxetine inhibited SARS-CoV-2 at a concentration of 0.8 mu g/ml significantly in these screenings, and the EC50 was determined with 387 ng/ml. Furthermore, Fluoxetine reduced viral infectivity in precision-cut human lung slices showing its activity in relevant human tissue targeted in severe infections. Fluoxetine treatment resulted in a decrease in viral protein expression. Fluoxetine is a racemate consisting of both stereoisomers, while the S-form is the dominant serotonin reuptake inhibitor. We found that both isomers show similar activity on the virus, indicating that the R-form might specifically be used for SARS-CoV-2 treatment. Fluoxetine inhibited neither Rabies virus, human respiratory syncytial virus replication nor the Human Herpesvirus 8 or Herpes simplex virus type 1 gene expression, indicating that it acts virus-specific. Moreover, since it is known that Fluoxetine inhibits cytokine release, we see the role of Fluoxetine in the treatment of SARS-CoV-2 infected patients of risk groups.}, language = {en} } @article{AvotaSchneiderSchaulies2014, author = {Avota, Elita and Schneider-Schaulies, Sibylle}, title = {The Role of Sphingomyelin Breakdown in Measles Virus Immunmodulation}, series = {Cellular Physiology and Biochemistry}, volume = {34}, journal = {Cellular Physiology and Biochemistry}, number = {1}, issn = {1015-8987}, doi = {10.1159/000362981}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-120004}, pages = {20-26}, year = {2014}, abstract = {Measles virus (MV) efficiently causes generalized immunosuppression which accounts to a major extent for cases of measles-asscociated severe morbidity and mortality. MV infections alter many functions of antigen presenting cells (APC) (dendritic cells (DCs)) and lymphocytes, yet many molecular targets of the virus remain poorly defined. Cellular interactions and effector functions of DCs and lymphocytes are regulated by surface receptors. Associating with other proteins involved in cell signaling, receptors form part of receptosomes that respond to and transmit external signals through dynamic interctions with the cytoskeleton. Alterations in the composition and metabolism of membrane sphingolipids have a substantial impact on both processes. In this review we focus on the regulation of sphingomyelinase activity and ceramide release in cells exposed to MV and discuss the immunosuppressive role of sphingomyelin breakdown induced by MV.}, language = {en} } @article{SchneiderSchauliesSchnorrDunsteretal.1994, author = {Schneider-Schaulies, Sibylle and Schnorr, J.-J. and Dunster, L. M. and Schneider-Schaulies, J{\"u}rgen and ter Meulen, Volker}, title = {The role of host factors in measles virus persistence}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-54944}, year = {1994}, abstract = {As critical steps in the life cycle oJ measles virus (Mfl), the e.fficiency of uptake into and replication in susceptible host cells are governed by cellular determinants. Measles virus infections of cells of the human CNS are characterized by particular constraints imposed on v1:ral transcription and translation attenuating viral gene Junctions and thus contributing to the pathogenesis oJ MV persistence in these cells.}, subject = {Immunologie}, language = {en} } @article{SpannausHartlWoehrletal.2012, author = {Spannaus, Ralf and Hartl, Maximilian J. and W{\"o}hrl, Birgitta M. and Rethwilm, Axel and Bodem, Jochen}, title = {The prototype foamy virus protease is active independently of the integrase domain}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75370}, year = {2012}, abstract = {Background: Recently, contradictory results on foamy virus protease activity were published. While our own results indicated that protease activity is regulated by the viral RNA, others suggested that the integrase is involved in the regulation of the protease. Results: To solve this discrepancy we performed additional experiments showing that the protease-reverse transcriptase (PR-RT) exhibits protease activity in vitro and in vivo, which is independent of the integrase domain. In contrast, Pol incorporation, and therefore PR activity in the viral context, is dependent on the integrase domain. To further analyse the regulation of the protease, we incorporated Pol in viruses by expressing a GagPol fusion protein, which supported near wild-type like infectivity. A GagPR-RT fusion, lacking the integrase domain, also resulted in wild-type like Gag processing, indicating that the integrase is dispensable for viral Gag maturation. Furthermore, we demonstrate with a trans-complementation assays that the PR in the context of the PR-RT protein supports in trans both, viral maturation and infectivity. Conclusion: We provide evidence that the FV integrase is required for Pol encapsidation and that the FV PR activity is integrase independent. We show that an active PR can be encapsidated in trans as a GagPR-RT fusion protein.}, subject = {Medizin}, language = {en} } @article{BoertleinDraegerSchoenaueretal.2018, author = {B{\"o}rtlein, Charlene and Draeger, Annette and Schoenauer, Roman and Kuhlemann, Alexander and Sauer, Markus and Schneider-Schaulies, Sybille and Avota, Elita}, title = {The neutral sphingomyelinase 2 is required to polarize and sustain T Cell receptor signaling}, series = {Frontiers in Immunology}, volume = {9}, journal = {Frontiers in Immunology}, number = {815}, doi = {10.3389/fimmu.2018.00815}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-176572}, year = {2018}, abstract = {By promoting ceramide release at the cytosolic membrane leaflet, the neutral sphingomyelinase 2 (NSM) is capable of organizing receptor and signalosome segregation. Its role in T cell receptor (TCR) signaling remained so far unknown. We now show that TCR-driven NSM activation is dispensable for TCR clustering and initial phosphorylation, but of crucial importance for further signal amplification. In particular, at low doses of TCR stimulatory antibodies, NSM is required for Ca\(^{2+}\) mobilization and T cell proliferation. NSM-deficient T cells lack sustained CD3ζ and ZAP-70 phosphorylation and are unable to polarize and stabilize their microtubular system. We identified PKCζ as the key NSM downstream effector in this second wave of TCR signaling supporting dynamics of microtubule-organizing center (MTOC). Ceramide supplementation rescued PKCζ membrane recruitment and MTOC translocation in NSM-deficient cells. These findings identify the NSM as essential in TCR signaling when dynamic cytoskeletal reorganization promotes continued lateral and vertical supply of TCR signaling components: CD3ζ, Zap70, and PKCζ, and functional immune synapses are organized and stabilized via MTOC polarization.