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@article{faucris.210555523,
abstract = {Kaposi's sarcoma-associated herpesvirus (KSHV) is a human oncogenic virus associated with Kaposi's sarcoma and two B-cell malignancies. The rhesus monkey rhadinovirus (RRV) is a virus of nonhuman primates that is closely related to KSHV. Eph family receptor tyrosine kinases (Ephs) are cellular receptors for the gH/gL glycoprotein complexes of both KSHV and RRV. Through sequence analysis and mutational screens, we identified conserved residues in the N-terminal domain of KSHV and RRV glycoprotein H that are critical for Eph-binding in vitro. Homology-based structural predictions of the KSHV and RRV gH/gL complexes based on the Epstein-Barr-Virus gH/gL crystal structure located these amino acids in a beta-hairpin on gH, which is likely stabilized by gL and is optimally positioned for protein-protein interactions. Guided by these predictions, we generated recombinant RRV and KSHV strains mutated in the conserved motif as well as an RRV gL null mutant. Inhibition experiments using these mutants confirmed that disruption of the identified Eph-interaction motif or of gL expression resulted in complete detargeting from Ephs. However, all mutants were infectious on all cell types tested, exhibiting normal attachment but a reduction in infectivity of up to one log order of magnitude. While Eph-binding-negative RRV mutants were replication-competent on fibroblasts, their infectivity was comparatively more reduced on endothelial cells with a substantial subpopulation of endothelial cells remaining resistant to infection. Together, this provides evidence for a cell type-specific use of Ephs by RRV. Furthermore, our results demonstrate that gL is dispensable for infection by RRV. Its deletion caused a reduction in infectivity similar to that observed after mutation of Eph-binding residues in gH. Our findings would be compatible with an ability of KSHV and RRV to use other, less efficient entry mediators in lieu of Ephs, although these host factors may not be uniformly expressed by all cells.},
author = {Grosskopf, Anna K. and Enßer, Armin and Neipel, Frank and Jungnickl, Doris and Schlagowski, Sarah and Desrosiers, Ronald C. and Hahn, Alexander S.},
doi = {10.1371/journal.ppat.1006912},
faupublication = {yes},
journal = {PLoS Pathogens},
note = {EVALuna2:35289},
peerreviewed = {Yes},
title = {{A} conserved {Eph} family receptor-binding motif on the {gH}/{gL} complex of {Kaposi}'s sarcoma-associated herpesvirus and rhesus monkey rhadinovirus},
volume = {14},
year = {2018}
}
@article{faucris.210556217,
abstract = {Bispecific T cell engager (BiTE) antibody constructs are successfully used as cancer therapeutics. We hypothesized that this treatment strategy could also be applicable for therapy of human cytomegalovirus (HCMV) infection, since HCMV-encoded proteins are abundantly expressed on the surface of infected cells. Here we show that a BiTE antibody construct directed against HCMV glycoprotein B (gB) and CD3 efficiently triggers T cells to secrete IFN-gamma and TNF upon co-culture with fibroblasts infected with HCMV strain AD169, Towne or Toledo. Titration of gB expression levels in non-infected cells confirmed that already low levels of gB are sufficient for efficient triggering of T cells in presence of the BiTE antibody construct. Comparison of redirecting T cells with the bispecific antibody versus a chimeric antigen receptor (CAR) based on the same scFv showed a similar sensitivity for gB expression. Although lysis of infected target cells was absent, the BiTE antibody construct inhibited HCMV replication by triggering cytokine production. Notably, even strongly diluted supernatants of the activated T cells efficiently blocked the replication of HCMV in infected primary fibroblasts. In summary, our data prove the functionality of the first BiTE antibody construct targeting an HCMV-encoded glycoprotein for inhibiting HCMV replication in infected cells.},
author = {Brey, Charlotte U. and Proff, Julia and Teufert, Natascha and Salzer, Benjamin and Brozy, Johannes and Muenz, Markus and Pendzialek, Jochen and Enßer, Armin and Holter, Wolfgang and Lehner, Manfred},
doi = {10.1038/s41598-018-36055-2},
faupublication = {yes},
journal = {Scientific Reports},
