@article{TiwarekarFehrholzSchneiderSchaulies2019,
  author    = {Tiwarekar, Vishakha and Fehrholz, Markus and Schneider-Schaulies, J{\"u}rgen},
  title     = {KDELR2 competes with measles virus envelope proteins for cellular chaperones reducing their chaperone-mediated cell surface transport},
  series = {Viruses},
  volume    = {11},
  journal   = {Viruses},
  number    = {1},
  issn      = {1999-4915},
  doi       = {10.3390/v11010027},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-197468},
  pages     = {27},
  year      = {2019},
  abstract  = {Recently, we found that the cytidine deaminase APOBEC3G (A3G) inhibits measles (MV) replication. Using a microarray, we identified differential regulation of several host genes upon ectopic expression of A3G. One of the up-regulated genes, the endoplasmic reticulum (ER) protein retention receptor KDELR2, reduced MV replication ~5 fold when it was over-expressed individually in Vero and CEM-SS T cells. Silencing of KDELR2 in A3G-expressing Vero cells abrogated the antiviral activity induced by A3G, confirming its role as an A3G-regulated antiviral host factor. Recognition of the KDEL (Lys-Asp-Glu-Leu) motif by KDEL receptors initiates the retrograde transport of soluble proteins that have escaped the ER and play an important role in ER quality control. Although KDELR2 over-expression reduced MV titers in cell cultures, we observed no interaction between KDELR2 and the MV hemagglutinin (H) protein. Instead, KDELR2 retained chaperones in the ER, which are required for the correct folding and transport of the MV envelope glycoproteins H and fusion protein (F) to the cell surface. Our data indicate that KDELR2 competes with MV envelope proteins for binding to calnexin and GRP78/Bip, and that this interaction limits the availability of the chaperones for MV proteins, causing the reduction of virus spread and titers.},
  language  = {en}
}
@article{SchneiderSchauliesBieringerHanetal.2013,
  author    = {Schneider-Schaulies, J{\"u}rgen and Bieringer, Maria and Han, Jung Woo and Kendl, Sabine and Khosravi, Mojtaba and Plattet, Philippe},
  title     = {Experimental Adaptation of Wild-Type Canine Distemper Virus (CDV) to the Human Entry Receptor CD150},
  series = {PLoS ONE},
  journal   = {PLoS ONE},
  doi       = {10.1371/journal.pone.0057488},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-96537},
  year      = {2013},
  abstract  = {Canine distemper virus (CDV), a close relative of measles virus (MV), is widespread and well known for its broad host range. When the goal of measles eradication may be achieved, and when measles vaccination will be stopped, CDV might eventually cross the species barrier to humans and emerge as a new human pathogen. In order to get an impression how fast such alterations may occur, we characterized required adaptive mutations to the human entry receptors CD150 (SLAM) and nectin-4 as first step to infect human target cells. Recombinant wild-type CDV-A75/17red adapted quickly to growth in human H358 epithelial cells expressing human nectin-4. Sequencing of the viral attachment proteins (hemagglutinin, H, and fusion protein, F) genes revealed that no adaptive alteration was required to utilize human nectin-4. In contrast, the virus replicated only to low titres (102 pfu/ml) in Vero cells expressing human CD150 (Vero-hSLAM). After three passages using these cells virus was adapted to human CD150 and replicated to high titres (105 pfu/ml). Sequence analyses revealed that only one amino acid exchange in the H-protein at position 540 Asp→Gly (D540G) was required for functional adaptation to human CD150. Structural modelling suggests that the adaptive mutation D540G in H reflects the sequence alteration from canine to human CD150 at position 70 and 71 from Pro to Leu (P70L) and Gly to Glu (G71E), and compensates for the gain of a negative charge in the human CD150 molecule. Using this model system our data indicate that only a minimal alteration, in this case one adaptive mutation, is required for adaptation of CDV to the human entry receptors, and help to understand the molecular basis why this adaptive mutation occurs.},
  language  = {en}
}
@article{RiedelMofoloAvotaetal.2013,
  author    = {Riedel, Alice and Mofolo, Boitumelo and Avota, Elita and Schneider-Schaulies, Sibylle and Meintjes, Ayton and Mulder, Nicola and Kneitz, Susanne},
  title     = {Accumulation of Splice Variants and Transcripts in Response to PI3K Inhibition in T Cells},
  series = {PLoS ONE},
  volume    = {8},
  journal   = {PLoS ONE},
  number    = {2},
  doi       = {10.1371/journal.pone.0050695},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130335},
  pages     = {e50695},
  year      = {2013},
