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Talimogene laherparepvec (T-VEC), an oncolytic herpes simplex virus, is approved for intralesional injection of unresectable stage IIIB/IVM1a melanoma. However, it is still unclear which parameter(s) predict treatment response or failure. Our study aimed at characterizing surface receptors Nectin-1 and the herpes virus entry mediator (HVEM) in addition to intracellular molecules cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) as potential bio-markers for oncolytic virus treatment. In 20 melanoma cell lines, oncolytic activity of T-VEC was correlated with the expression of Nectin-1 but not HVEM, as evaluated via flow cytometry and immunohistochemistry. Knockout using CRISPR/Cas9 technology confirmed the superior role of Nectin-1 over HVEM for entry and oncolytic activity of T-VEC. Neither cGAS nor STING as evaluated by Western Blot and immunohistochemistry correlated with T-VEC induced oncolysis. The role of these biomarkers was retrospectively analyzed for the response of 35 cutaneous melanoma metastases of 21 patients to intralesional T-VEC injection, with 21 (60.0%) of these lesions responding with complete (n = 16) or partial regression (n = 5). Nectin-1 expression in pretreatment biopsies significantly predicted treatment outcome, while the expression of HVEM, cGAS, and STING was not prognostic. Altogether, Nectin-1 served as biomarker for T-VEC-induced melanoma regression in vitro and in vivo.
Barbara Schwertner; Georg Lindner; Camila Toledo Stauner; Elisa Klapproth; Clara Magnus; Anette Rohrhofer; Stefanie Gross; Beatrice Schuler-Thurner; Veronika Öttl; Nicole Feichtgruber; Konstantin Drexler; Katja Evert; Michael Krahn; Mark Berneburg; Barbara Schmidt; Philipp Schuster; Sebastian Haferkamp. Nectin-1 Expression Correlates with the Susceptibility of Malignant Melanoma to Oncolytic Herpes Simplex Virus In Vitro and In Vivo. Cancers 2021, 13, 3058 .
AMA StyleBarbara Schwertner, Georg Lindner, Camila Toledo Stauner, Elisa Klapproth, Clara Magnus, Anette Rohrhofer, Stefanie Gross, Beatrice Schuler-Thurner, Veronika Öttl, Nicole Feichtgruber, Konstantin Drexler, Katja Evert, Michael Krahn, Mark Berneburg, Barbara Schmidt, Philipp Schuster, Sebastian Haferkamp. Nectin-1 Expression Correlates with the Susceptibility of Malignant Melanoma to Oncolytic Herpes Simplex Virus In Vitro and In Vivo. Cancers. 2021; 13 (12):3058.
Chicago/Turabian StyleBarbara Schwertner; Georg Lindner; Camila Toledo Stauner; Elisa Klapproth; Clara Magnus; Anette Rohrhofer; Stefanie Gross; Beatrice Schuler-Thurner; Veronika Öttl; Nicole Feichtgruber; Konstantin Drexler; Katja Evert; Michael Krahn; Mark Berneburg; Barbara Schmidt; Philipp Schuster; Sebastian Haferkamp. 2021. "Nectin-1 Expression Correlates with the Susceptibility of Malignant Melanoma to Oncolytic Herpes Simplex Virus In Vitro and In Vivo." Cancers 13, no. 12: 3058.
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) RNA is detected by reverse-transcription quantitative real-time PCR (RT-qPCR) from respiratory specimens. This study compares throat washings (TW), nasopharyngeal swabs (NS) and oropharyngeal swabs (OS). A total of 102 samples from 34 adult patients with confirmed SARS-CoV-2 infection were analysed by RT-qPCR with absolute quantification. The median concentrations and diagnostic sensitivities were
Florian Hitzenbichler; Stilla Bauernfeind; Bernd Salzberger; Barbara Schmidt; Jürgen Wenzel. Comparison of Throat Washings, Nasopharyngeal Swabs and Oropharyngeal Swabs for Detection of SARS-CoV-2. Viruses 2021, 13, 653 .
AMA StyleFlorian Hitzenbichler, Stilla Bauernfeind, Bernd Salzberger, Barbara Schmidt, Jürgen Wenzel. Comparison of Throat Washings, Nasopharyngeal Swabs and Oropharyngeal Swabs for Detection of SARS-CoV-2. Viruses. 2021; 13 (4):653.
Chicago/Turabian StyleFlorian Hitzenbichler; Stilla Bauernfeind; Bernd Salzberger; Barbara Schmidt; Jürgen Wenzel. 2021. "Comparison of Throat Washings, Nasopharyngeal Swabs and Oropharyngeal Swabs for Detection of SARS-CoV-2." Viruses 13, no. 4: 653.