}, language = {en} } @article{AvotaBodemChithelenetal.2021, author = {Avota, Elita and Bodem, Jochen and Chithelen, Janice and Mandasari, Putri and Beyersdorf, Niklas and Schneider-Schaulies, J{\"u}rgen}, title = {The Manifold Roles of Sphingolipids in Viral Infections}, series = {Frontiers in Physiology}, volume = {12}, journal = {Frontiers in Physiology}, issn = {1664-042X}, doi = {10.3389/fphys.2021.715527}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-246975}, year = {2021}, abstract = {Sphingolipids are essential components of eukaryotic cells. In this review, we want to exemplarily illustrate what is known about the interactions of sphingolipids with various viruses at different steps of their replication cycles. This includes structural interactions during entry at the plasma membrane or endosomal membranes, early interactions leading to sphingolipid-mediated signal transduction, interactions with internal membranes and lipids during replication, and interactions during virus assembly and budding. Targeted interventions in sphingolipid metabolism - as far as they can be tolerated by cells and organisms - may open novel possibilities to support antiviral therapies. Human immunodeficiency virus type 1 (HIV-1) infections have intensively been studied, but for other viral infections, such as influenza A virus (IAV), measles virus (MV), hepatitis C virus (HCV), dengue virus, Ebola virus, and severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), investigations are still in their beginnings. As many inhibitors of sphingolipid metabolism are already in clinical use against other diseases, repurposing studies for applications in some viral infections appear to be a promising approach.}, language = {en} } @article{DjakovicHennigReinischetal.2023, author = {Djakovic, Lara and Hennig, Thomas and Reinisch, Katharina and Milić, Andrea and Whisnant, Adam W. and Wolf, Katharina and Weiß, Elena and Haas, Tobias and Grothey, Arnhild and J{\"u}rges, Christopher S. and Kluge, Michael and Wolf, Elmar and Erhard, Florian and Friedel, Caroline C. and D{\"o}lken, Lars}, title = {The HSV-1 ICP22 protein selectively impairs histone repositioning upon Pol II transcription downstream of genes}, series = {Nature Communications}, volume = {14}, journal = {Nature Communications}, doi = {10.1038/s41467-023-40217-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-358161}, year = {2023}, abstract = {Herpes simplex virus 1 (HSV-1) infection and stress responses disrupt transcription termination by RNA Polymerase II (Pol II). In HSV-1 infection, but not upon salt or heat stress, this is accompanied by a dramatic increase in chromatin accessibility downstream of genes. Here, we show that the HSV-1 immediate-early protein ICP22 is both necessary and sufficient to induce downstream open chromatin regions (dOCRs) when transcription termination is disrupted by the viral ICP27 protein. This is accompanied by a marked ICP22-dependent loss of histones downstream of affected genes consistent with impaired histone repositioning in the wake of Pol II. Efficient knock-down of the ICP22-interacting histone chaperone FACT is not sufficient to induce dOCRs in ΔICP22 infection but increases dOCR induction in wild-type HSV-1 infection. Interestingly, this is accompanied by a marked increase in chromatin accessibility within gene bodies. We propose a model in which allosteric changes in Pol II composition downstream of genes and ICP22-mediated interference with FACT activity explain the differential impairment of histone repositioning downstream of genes in the wake of Pol II in HSV-1 infection.}, language = {en} } @article{LodhaErhardDoelkenetal.2022, author = {Lodha, Manivel and Erhard, Florian and D{\"o}lken, Lars and Prusty, Bhupesh K.}, title = {The hidden enemy within: non-canonical peptides in virus-induced autoimmunity}, series = {Frontiers in Microbiology}, volume = {13}, journal = {Frontiers in Microbiology}, issn = {1664-302X}, doi = {10.3389/fmicb.2022.840911}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-263053}, year = {2022}, abstract = {Viruses play a key role in explaining the pathogenesis of various autoimmune disorders, whose underlying principle is defined by the activation of autoreactive T-cells. In many cases, T-cells escape self-tolerance due to the failure in encountering certain MHC-I self-peptide complexes at substantial levels, whose peptides remain invisible from the immune system. Over the years, contribution of unstable defective ribosomal products (DRiPs) in immunosurveillance has gained prominence. A class of unstable products emerge from non-canonical translation and processing of unannotated mammalian and viral ORFs and their peptides are cryptic in nature. Indeed, high throughput sequencing and proteomics have revealed that a substantial portion of our genomes comprise of non-canonical ORFs, whose generation is significantly modulated during disease. Many of these ORFs comprise short ORFs (sORFs) and upstream ORFs (uORFs) that resemble DRiPs and may hence be preferentially presented. Here, we discuss how such products, normally "hidden" from the immune system, become abundant in viral infections activating autoimmune T-cells, by discussing their emerging role in infection and disease. Finally, we provide a perspective on how these mechanisms can explain several autoimmune disorders in the wake of the COVID-19 pandemic.