note = {EVALuna2:35260},
peerreviewed = {Yes},
title = {{A} {gB}/{CD3} bispecific {BiTE} antibody construct for targeting {Human} {Cytomegalovirus}-infected cells},
volume = {8},
year = {2018}
}
@article{faucris.310764314,
abstract = {Granzyme B (GZMB) is a key enzyme released by cytotoxic T lymphocytes (CTL) and natural killer (NK) cells to induce apoptosis in target cells. We designed a novel fluorogenic biosensor which is able to assess GZMB activity in a specific and sensitive manner. This cleavage-responsive sensor for T cell activity level (CRSTAL) is based on a fluorescent protein that is only activated upon cleavage by GZMB or caspase-8. CRSTAL was tested in stable cell lines and demonstrated a strong and long-lasting fluorescence signal upon induction with GZMB. It can detect GZMB activity not only by overexpression of GZMB in target cells but also following transfer of GZMB and perforin from effector cells during cytotoxicity. This feature has significant implications for cancer immunotherapy, particularly in monitoring the efficacy of chimeric antigen receptor (CAR)-T cells. CAR-T cells are a promising therapy option for various cancer types, but monitoring their activity in vivo is challenging. The development of biosensors like CRSTAL provides a valuable tool for monitoring of CAR-T cell activity. In summary, CRSTAL is a highly sensitive biosensor that can detect GZMB activity in target cells, providing a means for evaluating the cytotoxic activity of immune cells and monitoring T cell activity in real time.},
author = {Bednar, Christopher and Kübel, Sabrina and Cordsmeier, Arne and Scholz, Brigitte and Menschikowski, Hanna and Enßer, Armin},
doi = {10.3390/ijms241713589},
faupublication = {yes},
journal = {International Journal of Molecular Sciences},
keywords = {CAR-T cells; fluorogenic biosensor; granzyme B; T cell cytotoxicity},
note = {CRIS-Team Scopus Importer:2023-09-22},
peerreviewed = {Yes},
title = {{A} {Genetically} {Encoded} {Dark}-to-{Bright} {Biosensor} for {Visualisation} of {Granzyme}-{Mediated} {Cytotoxicity}},
volume = {24},
year = {2023}
}
@article{faucris.110988944,
abstract = {Constitutive STAT signaling provides growth promoting signals in many forms of malignancy. We performed molecular modeling and molecular dynamics studies of the interaction between the regulatory Src homology 2 (SH2) domains of STAT3 and 6 with phosphorylated peptides of the herpesviral oncoprotein Tip, which facilitates Src kinase mediated STAT-activation and T cell proliferation. The studies give insight into the ligand binding specificity of the STAT SH2 domains and provide the first model for the differential activation of STAT3 or STAT6 by two distinct regions of the viral Tip protein. The biological relevance of the modeled interactions was then confirmed by activation studies using corresponding recombinant oncoproteins, and finally by respective recombinant viruses. The functional data give experimental validation of the molecular dynamics study, and provide evidence for the involvement of STAT6 in the herpesvirus induced T cell proliferation.},
author = {Mazumder, Eman Dey and Jardin, Christophe and Vogel, Benjamin and Heck, Elke and Scholz, Brigitte and Lengenfelder, Doris and Sticht, Heinrich and Enßer, Armin},
doi = {10.1371/journal.pone.0034306},
faupublication = {yes},
journal = {PLoS ONE},
note = {EVALuna2:8146},
pages = {e34306},
peerreviewed = {Yes},
title = {{A} molecular model for the differential activation of {STAT3} and {STAT6} by the herpesviral oncoprotein tip},
volume = {7},
year = {2012}
}
@article{faucris.302871799,
abstract = {SARS-CoV-2, the causative agent of COVID-19, has spread around the world with more than 700 million cases and 6.8 million deaths. Various variants of concern (VoC) have emerged due to mutations and recombination and concurrent selection for increased viral fitness and immune evasion. The viral protein that primarily determines the pathogenicity, infectivity, and transmissibility is the Spike protein. To analyze the specific impact of variant Spike proteins on infection dynamics, we constructed SARS-CoV-2 with a uniform B.1 backbone but with alternative Spike proteins. In addition, ORF6 was replaced by EYFP as a biological safety measure, and for use of this well-established reporter. We show that namely the delta variant Spike proteins cause a distinct phenotype from the wild type (B.1, D614G) and other variants of concern. Furthermore, we demonstrate that the omicron BA.1 Spike results in lower viral loads and a less efficient spread in vitro. Finally, we utilized viruses with the two different reporters EYFP and mCherry to establish a competitive growth assay, demonstrating that most but not all Spike variant viruses were able to outcompete wild type SARS-CoV-2 B.1.},