Serological testing is crucial in detection of previous infection and in monitoring convalescent and vaccine-induced immunity. During the Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) pandemic, numerous assay platforms have been developed and marketed for clinical use. Several studies recently compared clinical performance of a limited number of serological tests, but broad comparative evaluation is currently missing. Within this study, a panel of 161 sera from SARS-CoV-2 infected, seasonal CoV-infected and SARS-CoV-2 naïve subjects was enrolled to evaluate 16 ELISA/ECLIA-based and 16 LFA-based tests. Specificities of all ELISA/ECLIA-based assays were acceptable and generally in agreement with the providers’ specifications, but sensitivities were lower as specified. Results of the LFAs were less accurate as compared to the ELISAs, albeit with some exceptions. We found a sporadic unequal immune response for different antigens and thus recommend the use of a nucleocapsid protein (N)- and spike protein (S)-based test combination when maximal sensitivity is necessary. Finally, the quality of the immune response in terms of neutralization should be tested using S-based IgG tests.
Maren Werner; Philip Pervan; Vivian Glück; Florian Zeman; Michael Koller; Ralph Burkhardt; Thomas Glück; Jürgen Wenzel; Barbara Schmidt; André Gessner; David Peterhoff. Evaluation of a Broad Panel of SARS-CoV-2 Serological Tests for Diagnostic Use. Journal of Clinical Medicine 2021, 10, 1580 .
AMA StyleMaren Werner, Philip Pervan, Vivian Glück, Florian Zeman, Michael Koller, Ralph Burkhardt, Thomas Glück, Jürgen Wenzel, Barbara Schmidt, André Gessner, David Peterhoff. Evaluation of a Broad Panel of SARS-CoV-2 Serological Tests for Diagnostic Use. Journal of Clinical Medicine. 2021; 10 (8):1580.
Chicago/Turabian StyleMaren Werner; Philip Pervan; Vivian Glück; Florian Zeman; Michael Koller; Ralph Burkhardt; Thomas Glück; Jürgen Wenzel; Barbara Schmidt; André Gessner; David Peterhoff. 2021. "Evaluation of a Broad Panel of SARS-CoV-2 Serological Tests for Diagnostic Use." Journal of Clinical Medicine 10, no. 8: 1580.
Treatment of advanced melanoma with combined PD-1/CTLA-4 blockade commonly causes serious immune-mediated complications. Here, we identify a subset of patients predisposed to immune checkpoint blockade-related hepatitis who are distinguished by chronic expansion of effector memory CD4+ T cells (TEM cells). Pre-therapy CD4+ TEM cell expansion occurs primarily during autumn or winter in patients with metastatic disease and high cytomegalovirus (CMV)-specific serum antibody titres. These clinical features implicate metastasis-dependent, compartmentalised CMV reactivation as the cause of CD4+ TEM expansion. Pre-therapy CD4+ TEM expansion predicts hepatitis in CMV-seropositive patients, opening possibilities for avoidance or prevention. 3 of 4 patients with pre-treatment CD4+ TEM expansion who received αPD-1 monotherapy instead of αPD-1/αCTLA-4 therapy remained hepatitis-free. 4 of 4 patients with baseline CD4+ TEM expansion given prophylactic valganciclovir and αPD-1/αCTLA-4 therapy remained hepatitis-free. Our findings exemplify how pathogen exposure can shape clinical reactions after cancer therapy and how this insight leads to therapeutic innovations.
James A. Hutchinson; Katharina Kronenberg; Paloma Riquelme; Jürgen J. Wenzel; Gunther Glehr; Hannah-Lou Schilling; Florian Zeman; Katja Evert; Martin Schmiedel; Marion Mickler; Konstantin Drexler; Florian Bitterer; Laura Cordero; Lukas Beyer; Christian Bach; Josef Koestler; Ralph Burkhardt; Hans J. Schlitt; Dirk Hellwig; Jens M. Werner; Rainer Spang; Barbara Schmidt; Edward K. Geissler; Sebastian Haferkamp. Virus-specific memory T cell responses unmasked by immune checkpoint blockade cause hepatitis. Nature Communications 2021, 12, 1 -15.
AMA StyleJames A. Hutchinson, Katharina Kronenberg, Paloma Riquelme, Jürgen J. Wenzel, Gunther Glehr, Hannah-Lou Schilling, Florian Zeman, Katja Evert, Martin Schmiedel, Marion Mickler, Konstantin Drexler, Florian Bitterer, Laura Cordero, Lukas Beyer, Christian Bach, Josef Koestler, Ralph Burkhardt, Hans J. Schlitt, Dirk Hellwig, Jens M. Werner, Rainer Spang, Barbara Schmidt, Edward K. Geissler, Sebastian Haferkamp. Virus-specific memory T cell responses unmasked by immune checkpoint blockade cause hepatitis. Nature Communications. 2021; 12 (1):1-15.