}, language = {en} } @article{ProttengeierKoutsilieriScheller2014, author = {Prottengeier, Johannes and Koutsilieri, Eleni and Scheller, Carsten}, title = {The effects of opioids on HIV reactivation in latently-infected T-lymphoblasts}, series = {AIDS Research and Therapy}, volume = {11}, journal = {AIDS Research and Therapy}, number = {17}, issn = {1742-6405}, doi = {10.1186/1742-6405-11-17}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-115860}, year = {2014}, abstract = {Background: Opioids may have effects on susceptibility to HIV-infection, viral replication and disease progression. Injecting drug users (IDU), as well as anyone receiving opioids for anesthesia and analgesia may suffer the clinical consequences of such interactions. There is conflicting data between in vitro experiments showing an enhancing effect of opioids on HIV replication and clinical data, mostly showing no such effect. For clarification we studied the effects of the opioids heroin and morphine on HIV replication in cultured CD4-positive T cells at several concentrations and we related the observed effects with the relevant reached plasma concentrations found in IDUs. Methods: Latently-infected ACH-2 T lymphoblasts were incubated with different concentrations of morphine and heroine. Reactivation of HIV was assessed by intracellular staining of viral Gag p24 protein and subsequent flow cytometric quantification of p24-positive cells. The influence of the opioid antagonist naloxone and the antioxidants N-acetyl-cysteine (NAC) and glutathione (GSH) on HIV reactivation was determined. Cell viability was investigated by 7-AAD staining and flow cytometric quantification. Results: Morphine and heroine triggered reactivation of HIV replication in ACH-2 cells in a dose-dependent manner at concentrations above 1 mM (EC50 morphine 2.82 mM; EC50 morphine 1.96 mM). Naloxone did not interfere with heroine-mediated HIV reactivation, even at high concentrations (1 mM). Opioids also triggered necrotic cell death at similar concentrations at which HIV reactivation was observed. Both opioid-mediated reactivation of HIV and opioid-triggered cell death could be inhibited by the antioxidants GSH and NAC. Conclusions: Opioids reactivate HIV in vitro but at concentrations that are far above the plasma levels of analgesic regimes or drug concentrations found in IDUs. HIV reactivation was mediated by effects unrelated to opioid-receptor activation and was tightly linked to the cytotoxic activity of the substances at millimolar concentrations, suggesting that opioid-mediated reactivation of HIV was due to accompanying effects of cellular necrosis such as activation of reactive oxygen species and NF-kB.}, language = {en} } @article{FichtnerKarunakaranStaricketal.2018, author = {Fichtner, Alina Suzann and Karunakaran, Mohindar Murugesh and Starick, Lisa and Truman, Richard W. and Herrmann, Thomas}, title = {The armadillo (Dasypus novemcinctus): a witness but not a functional example for the emergence of the butyrophilin 3/Vγ9Vδ2 system in placental mammals}, series = {Frontiers in Immunology}, volume = {9}, journal = {Frontiers in Immunology}, number = {265}, doi = {10.3389/fimmu.2018.00265}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-176044}, year = {2018}, abstract = {1-5\% of human blood T cells are Vγ9Vδ2 T cells whose T cell receptor (TCR) contain a TRGV9/TRGJP rearrangement and a TRDV2 comprising Vδ2-chain. They respond to phosphoantigens (PAgs) like isopentenyl pyrophosphate or (E)-4-hydroxy-3-methyl-but-2-enyl-pyrophosphate (HMBPP) in a butyrophilin 3 (BTN3)-dependent manner and may contribute to the control of mycobacterial infections. These cells were thought to be restricted to primates, but we demonstrated by analysis of genomic databases that TRGV9, TRDV2, and BTN3 genes coevolved and emerged together with placental mammals. Furthermore, we identified alpaca (Vicugna pacos) as species with typical Vγ9Vδ2 TCR rearrangements and currently aim to directly identify Vγ9Vδ2 T cells and BTN3. Other candidates to study this coevolution are the bottlenose dolphin (Tursiops truncatus) and the nine-banded armadillo (Dasypus novemcinctus) with genomic sequences encoding open reading frames for TRGV9, TRDV2, and the extracellular part of BTN3. Dolphins have been shown to express Vγ9- and Vδ2-like TCR chains and possess a predicted BTN3-like gene homologous to human BTN3A3. The other candidate, the armadillo, is of medical interest since it serves as a natural reservoir for Mycobacterium leprae. In this study, we analyzed the armadillo genome and found evidence for multiple non-functional BTN3 genes including genomic context which closely resembles the organization of the human, alpaca, and dolphin BTN3A3 loci. However, no BTN3 transcript could be detected in armadillo cDNA. Additionally, attempts to identify a functional TRGV9/TRGJP rearrangement via PCR failed. In contrast, complete TRDV2 gene segments preferentially rearranged with a TRDJ4 homolog were cloned and co-expressed with a human Vγ9-chain in murine hybridoma cells. These cells could be stimulated by immobilized anti-mouse CD3 antibody but not with human RAJI-RT1Bl cells and HMBPP. So far, the lack of expression of TRGV9 rearrangements and BTN3 renders the armadillo an unlikely candidate species for PAg-reactive Vγ9Vδ2 T cells. This is in line with the postulated coevolution of the three genes, where occurrence of Vγ9Vδ2 TCRs coincides with a functional BTN3 molecule.}, language = {en} } @article{CollenburgBeyersdorfWieseetal.2017, author = {Collenburg, Lena and Beyersdorf, Niklas and Wiese, Teresa and Arenz, Christoph and Saied, Essa M. and Becker-Flegler, Katrin Anne and Schneider-Schaulies, Sibylle and Avota, Elita}, title = {The activity of the neutral sphingomyelinase is important in T cell recruitment and directional migration}, series = {Frontiers in Immunology}, volume = {8}, journal = {Frontiers in Immunology}, number = {1007}, doi = {10.3389/fimmu.2017.01007}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158944}, year = {2017}, abstract = {Breakdown of sphingomyelin as catalyzed by the activity of sphingomyelinases profoundly affects biophysical properties of cellular membranes which is particularly important with regard to compartmentalization of surface receptors and their signaling relay. As it is activated both upon TCR ligation and co-stimulation in a spatiotemporally controlled manner, the neutral sphingomyelinase (NSM) has proven to be important in T cell activation, where it appears to play a particularly important role in cytoskeletal reorganization and cell polarization. Because these are important parameters in directional T cell migration and motility in tissues, we analyzed the role of the NSM in these processes. Pharmacological inhibition of NSM interfered with early lymph node homing of T cells in vivo indicating that the enzyme impacts on endothelial adhesion, transendothelial migration, sensing of chemokine gradients or, at a cellular level, acquisition of a polarized phenotype. NSM inhibition reduced adhesion of T cells to TNF-α/IFN-γ activated, but not resting endothelial cells, most likely via inhibiting high-affinity LFA-1 clustering. NSM activity proved to be highly important in directional T cell motility in response to SDF1-α, indicating that their ability to sense and translate chemokine gradients might be NSM dependent. In fact, pharmacological or genetic NSM ablation interfered with T cell polarization both at an overall morphological level and redistribution of CXCR4 and pERM proteins on endothelial cells or fibronectin, as well as with F-actin polymerization in response to SDF1-α stimulation, indicating that efficient directional perception and signaling relay depend on NSM activity. Altogether, these data support a central role of the NSM in T cell recruitment and migration both under homeostatic and inflamed conditions by regulating polarized redistribution of receptors and their coupling to the cytoskeleton.