  abstract  = {Background Measles virus (MV) causes T cell suppression by interference with phosphatidylinositol-3-kinase (PI3K) activation. We previously found that this interference affected the activity of splice regulatory proteins and a T cell inhibitory protein isoform was produced from an alternatively spliced pre-mRNA. Hypothesis Differentially regulated and alternatively splice variant transcripts accumulating in response to PI3K abrogation in T cells potentially encode proteins involved in T cell silencing. Methods To test this hypothesis at the cellular level, we performed a Human Exon 1.0 ST Array on RNAs isolated from T cells stimulated only or stimulated after PI3K inhibition. We developed a simple algorithm based on a splicing index to detect genes that undergo alternative splicing (AS) or are differentially regulated (RG) upon T cell suppression. Results Applying our algorithm to the data, 9\% of the genes were assigned as AS, while only 3\% were attributed to RG. Though there are overlaps, AS and RG genes differed with regard to functional regulation, and were found to be enriched in different functional groups. AS genes targeted extracellular matrix (ECM)-receptor interaction and focal adhesion pathways, while RG genes were mainly enriched in cytokine-receptor interaction and Jak-STAT. When combined, AS/RG dependent alterations targeted pathways essential for T cell receptor signaling, cytoskeletal dynamics and cell cycle entry. Conclusions PI3K abrogation interferes with key T cell activation processes through both differential expression and alternative splicing, which together actively contribute to T cell suppression.},
  language  = {en}
}
@article{ReuterSparwasserHuenigetal.2012,
  author    = {Reuter, Dajana and Sparwasser, Tim and H{\"u}nig, Thomas and Schneider-Schaulies, J{\"u}rgen},
  title     = {Foxp3\(^+\) Regulatory T Cells Control Persistence of Viral CNS Infection},
  series = {PLoS One},
  volume    = {7},
  journal   = {PLoS One},
  number    = {3},
  doi       = {10.1371/journal.pone.0033989},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134248},
  pages     = {e33989},
  year      = {2012},
  abstract  = {We earlier established a model of a persistent viral CNS infection using two week old immunologically normal (genetically unmodified) mice and recombinant measles virus (MV). Using this model infection we investigated the role of regulatory T cells (Tregs) as regulators of the immune response in the brain, and assessed whether the persistent CNS infection can be modulated by manipulation of Tregs in the periphery. CD4\(^+\) CD25\(^+\) Foxp3\(^+\) Tregs were expanded or depleted during the persistent phase of the CNS infection, and the consequences for the virus-specific immune response and the extent of persistent infection were analyzed. Virus-specific CD8\(^+\) T cells predominantly recognising the H-2D(b)-presented viral hemagglutinin epitope MV-H22-30 (RIVINREHL) were quantified in the brain by pentamer staining. Expansion of Tregs after intraperitoneal (i.p.) application of the superagonistic anti-CD28 antibody D665 inducing transient immunosuppression caused increased virus replication and spread in the CNS. In contrast, depletion of Tregs using diphtheria toxin (DT) in DEREG (depletion of regulatory T cells)-mice induced an increase of virus-specific CD8\(^+\) effector T cells in the brain and caused a reduction of the persistent infection. These data indicate that manipulation of Tregs in the periphery can be utilized to regulate virus persistence in the CNS.},
  language  = {en}
}
@article{KimGrimmigGrimmetal.2013,
  author    = {Kim, Mia and Grimmig, Tanja and Grimm, Martin and Lazariotou, Maria and Meier, Eva and Rosenwald, Andreas and Tsaur, Igor and Blaheta, Roman and Heemann, Uwe and Germer, Christoph-Thomas and Waaga-Gasser, Ana Maria and Gasser, Martin},
  title     = {Expression of Foxp3 in Colorectal Cancer but Not in Treg Cells Correlates with Disease Progression in Patients with Colorectal Cancer},
  series = {PLoS ONE},
  volume    = {8},
  journal   = {PLoS ONE},
  number    = {1},
  doi       = {10.1371/journal.pone.0053630},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130340},
  pages     = {e53630},
  year      = {2013},
  abstract  = {Background Measles virus (MV) causes T cell suppression by interference with phosphatidylinositol-3-kinase (PI3K) activation. We previously found that this interference affected the activity of splice regulatory proteins and a T cell inhibitory protein isoform was produced from an alternatively spliced pre-mRNA. Hypothesis Differentially regulated and alternatively splice variant transcripts accumulating in response to PI3K abrogation in T cells potentially encode proteins involved in T cell silencing. Methods To test this hypothesis at the cellular level, we performed a Human Exon 1.0 ST Array on RNAs isolated from T cells stimulated only or stimulated after PI3K inhibition. We developed a simple algorithm based on a splicing index to