Chicago/Turabian StyleJames A. Hutchinson; Katharina Kronenberg; Paloma Riquelme; Jürgen J. Wenzel; Gunther Glehr; Hannah-Lou Schilling; Florian Zeman; Katja Evert; Martin Schmiedel; Marion Mickler; Konstantin Drexler; Florian Bitterer; Laura Cordero; Lukas Beyer; Christian Bach; Josef Koestler; Ralph Burkhardt; Hans J. Schlitt; Dirk Hellwig; Jens M. Werner; Rainer Spang; Barbara Schmidt; Edward K. Geissler; Sebastian Haferkamp. 2021. "Virus-specific memory T cell responses unmasked by immune checkpoint blockade cause hepatitis." Nature Communications 12, no. 1: 1-15.
Co‐infection with the human pegivirus 1 (HPgV‐1) often has a beneficial effect on disease progression in HIV‐1 infected individuals. Several HPgV‐1 proteins and peptides, including a 20‐mer peptide (P6‐2) derived from the N‐terminal region of the HPgV‐1 surface protein E2, have been associated with this phenomenon, which is refered to as viral interference. We identified the cysteine residues, the hydrophobic core tetrapeptide, as well as the C‐terminal negative charge as key factors for HIV‐1 inhibitory activity of P6‐2. Analysis of mutations in P6‐2 resistant HIV‐1 indicated a binding site for the peptide in the HIV‐1 envelope glycoprotein gp120. In fact, P6‐2 was shown to bind to soluble gp120, as well as to a peptide presenting the gp120 V3 loop. Furthermore, the HIV‐1 inhibitory activity of P6‐2 could be revoked by the V3 loop peptide, indicating a molecular mechanism that involves interaction of P6‐2 with the gp120 V3 loop.
Rebecca Hoffmann; Tamara Ruegamer; Johanna Schaubächer; Anette Rohrhofer; Peter Kirmeß; Karen M. Fiebig; Barbara Schmidt; Jutta Eichler. Exploring Viral Interference Using Peptides: Molecular Determinants of HIV‐1 Inhibition by a Peptide Derived from Human Pegivirus‐1 Envelope Protein E2. ChemMedChem 2020, 16, 1290 -1296.
AMA StyleRebecca Hoffmann, Tamara Ruegamer, Johanna Schaubächer, Anette Rohrhofer, Peter Kirmeß, Karen M. Fiebig, Barbara Schmidt, Jutta Eichler. Exploring Viral Interference Using Peptides: Molecular Determinants of HIV‐1 Inhibition by a Peptide Derived from Human Pegivirus‐1 Envelope Protein E2. ChemMedChem. 2020; 16 (8):1290-1296.
Chicago/Turabian StyleRebecca Hoffmann; Tamara Ruegamer; Johanna Schaubächer; Anette Rohrhofer; Peter Kirmeß; Karen M. Fiebig; Barbara Schmidt; Jutta Eichler. 2020. "Exploring Viral Interference Using Peptides: Molecular Determinants of HIV‐1 Inhibition by a Peptide Derived from Human Pegivirus‐1 Envelope Protein E2." ChemMedChem 16, no. 8: 1290-1296.
We report a laboratory-based surveillance for SARS-CoV-2 using minipools of respiratory samples submitted for routine diagnostics. We tested a total of 70 minipools resembling 700 samples shortly before the upsurge of cases in Germany. We identified one SARS-CoV-2 positive patient. Our approach proved its concept, is easily adaptable and resource-saving.
Anna M. Eis-Hübinger; Mario Hoenemann; Juergen J. Wenzel; Annemarie Berger; Marek Widera; Barbara Schmidt; Souhaib Aldabbagh; Benjamin Marx; Hendrik Streeck; Sandra Ciesek; Uwe. G. Liebert; Daniela Huzly; Hartmut Hengel; Marcus Panning. Ad hoc laboratory-based surveillance of SARS-CoV-2 by real-time RT-PCR using minipools of RNA prepared from routine respiratory samples. 2020, 1 .