}, language = {en} } @article{GeigerKerstingSchlegeletal.2022, author = {Geiger, Nina and Kersting, Louise and Schlegel, Jan and Stelz, Linda and F{\"a}hr, Sofie and Diesendorf, Viktoria and Roll, Valeria and Sostmann, Marie and K{\"o}nig, Eva-Maria and Reinhard, Sebastian and Brenner, Daniela and Schneider-Schaulies, Sibylle and Sauer, Markus and Seibel, J{\"u}rgen and Bodem, Jochen}, title = {The acid ceramidase is a SARS-CoV-2 host factor}, series = {Cells}, volume = {11}, journal = {Cells}, number = {16}, issn = {2073-4409}, doi = {10.3390/cells11162532}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-286105}, year = {2022}, abstract = {SARS-CoV-2 variants such as the delta or omicron variants, with higher transmission rates, accelerated the global COVID-19 pandemic. Thus, novel therapeutic strategies need to be deployed. The inhibition of acid sphingomyelinase (ASM), interfering with viral entry by fluoxetine was reported. Here, we described the acid ceramidase as an additional target of fluoxetine. To discover these effects, we synthesized an ASM-independent fluoxetine derivative, AKS466. High-resolution SARS-CoV-2-RNA FISH and RTqPCR analyses demonstrate that AKS466 down-regulates viral gene expression. It is shown that SARS-CoV-2 deacidifies the lysosomal pH using the ORF3 protein. However, treatment with AKS488 or fluoxetine lowers the lysosomal pH. Our biochemical results show that AKS466 localizes to the endo-lysosomal replication compartments of infected cells, and demonstrate the enrichment of the viral genomic, minus-stranded RNA and mRNAs there. Both fluoxetine and AKS466 inhibit the acid ceramidase activity, cause endo-lysosomal ceramide elevation, and interfere with viral replication. Furthermore, Ceranib-2, a specific acid ceramidase inhibitor, reduces SARS-CoV-2 replication and, most importantly, the exogenous supplementation of C6-ceramide interferes with viral replication. These results support the hypotheses that the acid ceramidase is a SARS-CoV-2 host factor.}, language = {en} } @article{LutzHeuerBehlichetal.2013, author = {Lutz, Manfred B. and Heuer, Marion and Behlich, Anna-Sophie and Lee, Ji-Sook and Ribechini, Eliana and Jo, Eun-Kyeong}, title = {The 30-kDa and 38-kDa antigens from Mycobacterium tuberculosis induce partial maturation of human dendritic cells shifting CD4+ T cell responses towards IL-4 production}, series = {BMC Immunology}, journal = {BMC Immunology}, doi = {10.1186/1471-2172-14-48}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-96871}, year = {2013}, abstract = {Background Mycobacterium tuberculosis (Mtb) infections are still a major cause of death among all infectious diseases. Although 99\% of individuals infected with Mtb develop a CD4+ Th1 and CD8+ T cell mediated immunity as measured by tuberculin skin test, this results only in partial protection and Mtb vaccines are not effective. Deviation of immune responses by pathogens towards a Th2 profile is a common mechanism of immune evasion, typically leading to the persistence of the microbes. Results Here we tested the stimulatory capacity of selective Mtb antigens on human monocyte-derived dendritic cell (DC) maturation and cytokine production. DC maturation markers CD80, CD86 and CD83 were readily upregulated by H37Ra- and H37Rv-associated antigens, the 30-kDa (from Ag85 B complex) and 38-KDa Mtb antigens only partially induced these markers. All Mtb antigens induced variable levels of IL-6 and low levels of IL-10, there was no release of IL-12p70 detectable. Substantial IL-12p40 production was restricted to LPS or H37Ra and H37Rv preparations. Although the proliferation levels of primary T cell responses were comparable using all the differentially stimulated DC, the 30-kDa and 38-kDa antigens showed a bias towards IL-4 secretion of polarized CD4+ T cells after secondary stimulation as compared to H37Ra and H37Rv preparations. Conclusion Together our data indicate that 30-kDa and 38-kDa Mtb antigens induced only partial DC maturation shifting immune responses towards a Th2 profile.}, language = {en} } @article{OttoSchmidtKastneretal.2019, author = {Otto, C. and Schmidt, S. and Kastner, C. and Denk, S. and Kettler, J. and M{\"u}ller, N. and Germer, C.T. and Wolf, E. and Gallant, P. and Wiegering, A.}, title = {Targeting bromodomain-containing protein 4 (BRD4) inhibits MYC expression in colorectal cancer cells}, series = {Neoplasia}, volume = {21}, journal = {Neoplasia}, number = {11}, doi = {10.1016/j.neo.2019.10.003}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202451}, pages = {1110-1120}, year = {2019}, abstract = {The transcriptional regulator BRD4 has been shown to be important for the expression of several oncogenes including MYC. Inhibiting of BRD4 has broad antiproliferative activity in different cancer cell types. The small molecule JQ1 blocks the interaction of BRD4 with acetylated histones leading to transcriptional modulation. Depleting BRD4 via engineered bifunctional small molecules named PROTACs (proteolysis targeting chimeras) represents the next-generation approach to JQ1-mediated BRD4 inhibition. PROTACs trigger BRD4 for proteasomale degradation by recruiting E3 ligases. The aim of this study was therefore to validate the importance of BRD4 as a relevant target in colorectal cancer (CRC) cells and to compare the efficacy of BRD4 inhibition with BRD4 degradation on downregulating MYC expression. JQ1 induced a downregulation of both MYC mRNA and MYC protein associated with an antiproliferative phenotype in CRC cells. dBET1 and MZ1 induced degradation of BRD4 followed by a reduction in MYC expression and CRC cell proliferation. In SW480 cells, where dBET1 failed, we found significantly lower levels of the E3 ligase cereblon, which is essential for dBET1-induced BRD4 degradation. To gain mechanistic insight into the unresponsiveness to dBET1, we generated dBET1-resistant LS174t cells and found a strong downregulation of cereblon protein. These findings suggest that inhibition of BRD4 by JQ1 and degradation of BRD4 by dBET1 and MZ1 are powerful tools for reducing MYC expression and CRC cell proliferation. In addition, downregulation of cereblon may be an important mechanism for developing dBET1 resistance, which can be evaded by incubating dBET1-resistant cells with JQ1 or MZ1.