author = {Cordsmeier, Arne and Jungnickl, Doris and Herrmann, Alexandra and Korn, Klaus and Enßer, Armin},
doi = {10.3390/ijms24098156},
faupublication = {yes},
journal = {International Journal of Molecular Sciences},
keywords = {SARS-CoV-2; Spike protein; variants of concern},
note = {CRIS-Team Scopus Importer:2023-05-26},
peerreviewed = {Yes},
title = {{Analysis} of {SARS}-{CoV}-2 {Spike} {Protein} {Variants} with {Recombinant} {Reporter} {Viruses} {Created} from a {Bacmid} {System}},
volume = {24},
year = {2023}
}
@article{faucris.271373252,
abstract = {Kaposi’s sarcoma herpesvirus (KSHV) is associated with a significant disease burden, in particular in Sub-Sahara Africa. A KSHV vaccine would be highly desirable, but the mechanisms underlying neutralizing antibody responses against KSHV remain largely unexplored. The complex made of glycoproteins H and L (gH/gL) activates gB for the fusion of viral and cellular membranes in all herpesviruses. KSHV gH/gL also interacts with cellular Eph family receptors. To identify optimal antigens for vaccination and to elucidate neutralization mechanisms, we primed mice with recombinantly expressed, soluble gH/gL (gHecto/gL) that was either wildtype (WT), lacking defined glycosylation sites or bearing modified glycosylation, followed by boosts with WT gHecto/gL. We also immunized with a gL-gHecto fusion protein or a gHecto-ferritin/gL nanoparticle. Immune sera neutralized KSHV and inhibited EphA2 receptor binding. None of the regimens was superior to immunization with WT gHecto/gL with regard to neutralizing activity and EphA2 blocking activity, the gL-gHecto fusion protein was equally effective, and the ferritin construct was inferior. gH/gL-targeting sera inhibited gB-mediated membrane fusion and inhibited infection also independently from receptor binding and gL, as demonstrated by neutralization of a novel KSHV mutant that does not or only marginally incorporate gL into the gH/gL complex and infects through an Eph-independent route.},
author = {Fricke, Thomas and Großkopf, Anna K. and Enßer, Armin and Backovic, Marija and Hahn, Alexander S.},
doi = {10.3390/v14030541},
faupublication = {yes},
journal = {Viruses},
keywords = {Fusion; GH/gL; Herpesvirus entry; HHV-8; KSHV; Neutralizing antibodies},
note = {CRIS-Team Scopus Importer:2022-03-25},
peerreviewed = {Yes},
title = {{Antibodies} {Targeting} {KSHV} {gH}/{gL} {Reveal} {Distinct} {Neutralization} {Mechanisms}},
volume = {14},
year = {2022}
}
@article{faucris.262566065,
abstract = {TRIANNI mice carry an entire set of human immunoglobulin V region gene segments and are a powerful tool to rapidly isolate human monoclonal antibodies. After immunizing these mice with DNA encoding the spike protein of SARS-CoV-2 and boosting with spike protein, we identified 29 hybridoma antibodies that reacted with the SARS-CoV-2 spike protein. Nine antibodies neutralize SARS-CoV-2 infection at IC50 values in the subnanomolar range. ELISA-binding studies and DNA sequence analyses revealed one cluster of three clonally related neutralizing antibodies that target the receptor-binding domain and compete with the cellular receptor hACE2. A second cluster of six clonally related neutralizing antibodies bind to the N-terminal domain of the spike protein without competing with the binding of hACE2 or cluster 1 antibodies. SARS-CoV-2 mutants selected for resistance to an antibody from one cluster are still neutralized by an antibody from the other cluster. Antibodies from both clusters markedly reduced viral spread in mice transgenic for human ACE2 and protected the animals from SARS-CoV-2-induced weight loss. The two clusters of potent non-competing SARS-CoV-2 neutralizing antibodies provide potential candidates for therapy and prophylaxis of COVID-19. The study further supports transgenic animals with a human immunoglobulin gene repertoire as a powerful platform in pandemic preparedness initiatives.},