AMA StyleAnna M. Eis-Hübinger, Mario Hoenemann, Juergen J. Wenzel, Annemarie Berger, Marek Widera, Barbara Schmidt, Souhaib Aldabbagh, Benjamin Marx, Hendrik Streeck, Sandra Ciesek, Uwe. G. Liebert, Daniela Huzly, Hartmut Hengel, Marcus Panning. Ad hoc laboratory-based surveillance of SARS-CoV-2 by real-time RT-PCR using minipools of RNA prepared from routine respiratory samples. . 2020; ():1.
Chicago/Turabian StyleAnna M. Eis-Hübinger; Mario Hoenemann; Juergen J. Wenzel; Annemarie Berger; Marek Widera; Barbara Schmidt; Souhaib Aldabbagh; Benjamin Marx; Hendrik Streeck; Sandra Ciesek; Uwe. G. Liebert; Daniela Huzly; Hartmut Hengel; Marcus Panning. 2020. "Ad hoc laboratory-based surveillance of SARS-CoV-2 by real-time RT-PCR using minipools of RNA prepared from routine respiratory samples." , no. : 1.
The major type I interferon-producing plasmacytoid dendritic cells (pDC) surround and infiltrate certain tumors like malignant melanoma, head and neck cancer, and ovarian and breast cancer. The presence of pDC in these tumors is associated with an unfavorable prognosis for the patients as long as these cells are unstimulated. Upon activation by synthetic Toll-like receptor agonists or viruses, however, pDC develop cytotoxic activities. Viruses have the additional advantage to augment cytotoxic activities of pDC via lytic replication in malignant lesions. These effects turn cold tumors into hotspots, recruiting further immune cells to the site of inflammation. Activated pDC contribute to cross-presentation of tumor-associated antigens by classical dendritic cells, which induce cytotoxic T-cells in particular in the presence of checkpoint inhibitors. The modification of oncolytic herpes viruses via genetic engineering favorably affects this process through the enhanced production of pro-inflammatory cytokines, curbing of tumor blood supply, and removal of extracellular barriers for efficient viral spread. Importantly, viral vectors may contribute to stimulation of memory-type adaptive immune responses through presentation of tumor-related neo- and/or self-antigens. Eventually, both replication-competent and replication-deficient herpes simplex virus 1 (HSV-1) may serve as vaccine vectors, which contribute to tumor regression by the stimulation of pDC and other dendritic cells in adjuvant and neo-adjuvant situations.
Philipp Schuster; Georg Lindner; Sabrina Thomann; Sebastian Haferkamp; Barbara Schmidt. Prospect of Plasmacytoid Dendritic Cells in Enhancing Anti-Tumor Immunity of Oncolytic Herpes Viruses. Cancers 2019, 11, 651 .
AMA StylePhilipp Schuster, Georg Lindner, Sabrina Thomann, Sebastian Haferkamp, Barbara Schmidt. Prospect of Plasmacytoid Dendritic Cells in Enhancing Anti-Tumor Immunity of Oncolytic Herpes Viruses. Cancers. 2019; 11 (5):651.
Chicago/Turabian StylePhilipp Schuster; Georg Lindner; Sabrina Thomann; Sebastian Haferkamp; Barbara Schmidt. 2019. "Prospect of Plasmacytoid Dendritic Cells in Enhancing Anti-Tumor Immunity of Oncolytic Herpes Viruses." Cancers 11, no. 5: 651.
Robust anti-tumor immunity requires innate as well as adaptive immune responses. We have shown that plasmacytoid dendritic cells develop killer cell-like activity in melanoma cell cocultures after exposure to the infectious but replication-deficient herpes simplex virus 1 (HSV-1) d106S. To combine this innate effect with an enhanced adaptive immune response, the gene encoding human MelanA/MART-1 was inserted into HSV-1 d106S via homologous recombination to increase direct expression of this tumor antigen. Infection of Vero cells using this recombinant virus confirmed MelanA expression by Western blotting, flow cytometry, and immunofluorescence. HSV-1 d106S-MelanA induced expression of the transgene in fibroblast and melanoma cell lines not naturally expressing MelanA. Infection of a melanoma cell line with CRISPR-Cas9-mediated knockout of MelanA confirmed de novo expression of the transgene in the viral context. Dependent on MelanA expression, infected fibroblast and melanoma cell lines induced degranulation of HLA-matched MelanA-specific CD8+ T cells, followed by killing of infected cells. To study infection of immune cells, we exposed peripheral blood mononuclear cells and in vitro-differentiated macrophages to the parental HSV-1 d106S, resulting in expression of the transgene GFP in CD11c+ cells and macrophages. These data provide evidence that the application of MelanA-encoding HSV-1 d106S could enhance adaptive immune responses and re-direct MelanA-specific CD8+ T cells to tumor lesions, which have escaped adaptive immune responses via downregulation of their tumor antigen. Hence, HSV-1 d106S-MelanA harbors the potential to induce innate immune responses in conjunction with adaptive anti-tumor responses by CD8+ T cells, which should be evaluated in further studies.