}, language = {en} } @article{EderHollmannMandasarietal.2022, author = {Eder, Sascha and Hollmann, Claudia and Mandasari, Putri and Wittmann, Pia and Schumacher, Fabian and Kleuser, Burkhard and Fink, Julian and Seibel, J{\"u}rgen and Schneider-Schaulies, J{\"u}rgen and Stigloher, Christian and Beyersdorf, Niklas and Dembski, Sofia}, title = {Synthesis and characterization of ceramide-containing liposomes as membrane models for different T cell subpopulations}, series = {Journal of Functional Biomaterials}, volume = {13}, journal = {Journal of Functional Biomaterials}, number = {3}, issn = {2079-4983}, doi = {10.3390/jfb13030111}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-286130}, year = {2022}, abstract = {A fine balance of regulatory (T\(_{reg}\)) and conventional CD4\(^+\) T cells (T\(_{conv}\)) is required to prevent harmful immune responses, while at the same time ensuring the development of protective immunity against pathogens. As for many cellular processes, sphingolipid metabolism also crucially modulates the T\(_{reg}\)/T\(_{conv}\) balance. However, our understanding of how sphingolipid metabolism is involved in T cell biology is still evolving and a better characterization of the tools at hand is required to advance the field. Therefore, we established a reductionist liposomal membrane model system to imitate the plasma membrane of mouse T\(_{reg}\) and T\(_{conv}\) with regards to their ceramide content. We found that the capacity of membranes to incorporate externally added azide-functionalized ceramide positively correlated with the ceramide content of the liposomes. Moreover, we studied the impact of the different liposomal preparations on primary mouse splenocytes in vitro. The addition of liposomes to resting, but not activated, splenocytes maintained viability with liposomes containing high amounts of C\(_{16}\)-ceramide being most efficient. Our data thus suggest that differences in ceramide post-incorporation into T\(_{reg}\) and T\(_{conv}\) reflect differences in the ceramide content of cellular membranes.}, language = {en} } @article{TraubGrondeyGassenmaieretal.2022, author = {Traub, Jan and Grondey, Katja and Gassenmaier, Tobias and Schmitt, Dominik and Fette, Georg and Frantz, Stefan and Boivin-Jahns, Val{\´e}rie and Jahns, Roland and St{\"o}rk, Stefan and Stoll, Guido and Reiter, Theresa and Hofmann, Ulrich and Weber, Martin S. and Frey, Anna}, title = {Sustained increase in serum glial fibrillary acidic protein after first ST-elevation myocardial infarction}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {18}, issn = {1422-0067}, doi = {10.3390/ijms231810304}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-288261}, year = {2022}, abstract = {Acute ischemic cardiac injury predisposes one to cognitive impairment, dementia, and depression. Pathophysiologically, recent positron emission tomography data suggest astroglial activation after experimental myocardial infarction (MI). We analyzed peripheral surrogate markers of glial (and neuronal) damage serially within 12 months after the first ST-elevation MI (STEMI). Serum levels of glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) were quantified using ultra-sensitive molecular immunoassays. Sufficient biomaterial was available from 45 STEMI patients (aged 28 to 78 years, median 56 years, 11\% female). The median (quartiles) of GFAP was 63.8 (47.0, 89.9) pg/mL and of NfL 10.6 (7.2, 14.8) pg/mL at study entry 0-4 days after STEMI. GFAP after STEMI increased in the first 3 months, with a median change of +7.8 (0.4, 19.4) pg/mL (p = 0.007). It remained elevated without further relevant increases after 6 months (+11.7 (0.6, 23.5) pg/mL; p = 0.015), and 12 months (+10.3 (1.5, 22.7) pg/mL; p = 0.010) compared to the baseline. Larger relative infarction size was associated with a higher increase in GFAP (ρ = 0.41; p = 0.009). In contrast, NfL remained unaltered in the course of one year. Our findings support the idea of central nervous system involvement after MI, with GFAP as a potential peripheral biomarker of chronic glial damage as one pathophysiologic pathway.}, language = {en} } @article{HaackBaikerSchlegeletal.2021, author = {Haack, Stephanie and Baiker, Sarah and Schlegel, Jan and Sauer, Markus and Sparwasser, Tim and Langenhorst, Daniela and Beyersdorf, Niklas}, title = {Superagonistic CD28 stimulation induces IFN-γ release from mouse T helper 1 cells in vitro and in vivo}, series = {European Journal of Immunology}, volume = {51}, journal = {European Journal of Immunology}, number = {3}, doi = {10.1002/eji.202048803}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239028}, pages = {738 -- 741}, year = {2021}, abstract = {Like human Th1 cells, mouse Th1 cells also secrete IFN-γ upon stimulation with a superagonistic anti-CD28 monoclonal antibody (CD28-SA). Crosslinking of the CD28-SA via FcR and CD40-CD40L interactions greatly increased IFN-γ release. Our data stress the utility of the mouse as a model organism for immune responses in humans.}, language = {en} } @article{SaintFleurLominyMausVaethetal.2018, author = {Saint Fleur-Lominy, Shella and Maus, Mate and Vaeth, Martin and Lange, Ingo and Zee, Isabelle and Suh, David and Liu, Cynthia and Wu, Xiaojun and Tikhonova, Anastasia and Aifantis, Iannis and Feske, Stefan}, title = {STIM1 and STIM2 Mediate Cancer-Induced Inflammation in T Cell Acute Lymphoblastic Leukemia}, series = {Cell Reports}, volume = {24}, journal = {Cell Reports}, number = {11}, doi = {10.1016/j.celrep.2018.08.030}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227259}, pages = {3045-3060}, year = {2018}, abstract = {T cell acute lymphoblastic leukemia (T-ALL) is commonly associated with activating mutations in the NOTCH1 pathway. Recent reports have shown a link between NOTCH1 signaling and intracellular Ca2+ homeostasis in T-ALL. Here, we investigate the role of store-operated Ca2+ entry (SOCE) mediated by the Ca2+ channel ORAI1 and its activators STIM1 and STIM2 in T-ALL. Deletion of STIM1 and STIM2 in leukemic cells abolishes SOCE and significantly prolongs the survival of mice in a NOTCH1-dependent model of T-ALL. The survival advantage is unrelated to the leukemic cell burden but is associated with the SOCE-dependent ability of malignant T lymphoblasts to cause inflammation in leukemia-infiltrated organs. Mice with STIM1/STIM2-deficient T-ALL show a markedly reduced necroinflammatory response in leukemia-infiltrated organs and downregulation of signaling pathways previously linked to cancer-induced inflammation. Our study shows that leukemic T lymphoblasts cause inflammation of leukemia-infiltrated organs that is dependent on SOCE.