detect genes that undergo alternative splicing (AS) or are differentially regulated (RG) upon T cell suppression. Results Applying our algorithm to the data, 9\% of the genes were assigned as AS, while only 3\% were attributed to RG. Though there are overlaps, AS and RG genes differed with regard to functional regulation, and were found to be enriched in different functional groups. AS genes targeted extracellular matrix (ECM)-receptor interaction and focal adhesion pathways, while RG genes were mainly enriched in cytokine-receptor interaction and Jak-STAT. When combined, AS/RG dependent alterations targeted pathways essential for T cell receptor signaling, cytoskeletal dynamics and cell cycle entry. Conclusions PI3K abrogation interferes with key T cell activation processes through both differential expression and alternative splicing, which together actively contribute to T cell 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{DerakhshaniKurzJaptoketal.2019,
  author    = {Derakhshani, Shaghayegh and Kurz, Andreas and Japtok, Lukasz and Schumacher, Fabian and Pilgram, Lisa and Steinke, Maria and Kleuser, Burkhard and Sauer, Markus and Schneider-Schaulies, Sibylle and Avota, Elita},
  title     = {Measles virus infection fosters dendritic cell motility in a 3D environment to enhance transmission to target cells in the respiratory epithelium},
  series = {Frontiers in Immunology},
  volume    = {10},
  journal   = {Frontiers in Immunology},
  number    = {1294},
  doi       = {10.3389/fimmu.2019.01294},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201818},
  year      = {2019},
  abstract  = {Transmission of measles virus (MV) from dendritic to airway epithelial cells is considered as crucial to viral spread late in infection. Therefore, pathways and effectors governing this process are promising targets for intervention. To identify these, we established a 3D respiratory tract model where MV transmission by infected dendritic cells (DCs) relied on the presence of nectin-4 on H358 lung epithelial cells. Access to recipient cells is an important prerequisite for transmission, and we therefore analyzed migration of MV-exposed DC cultures within the model. Surprisingly, enhanced motility toward the epithelial layer was observed for MV-infected DCs as compared to their uninfected siblings. This occurred independently of factors released from H358 cells indicating that MV infection triggered cytoskeletal remodeling associated with DC polarization enforced velocity. Accordingly, the latter was also observed for MV-infected DCs in collagen matrices and was particularly sensitive to ROCK inhibition indicating infected DCs preferentially employed the amoeboid migration mode. This was also implicated by loss of podosomes and reduced filopodial activity both of which were retained in MV-exposed uninfected DCs. Evidently, sphingosine kinase (SphK) and sphingosine-1-phosphate (S1P) as produced in response to virus-infection in DCs contributed to enhanced velocity because this was abrogated upon inhibition of sphingosine kinase activity. These findings indicate that MV infection promotes a push-and-squeeze fast amoeboid migration mode via the SphK/S1P system characterized by loss of filopodia and podosome dissolution. Consequently, this enables rapid trafficking of virus toward epithelial cells during viral exit.},
  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{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{AvotaGassertSchneiderSchaulies2011,
  author    = {Avota, Elita and Gassert, Evelyn and Schneider-Schaulies, Sibylle},
  title     = {Cytoskeletal Dynamics: Concepts in Measles Virus Replication and Immunomodulation},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-69092},
  year      = {2011},
  abstract  = {In common with most viruses, measles virus (MV) relies on the integrity of the cytoskeleton of its host cells both with regard to efficient replication in these cells, but also retention of their motility which favors viral dissemination. It is, however, the surface interaction of the viral glycoprotein (gp) complex with receptors present on lymphocytes and dendritic cells (DCs), that signals effective initiation of host cell cytoskeletal dynamics. For DCs, these may act to regulate processes as diverse as viral uptake and sorting, but also the ability of these cells to successfully establish and maintain functional immune synapses (IS) with T cells. In T cells, MV signaling causes actin cytoskeletal paralysis associated with a loss of polarization, adhesion and motility, which has been linked to activation of sphingomyelinases and subsequent accumulation of membrane ceramides. MV modulation of both DC and T cell cytoskeletal dynamics may be important for the understanding of MV immunosuppression at the cellular level.},
  subject      = {Virologie},
  language  = {en}
}