Jan B. Boscheinen; Sabrina Thomann; David M. Knipe; Neal DeLuca; Beatrice Schuler-Thurner; Stefanie Gross; Jan Dörrie; Niels Schaft; Christian Bach; Anette Rohrhofer; Melanie Werner-Klein; Barbara Schmidt; Philipp Schuster. Generation of an Oncolytic Herpes Simplex Virus 1 Expressing Human MelanA. Frontiers in Immunology 2019, 10, 1 .
AMA StyleJan B. Boscheinen, Sabrina Thomann, David M. Knipe, Neal DeLuca, Beatrice Schuler-Thurner, Stefanie Gross, Jan Dörrie, Niels Schaft, Christian Bach, Anette Rohrhofer, Melanie Werner-Klein, Barbara Schmidt, Philipp Schuster. Generation of an Oncolytic Herpes Simplex Virus 1 Expressing Human MelanA. Frontiers in Immunology. 2019; 10 ():1.
Chicago/Turabian StyleJan B. Boscheinen; Sabrina Thomann; David M. Knipe; Neal DeLuca; Beatrice Schuler-Thurner; Stefanie Gross; Jan Dörrie; Niels Schaft; Christian Bach; Anette Rohrhofer; Melanie Werner-Klein; Barbara Schmidt; Philipp Schuster. 2019. "Generation of an Oncolytic Herpes Simplex Virus 1 Expressing Human MelanA." Frontiers in Immunology 10, no. : 1.
Our data indicate that the inhibitory effect of peptides derived from HPgV-1 E2 protein is dependent on the genotype, suggesting that coinfection with HPgV-1 GT1 is less likely to confer a beneficial effect on HIV-1 disease progression than GT2. The preferential suppression of more pathogenic CXCR4-tropic HIV-1 by peptides derived from HPgV-1 GT2 may explain the favorable effect in subjects harboring these HIV-1 isolates. Consequently, HPgV-1 genotype and HIV-1 coreceptor tropism are likely determinants for the beneficial effect of HPgV-1 co-infection in HIV-1 infected individuals.
Tamara Ruegamer; Rebecca Hoffmann; Anette Rohrhofer; Franz Audebert; Bernd Salzberger; Klaus Korn; Philipp Schuster; Jutta Eichler; Barbara Schmidt. Inhibition of HIV-1 infection by human pegivirus type 1-derived peptides is affected by human pegivirus type 1 genotype and HIV-1 coreceptor tropism. AIDS 2018, 32, 1951 -1957.
AMA StyleTamara Ruegamer, Rebecca Hoffmann, Anette Rohrhofer, Franz Audebert, Bernd Salzberger, Klaus Korn, Philipp Schuster, Jutta Eichler, Barbara Schmidt. Inhibition of HIV-1 infection by human pegivirus type 1-derived peptides is affected by human pegivirus type 1 genotype and HIV-1 coreceptor tropism. AIDS. 2018; 32 (14):1951-1957.
Chicago/Turabian StyleTamara Ruegamer; Rebecca Hoffmann; Anette Rohrhofer; Franz Audebert; Bernd Salzberger; Klaus Korn; Philipp Schuster; Jutta Eichler; Barbara Schmidt. 2018. "Inhibition of HIV-1 infection by human pegivirus type 1-derived peptides is affected by human pegivirus type 1 genotype and HIV-1 coreceptor tropism." AIDS 32, no. 14: 1951-1957.
Malignant melanoma is an aggressive tumor of the skin with increasing incidence, frequent metastasis, and poor prognosis. At the same time, it is an immunogenic type of cancer with spontaneous regressions. Most recently, the tumoricidal effect of plasmacytoid dendritic cells (PDC) and their capacity to overcome the immunosuppressive tumor microenvironment are being investigated. In this respect, we studied the effect of the infectious, but replication‐deficient HSV‐1 d106S vaccine strain, which lacks essential immediate early genes, in PDC co‐cultures with 11 melanoma cell lines. We observed a strong cytotoxic activity, inducing apoptotic and necrotic cell death in most melanoma cell lines. The cytotoxic activity of HSV‐1 d106S plus PDC was comparable to the levels of cytotoxicity induced by natural killer cells, but required only a fraction of cells with effector:target ratios of 1:20 (p<0.05). The suppressive activity of cell‐free supernatants derived from virus‐stimulated PDC was significantly neutralized using antibodies against the interferon‐α receptor (p<0.05). In addition to type I interferons, TRAIL and granzyme B contributed to the inhibitory effect of HSV‐1 d106S plus PDC to a minor extent. UV‐irradiated viral stocks were significantly less active than infectious particles, both in the absence and presence of PDC (p<0.05), indicating that residual activity of HSV‐1 d106S is a major component and sensitizes the tumor cells to interferon‐producing PDC. Three leukemic cell lines were also susceptible to this treatment, suggesting a general anti‐tumor effect. In conclusion, the potential of HSV‐1 d106S for therapeutic vaccination should be further evaluated in patients suffering from different malignancies. This article is protected by copyright. All rights reserved.