}, language = {en} } @article{StrengGoettlerHaerleinetal.2019, author = {Streng, Andrea and Goettler, David and Haerlein, Miriam and Lehmann, Lisa and Ulrich, Kristina and Prifert, Christiane and Krempl, Christine and Weißbrich, Benedikt and Liese, Johannes G.}, title = {Spread and clinical severity of respiratory syncytial virus A genotype ON1 in Germany, 2011-2017}, series = {BMC Infectious Diseases}, volume = {19}, journal = {BMC Infectious Diseases}, doi = {10.1186/s12879-019-4266-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201516}, pages = {613}, year = {2019}, abstract = {Background The Respiratory Syncytial Virus (RSV) A genotype ON1, which was first detected in Ontario (Canada) in 2010/11, appeared in Germany in 2011/12. Preliminary observations suggested a higher clinical severity in children infected with this new genotype. We investigated spread and disease severity of RSV-A ON1 in pediatric in- and outpatient settings. Methods During 2010/11 to 2016/17, clinical characteristics and respiratory samples from children with acute respiratory tract infections (RTI) were obtained from ongoing surveillance studies in 33 pediatric practices (PP), one pediatric hospital ward (PW) and 23 pediatric intensive care units (PICU) in Germany. RSV was detected in the respiratory samples by PCR; genotypes were identified by sequencing. Within each setting, clinical severity markers were compared between RSV-A ON1 and RSV-A non-ON1 genotypes. Results A total of 603 children with RSV-RTI were included (132 children in PP, 288 in PW, and 183 in PICU). Of these children, 341 (56.6\%) were infected with RSV-A, 235 (39.0\%) with RSV-B, and one child (0.2\%) with both RSV-A and RSV-B; in 26 (4.3\%) children, the subtype could not be identified. In the 341 RSV-A positive samples, genotype ON1 was detected in 247 (72.4\%), NA1 in 92 (26.9\%), and GA5 in 2 children (0.6\%). RSV-A ON1, rarely observed in 2011/12, was the predominant RSV-A genotype in all settings by 2012/13 and remained predominant until 2016/17. Children in PP or PW infected with RSV-A ON1 did not show a more severe clinical course of disease compared with RSV-A non-ON1 infections. In the PICU group, hospital stay was one day longer (median 8 days, inter-quartile range (IQR) 7-12 vs. 7 days, IQR 5-9; p = 0.02) and duration of oxygen treatment two days longer (median 6 days, IQR 4-9 vs. 4 days, IQR 2-6; p = 0.03) for children infected with RSV-A ON1. Conclusions In children, RSV-A ON1 largely replaced RSV-A non-ON1 genotypes within two seasons and remained the predominant RSV-A genotype in Germany during subsequent seasons. A higher clinical severity of RSV-A ON1 was observed within the group of children receiving PICU treatment, whereas in other settings clinical severity of RSV-A ON1 and non-ON1 genotypes was largely similar.}, language = {en} } @article{SchneiderSchauliesSchneiderSchauliesBayeretal.1993, author = {Schneider-Schaulies, Sibylle and Schneider-Schaulies, J{\"u}rgen and Bayer, M. and L{\"o}ffler, S. and ter Meulen, V.}, title = {Spontaneous and differentiation dependent regulation of measles virus gene expression in human glial cells}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-54913}, year = {1993}, abstract = {The expression of measles virus (MV) in six different permanent human glioma cell lines (D-54, U-251, U-138, U-105, U-373, and D-32) was analyzed. Although all celllines were permissive for productive replication of all MV strains tested, U-251, D-54, and D-32 cells spontaneously revealed restrictions of MV transcription similar to those observed for primary rat astroglial cells and brain tissue. In vitro differentiation of D-54 and U-251 cells by substances affecting tbe intracellular cyclic AMP Ievel caused a significant reduction of tbe expression of tbe viral proteins after 18, 72, and 144 b of infection. This pronounced restriction was not paralleled to a comparable Ievel by an inhibition of tbe syntbesis and biological activity in vitro of virus·specific mRNAs as sbown by quantitative Northem (RNA) blot analyses and in vitro translation. The block in viral protein syntbesis could not be attributed to tbe induction of type I interferon by any of tbe substances tested. Our findings indicate tbat down-regulation of MV gene expression in human brain cells can occur by a cell type-rlependent regulation of tbe viral mRNA transcription and a differentiation-dependent regulation of translation, botb of wbicb may be crucial for the establisbment of persistent MV infections in tbe centrat nervous system.}, subject = {Immunologie}, language = {en} } @article{AvotadeLiraSchneiderSchaulies2019, author = {Avota, Elita and de Lira, Maria Nathalia and Schneider-Schaulies, Sibylle}, title = {Sphingomyelin breakdown in T cells: role of membrane compartmentalization in T cell signaling and interference by a pathogen}, series = {Frontiers in Cell and Developmental Biology}, volume = {7}, journal = {Frontiers in Cell and Developmental Biology}, number = {152}, issn = {2296-634X}, doi = {10.3389/fcell.2019.00152}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-199168}, year = {2019}, abstract = {Sphingolipids are major components of cellular membranes, and at steady-state level, their metabolic fluxes are tightly controlled. On challenge by external signals, they undergo rapid turnover, which substantially affects the biophysical properties of membrane lipid and protein compartments and, consequently, signaling and morphodynamics. In T cells, external cues translate into formation of membrane microdomains where proximal signaling platforms essential for metabolic reprograming and cytoskeletal reorganization are organized. This review will focus on sphingomyelinases, which mediate sphingomyelin breakdown and ensuing ceramide release that have been implicated in T-cell viability and function. Acting at the sphingomyelin pool at the extrafacial or cytosolic leaflet of cellular membranes, acid and neutral sphingomyelinases organize ceramide-enriched membrane microdomains that regulate T-cell homeostatic activity and, upon stimulation, compartmentalize receptors, membrane proximal signaling complexes, and cytoskeletal dynamics as essential for initiating T-cell motility and interaction with endothelia and antigen-presenting cells. Prominent examples to be discussed in this review include death receptor family members, integrins, CD3, and CD28 and their associated signalosomes. Progress made with regard to experimental tools has greatly aided our understanding of the role of bioactive sphingolipids in T-cell biology at a molecular level and of targets explored by a model pathogen (measles virus) to specifically interfere with their physiological activity.