Sabrina Thomann; Jan B. Boscheinen; Karin Vogel; David M. Knipe; Neal DeLuca; Stefanie Gross; Beatrice Schuler-Thurner; Philipp Schuster; Barbara Schmidt. Combined cytotoxic activity of an infectious, but non-replicative herpes simplex virus type 1 and plasmacytoid dendritic cells against tumour cells. Immunology 2015, 146, 327 -338.
AMA StyleSabrina Thomann, Jan B. Boscheinen, Karin Vogel, David M. Knipe, Neal DeLuca, Stefanie Gross, Beatrice Schuler-Thurner, Philipp Schuster, Barbara Schmidt. Combined cytotoxic activity of an infectious, but non-replicative herpes simplex virus type 1 and plasmacytoid dendritic cells against tumour cells. Immunology. 2015; 146 (2):327-338.
Chicago/Turabian StyleSabrina Thomann; Jan B. Boscheinen; Karin Vogel; David M. Knipe; Neal DeLuca; Stefanie Gross; Beatrice Schuler-Thurner; Philipp Schuster; Barbara Schmidt. 2015. "Combined cytotoxic activity of an infectious, but non-replicative herpes simplex virus type 1 and plasmacytoid dendritic cells against tumour cells." Immunology 146, no. 2: 327-338.
The chemokine receptor CXCR4 belongs to the family of seven-transmembrane G-protein coupled receptors (GPCRs). It is activated by its natural ligand SDF-1α. In addition, CXCR4, along with CCR5, serve as coreceptors during HIV-1 entry into its target cell. Recently, we introduced a CXCR4 mimetic peptide, termed CX4-M1, which presents the three extracellular loops (ECLs) of the receptor. CX4-M1 was shown to selectively bind to gp120 of X4-tropic, that is, CXCR4 using, HIV-1, as well as to peptides that present the V3-loops of these gp120 proteins. Furthermore, CX4-M1 selectively inhibits infection of cells with X4-tropic HIV-1. We have now adapted the sequence of the ECLs presented by CX4-M1 to the recently published crystal structure of CXCR4. The binding behavior, as well as the effect on HIV-1 infection, of the resulting peptide (CX4-Mc) was very similar to CX4-M1, validating retrospectively the original design of CX4-M1. A peptide presenting the ECLs of CCR5 (CR5-M), on the other hand, did neither bind to gp120 from X4-tropic HIV-1, nor did it inhibit infection of cells with X4-tropic HIV-1. Furthermore, we could show that CX4-M1, as well as CX4-Mc, but not CR5-M, are selectively recognized by anti-CXCR4 antibodies, bind to SDF-1α, and also inhibit SDF-1α signaling, extending the scope of selective functional CXCR4 mimicry through CX4-M1.
Andrea Groß; Regine Brox; Dominik Damm; Nuška Tschammer; Barbara Schmidt; Jutta Eichler. Ligand selectivity of a synthetic CXCR4 mimetic peptide. Bioorganic & Medicinal Chemistry 2015, 23, 4050 -4055.
AMA StyleAndrea Groß, Regine Brox, Dominik Damm, Nuška Tschammer, Barbara Schmidt, Jutta Eichler. Ligand selectivity of a synthetic CXCR4 mimetic peptide. Bioorganic & Medicinal Chemistry. 2015; 23 (14):4050-4055.
Chicago/Turabian StyleAndrea Groß; Regine Brox; Dominik Damm; Nuška Tschammer; Barbara Schmidt; Jutta Eichler. 2015. "Ligand selectivity of a synthetic CXCR4 mimetic peptide." Bioorganic & Medicinal Chemistry 23, no. 14: 4050-4055.
Classical and plasmacytoid dendritic cells (DC) play important roles in the defense against murine and human infections with herpes simplex virus (HSV). So far, CD8α expression has only been reported for murine DC. CD8α+ DC have prominent cross-presenting activities, which are enhanced by murine CD8α+ PDC. The human orthologue of murine CD8α+ DC, the CD141 (BDCA3)+ DC, mainly cross-present after TLR3 ligation. We report here the serendipitous finding that a subset of human PDC upregulates CD8α upon HSV-1 stimulation, as shown by gene array and flow cytometry analyses. CD8α, not CD8ß, was expressed upon exposure. Markers of activation, migration, and costimulation were upregulated on CD8α-expressing human PDC. In these cells, increased cytokine and chemokine levels were detected that enhance development and function of T, B, and NK cells, and recruit immature DC, monocytes, and Th1 cells, respectively. Altogether, human CD8α+ PDC exhibit a highly activated phenotype and appear to recruit other immune cells to the site of inflammation. Further studies will show whether CD8α-expressing PDC contribute to antigen cross-presentation, which may be important for immune defenses against HSV infections in vitro and in vivo.
Philipp Eschuster; Sabrina Ethomann; Maren Ewerner; Jã¶rg Vollmer; Barbara Schmidt. A subset of human plasmacytoid dendritic cells expresses CD8α upon exposure to herpes simplex virus type 1. Frontiers in Microbiology 2015, 6, 557 .
AMA StylePhilipp Eschuster, Sabrina Ethomann, Maren Ewerner, Jã¶rg Vollmer, Barbara Schmidt. A subset of human plasmacytoid dendritic cells expresses CD8α upon exposure to herpes simplex virus type 1. Frontiers in Microbiology. 2015; 6 ():557.
Chicago/Turabian StylePhilipp Eschuster; Sabrina Ethomann; Maren Ewerner; Jã¶rg Vollmer; Barbara Schmidt. 2015. "A subset of human plasmacytoid dendritic cells expresses CD8α upon exposure to herpes simplex virus type 1." Frontiers in Microbiology 6, no. : 557.
Herpes simplex virus type 1 (HSV‐1), a member of the herpes virus family, is characterized by a short replication cycle, high cytopathogenicity and distinct neurotropism. Primary infection and reactivation may cause severe diseases in immunocompetent and immunosuppressed individuals. This study investigated the role of human plasmacytoid dendritic cells (pDC) in the activation of natural killer (NK) cells for the control of herpesviral infections. Within peripheral blood mononuclear cells, UV‐inactivated HSV‐1 and CpG‐A induced CD69 up‐regulation on NK cells, whereas infectious HSV‐1 was particularly active in inducing NK cell effector functions interferon‐γ (IFN‐γ) secretion and degranulation. The pDC‐derived IFN‐α significantly contributed to NK cell activation, as evident from neutralization and cell depletion experiments. In addition, monocyte‐derived tumour necrosis factor‐α (TNF‐α) induced after exposure to infectious HSV‐1 was found to stimulate IFN‐γ secretion. A minority of monocytes was shown to be non‐productively infected in experiments using fluorescently labelled viruses and quantitative PCR analyses. HSV‐1‐exposed monocytes up‐regulated classical HLA‐ABC and non‐classical HLA‐E molecules at the cell surface in an IFN‐α‐dependent manner, whereas stress molecules MICA/B were not induced. Notably, depletion of monocytes reduced NK cell effector functions induced by infectious HSV‐1 (P < 0·05). Altogether, our data suggest a model in which HSV‐1‐stimulated pDC and monocytes activate NK cells via secretion of IFN‐α and TNF‐α. In addition, infection of monocytes induces NK cell effector functions via TNF‐α‐dependent and TNF‐α‐independent mechanisms. Hence, pDC and monocytes, which are among the first cells infiltrating herpetic lesions, appear to have important bystander functions for NK cells to control these viral infections.
Karin Vogel; Sabrina Thomann; Benjamin Vogel; Philipp Schuster; Barbara Schmidt. Both plasmacytoid dendritic cells and monocytes stimulate natural killer cells early during human herpes simplex virus type 1 infections. Immunology 2014, 143, 588 -600.
AMA StyleKarin Vogel, Sabrina Thomann, Benjamin Vogel, Philipp Schuster, Barbara Schmidt. Both plasmacytoid dendritic cells and monocytes stimulate natural killer cells early during human herpes simplex virus type 1 infections. Immunology. 2014; 143 (4):588-600.
Chicago/Turabian StyleKarin Vogel; Sabrina Thomann; Benjamin Vogel; Philipp Schuster; Barbara Schmidt. 2014. "Both plasmacytoid dendritic cells and monocytes stimulate natural killer cells early during human herpes simplex virus type 1 infections." Immunology 143, no. 4: 588-600.