}, language = {en} } @article{SchneiderSchauliesSchumacherWiggeretal.2021, author = {Schneider-Schaulies, Sibylle and Schumacher, Fabian and Wigger, Dominik and Sch{\"o}l, Marie and Waghmare, Trushnal and Schlegel, Jan and Seibel, J{\"u}rgen and Kleuser, Burkhard}, title = {Sphingolipids: effectors and Achilles heals in viral infections?}, series = {Cells}, volume = {10}, journal = {Cells}, number = {9}, issn = {2073-4409}, doi = {10.3390/cells10092175}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-245151}, year = {2021}, abstract = {As viruses are obligatory intracellular parasites, any step during their life cycle strictly depends on successful interaction with their particular host cells. In particular, their interaction with cellular membranes is of crucial importance for most steps in the viral replication cycle. Such interactions are initiated by uptake of viral particles and subsequent trafficking to intracellular compartments to access their replication compartments which provide a spatially confined environment concentrating viral and cellular components, and subsequently, employ cellular membranes for assembly and exit of viral progeny. The ability of viruses to actively modulate lipid composition such as sphingolipids (SLs) is essential for successful completion of the viral life cycle. In addition to their structural and biophysical properties of cellular membranes, some sphingolipid (SL) species are bioactive and as such, take part in cellular signaling processes involved in regulating viral replication. It is especially due to the progress made in tools to study accumulation and dynamics of SLs, which visualize their compartmentalization and identify interaction partners at a cellular level, as well as the availability of genetic knockout systems, that the role of particular SL species in the viral replication process can be analyzed and, most importantly, be explored as targets for therapeutic intervention.}, language = {en} } @article{PalettaFichtnerStaricketal.2015, author = {Paletta, Daniel and Fichtner, Alina Suzann and Starick, Lisa and Porcelli, Steven A. and Savage, Paul B. and Herrmann, Thomas}, title = {Species Specific Differences of CD1d Oligomer Loading In Vitro}, series = {PLoS One}, volume = {10}, journal = {PLoS One}, number = {11}, doi = {10.1371/journal.pone.0143449}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124879}, pages = {e0143449}, year = {2015}, abstract = {CD1d molecules are MHC class I-like molecules that present glycolipids to iNKT cells. The highly conserved interaction between CD1d:α-Galactosylceramide (αGC) complexes and the iNKT TCR not only defines this population of αβ T cells but can also be used for its direct identification. Therefore, CD1d oligomers are a widely used tool for iNKT cell related investigations. To this end, the lipid chains of the antigen have to be inserted into the hydrophobic pockets of the CD1d binding cleft, often with help of surfactants. In this study, we investigated the influence of different surfactants (Triton X-100, Tween 20, Tyloxapol) on in vitro loading of CD1d molecules derived from four different species (human, mouse, rat and cotton rat) with αGC and derivatives carrying modifications of the acyl-chain (DB01-1, PBS44) and a 6-acetamido-6-deoxy-addition at the galactosyl head group (PBS57). We also compared rat CD1d dimers with tetramers and staining of an iNKT TCR transductant was used as readout for loading efficacy. The results underlined the importance of CD1d loading efficacy for proper analysis of iNKT TCR binding and demonstrated the necessity to adjust loading conditions for each oligomer/glycolipid combination. The efficient usage of surfactants as a tool for CD1d loading was revealed to be species-specific and depending on the origin of the CD1d producing cells. Additional variation of surfactant-dependent loading efficacy between tested glycolipids was influenced by the acyl-chain length and the modification of the galactosyl head group with PBS57 showing the least dependence on surfactants and the lowest degree of species-dependent differences.}, language = {en} } @article{StrengPrifertWeissbrichetal.2022, author = {Streng, Andrea and Prifert, Christiane and Weissbrich, Benedikt and Sauerbrei, Andreas and Krumbholz, Andi and Schmid-Ott, Ruprecht and Liese, Johannes G.}, title = {Similar severity of influenza primary and re-infections in pre-school children requiring outpatient treatment due to febrile acute respiratory illness: prospective, multicentre surveillance study (2013-2015)}, series = {BMC Infectious Diseases}, volume = {22}, journal = {BMC Infectious Diseases}, doi = {10.1186/s12879-021-06988-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265841}, year = {2022}, abstract = {Background Influenza virus infections in immunologically na{\"i}ve children (primary infection) may be more severe than in children with re-infections who are already immunologically primed. We compared frequency and severity of influenza virus primary and re-infections in pre-school children requiring outpatient treatment. Methods Influenza-unvaccinated children 1-5 years of age presenting at pediatric practices with febrile acute respiratory infection < 48 h after symptom onset were enrolled in a prospective, cross-sectional, multicenter surveillance study (2013-2015). Influenza types/subtypes were PCR-confirmed from oropharyngeal swabs. Influenza type/subtype-specific IgG antibodies serving as surrogate markers for immunological priming were determined using ELISA/hemagglutination inhibition assays. The acute influenza disease was defined as primary infection/re-infection by the absence/presence of influenza type-specific immunoglobulin G (IgG) and, in a second approach, by the absence/presence of subtype-specific IgG. Socio-demographic and clinical data were also recorded. Results Of 217 influenza infections, 178 were due to influenza A (87 [49\%] primary infections, 91 [51\%] re-infections) and 39 were due to influenza B (38 [97\%] primary infections, one [3\%] re-infection). Children with "influenza A primary infections" showed fever with respiratory symptoms for a shorter period than children with "influenza A re-infections" (median 3 vs. 4 days; age-adjusted p = 0.03); other disease characteristics were similar. If primary infections and re-infections were defined based on influenza A subtypes, 122 (87\%) primary infections (78 "A(H3N2) primary infections", 44 "A(H1N1)pdm09 primary infections") and 18 (13\%) re-infections could be classified (14 "A(H3N2) re-infections" and 4 "A(H1N1)pdm09 re-infections"). Per subtype, primary infections and re-infections were of similar disease severity. Children with re-infections defined on the subtype level usually had non-protective IgG titers against the subtype of their acute infection (16 of 18; 89\%). Some patients infected by one of the influenza A subtypes showed protective IgG titers (≥ 1:40) against the other influenza A subtype (32/140; 23\%). Conclusions Pre-school children with acute influenza A primary infections and re-infections presented with similar frequency in pediatric practices. Contrary to expectation, severity of acute "influenza A primary infections" and "influenza A re-infections" were similar. Most "influenza A re-infections" defined on the type level turned out to be primary infections when defined based on the subtype. On the subtype level, re-infections were rare and of similar disease severity as primary infections of the same subtype. Subtype level re-infections were usually associated with low IgG levels for the specific subtype of the acute infection, suggesting only short-time humoral immunity induced by previous infection by this subtype. Overall, the results indicated recurring influenza virus infections in this age group and no or only limited heterosubtypic antibody-mediated cross-protection.}, language = {en} } @article{LangenhorstGogishviliRibechinietal.2012, author = {Langenhorst, Daniela and Gogishvili, Tea and Ribechini, Eliana and Kneitz, Susanne and McPherson, Kirsty and Lutz, Manfred B. and H{\"u}nig, Thomas}, title = {Sequential induction of effector function, tissue migration and cell death during polyclonal activation of mouse regulatory T-cells}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-76009}, year = {2012}, abstract = {The ability of CD4+Foxp3+ regulatory T-cells (Treg) to produce interleukin (IL)-10 is important for the limitation of inflammation at environmental interfaces like colon or lung. Under steady state conditions, however, few Tregs produce IL-10 ex vivo. To investigate the origin and fate of IL-10 producing Tregs we used a superagonistic mouse anti-mouse CD28 mAb (CD28SA) for polyclonal in vivo stimulation of Tregs, which not only led to their numeric expansion but also to a dramatic increase in IL-10 production. IL-10 secreting Tregs strongly upregulated surface receptors associated with suppressive function as compared to non-producing Tregs. Furthermore, polyclonally expanding Tregs shifted their migration receptor pattern after activation from a CCR7+CCR52 lymph node-seeking to a CCR72CCR5+ inflammationseeking phenotype, explaining the preferential recruitment of IL-10 producers to sites of ongoing immune responses. Finally, we observed that IL-10 producing Tregs from CD28SA stimulated mice were more apoptosis-prone in vitro than their IL-10 negative counterparts. These findings support a model where prolonged activation of Tregs results in terminal differentiation towards an IL-10 producing effector phenotype associated with a limited lifespan, implicating built-in termination of immunosuppression.}, subject = {Medizin}, language = {en} } @article{LangenhorstTabaresGuldeetal.2018, author = {Langenhorst, Daniela and Tabares, Paula and Gulde, Tobias and Becklund, Bryan R. and Berr, Susanne and Surh, Charles D. and Beyersdorf, Niklas and H{\"u}nig, Thomas}, title = {Self-recognition sensitizes mouse and human regulatory T cells to low-dose CD28 superagonist stimulation}, series = {Frontiers in Immunology}, volume = {8}, journal = {Frontiers in Immunology}, number = {1985}, doi = {10.3389/fimmu.2017.01985}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-159387}, year = {2018}, abstract = {In rodents, low doses of CD28-specific superagonistic monoclonal antibodies (CD28 superagonists, CD28SA) selectively activate regulatory T cells (Treg). This observation has recently been extended to humans, suggesting an option for the treatment of autoimmune and inflammatory diseases. However, a mechanistic explanation for this phenomenon is still lacking. Given that CD28SA amplify T cell receptor (TCR) signals, we tested the hypothesis that the weak tonic TCR signals received by conventional CD4\(^{+}\) T cells (Tconv) in the absence of cognate antigen require more CD28 signaling input for full activation than the stronger TCR signals received by self-reactive Treg. We report that in vitro, the response of mouse Treg and Tconv to CD28SA strongly depends on MHC class II expression by antigen-presenting cells. To separate the effect of tonic TCR signals from self-peptide recognition, we compared the response of wild-type Treg and Tconv to low and high CD28SA doses upon transfer into wild-type or H-2M knockout mice, which lack a self-peptide repertoire. We found that the superior response of Treg to low CD28SA doses was lost in the absence of self-peptide presentation. We also tested if potentially pathogenic autoreactive Tconv would benefit from self-recognition-induced sensitivity to CD28SA stimulation by transferring TCR transgenic OVA-specific Tconv into OVA-expressing mice and found that low-dose CD28SA application inhibited, rather than supported, their expansion, presumably due to the massive concomitant activation of Treg. Finally, we report that also in the in vitro response of human peripheral blood mononuclear cells to CD28SA, HLA II blockade interferes with the expansion of Treg by low-dose CD28SA stimulation. These results provide a rational basis for the further development of low-dose CD28SA therapy for the improvement of Treg activity.}, language = {en} }