This study tested the hypothesis that mtDNA fragments carry immunostimulatory motifs that naturally induce immune activation by PDC. Genomic and mtDNA induced similar IFN-α production after transfection into PBMCs using the liposomal transfection reagent DOTAP. Shortening of mtDNA to CpG islands enhanced the immunostimulatory activity, based on the presence of unmethylated CpG DNA. Further fragmentation into mtODN, which exhibited similarities to published CpG ODN, resulted in a strong immunostimulatory activity in addition to PDC maturation and migration. The addition of the human cathelicidin LL-37 to CpG islands induced spontaneous PDC IFN-α production. Notably, one phosphodiester mtODN with a double-palindromic structure induced PDC IFN-α production in the absence of DOTAP. Flow cytometry, life-cell, and confocal imaging revealed attachment and spontaneous uptake into PDC, colocalizing, in part, with TLR9 in early endosomal vesicles. This process was accompanied by a moderate but significant PDC maturation in addition to B cell and NK cell activation (P<0.05). Altogether, our data indicate that fragmented mtDNA, which may be released as a consequence of apoptotic, necrotic, and necroptotic cell death, can act as a DAMP. For the first time, our study provides a mechanism how longer and shorter mtDNA fragments can be taken up naturally by the PDC and thus, may contribute to acute and chronic immune activation.
Moritz Ries; Philipp Schuster; Sabrina Thomann; Norbert Donhauser; Jörg Vollmer; Barbara Schmidt. Identification of novel oligonucleotides from mitochondrial DNA that spontaneously induce plasmacytoid dendritic cell activation. Journal of Leukocyte Biology 2013, 94, 123 -135.
AMA StyleMoritz Ries, Philipp Schuster, Sabrina Thomann, Norbert Donhauser, Jörg Vollmer, Barbara Schmidt. Identification of novel oligonucleotides from mitochondrial DNA that spontaneously induce plasmacytoid dendritic cell activation. Journal of Leukocyte Biology. 2013; 94 (1):123-135.
Chicago/Turabian StyleMoritz Ries; Philipp Schuster; Sabrina Thomann; Norbert Donhauser; Jörg Vollmer; Barbara Schmidt. 2013. "Identification of novel oligonucleotides from mitochondrial DNA that spontaneously induce plasmacytoid dendritic cell activation." Journal of Leukocyte Biology 94, no. 1: 123-135.
We have recently designed a soluble synthetic peptide that functionally mimics the HIV-1 coreceptor CXCR4, which is a chemokine receptor that belongs to the family of seven-transmembrane GPCRs. This CXCR4 mimetic peptide, termed CX4-M1, presents the three extracellular loops (ECLs) of the receptor. In binding assays involving recombinant proteins, as well as in cellular infection assays, CX4-M1 was found to selectively recognize gp120 from HIV-1 strains that use CXCR4 for cell entry (X4 tropic HIV-1). Furthermore, anti-HIV-1 antibodies modulate this interaction in a molecular mechanism related to that of their impact on the gp120-CXCR4 interaction. We could now show that the selectivity of CX4-M1 pertains not only to gp120 from X4 tropic HIV-1, but also to synthetic peptides presenting the V3 loops of these gp120 proteins. The V3 loop is thought to be an essential part of the coreceptor binding site of gp120 that contacts the second ECL of the coreceptor. We were able to experimentally confirm this notion in binding assays using substitution analogs of CX4-M1 and the V3 loop peptides, respectively, as well as in cellular infection assays. These results indicate that interactions of the HIV-1 Env with coreceptors can be mimicked by synthetic peptides, which may be useful to explore these interactions at the molecular level in more detail.
Andrea Gross; Kalle Möbius; Christina Haußner; Norbert Donhauser; Barbara Schmidt; Jutta Eichler. Mimicking Protein–Protein Interactions through Peptide–Peptide Interactions: HIV-1 gp120 and CXCR4. Frontiers in Immunology 2013, 4, 257 .
AMA StyleAndrea Gross, Kalle Möbius, Christina Haußner, Norbert Donhauser, Barbara Schmidt, Jutta Eichler. Mimicking Protein–Protein Interactions through Peptide–Peptide Interactions: HIV-1 gp120 and CXCR4. Frontiers in Immunology. 2013; 4 ():257.
Chicago/Turabian StyleAndrea Gross; Kalle Möbius; Christina Haußner; Norbert Donhauser; Barbara Schmidt; Jutta Eichler. 2013. "Mimicking Protein–Protein Interactions through Peptide–Peptide Interactions: HIV-1 gp120 and CXCR4." Frontiers in Immunology 4, no. : 257.