author = {Peter, Antonia Sophia and Roth, Edith and Schulz, Sebastian and Fraedrich, Kirsten and Steinmetz, Tobit and Damm, Dominik and Hauke, Manuela and Richel, Elie and Müller-Schmucker, Sandra and Habenicht, Katharina Marie and Eberlein, Valentina and Issmail, Leila and Uhlig, Nadja and Dolles, Simon and Grüner, Eva and Peterhoff, David and Ciesek, Sandra and Hoffmann, Markus and Pöhlmann, Stefan and McKay, Paul F. and Shattock, Robin J. and Wölfel, Roman and Socher, Eileen and Wagner, Ralf and Eichler, Jutta and Sticht, Heinrich and Schuh, Wolfgang and Neipel, Frank and Enßer, Armin and Mielenz, Dirk and Tenbusch, Matthias and Winkler, Thomas and Grunwald, Thomas and Überla, Klaus and Jäck, Hans-Martin},
doi = {10.1002/eji.202149374},
faupublication = {yes},
journal = {European Journal of Immunology},
peerreviewed = {Yes},
title = {{A} pair of non‐competing neutralizing human monoclonal antibodies protecting from disease in a {SARS}‐{CoV}‐2 infection model},
year = {2021}
}
@article{faucris.232028302,
abstract = {A replication-competent, recombinant strain of rhesus monkey rhadinovirus (RRV) expressing the Gag protein of SIVmac239 was constructed in the context of a glycoprotein L (gL) deletion mutation. Deletion of gL detargets the virus from Eph family receptors. The ability of this gL-minus Gag recombinant RRV to infect, persist, and elicit immune responses was evaluated after intravenous inoculation of two Mamu-A*01+ RRV-naive rhesus monkeys. Both monkeys responded with an anti-RRV antibody response, and quantitation of RRV DNA in peripheral blood mononuclear cells (PBMC) by real-time PCR revealed levels similar to those in monkeys infected with recombinant gL+ RRV. Comparison of RRV DNA levels in sorted CD3+ versus CD20+ versus CD14+ PBMC subpopulations indicated infection of the CD20+ subpopulation by the gL-minus RRV. This contrasts with results obtained with transformed B cell lines in vitro, in which deletion of gL resulted in markedly reduced infectivity. Over a period of 20 weeks, Gag-specific CD8+ T cell responses were documented by major histocompatibility complex class I (MHC-I) tetramer staining. Vaccine-induced CD8+ T cell responses, which were predominantly directed against the Mamu-A*01-restricted Gag181-189CM9 epitope, could be inhibited by blockade of MHC-I presentation. Our results indicate that gL and the interaction with Eph family receptors are dispensable for the colonization of the B cell compartment following high-dose infection by the intravenous route, which suggests the existence of alternative receptors. Further, gL-minus RRV elicits cellular immune responses that are predominantly canonical in nature.IMPORTANCE Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with a substantial disease burden in sub-Saharan Africa, often in the context of human immunodeficiency virus (HIV) infection. The related rhesus monkey rhadinovirus (RRV) has shown potential as a vector to immunize monkeys with antigens from simian immunodeficiency virus (SIV), the macaque model for HIV. KSHV and RRV engage cellular receptors from the Eph family via the viral gH/gL glycoprotein complex. We have now generated a recombinant RRV that expresses the SIV Gag antigen and does not express gL. This recombinant RRV was infectious by the intravenous route, established persistent infection in the B cell compartment, and elicited strong immune responses to the SIV Gag antigen. These results argue against a role for gL and Eph family receptors in B cell infection by RRV in vivo and have implications for the development of a live-attenuated KSHV vaccine or vaccine vector.},
author = {Hahn, Alexander S. and Bischof, Georg F. and Grosskopf, Anna K. and Shin, Young C. and Domingues, Aline and Gonzalez-Nieto, Lucas and Rakasz, Eva G. and Watkins, David I. and Enßer, Armin and Martins, Mauricio A. and Desrosiers, Ronald C.},
doi = {10.1128/JVI.01093-19},
faupublication = {yes},
journal = {Journal of Virology},
keywords = {glycoproteins; live vector vaccines; rhadinovirus; simian immunodeficiency virus},
month = {Jan},
note = {CRIS-Team Scopus Importer:2020-01-21},
peerreviewed = {unknown},
title = {{A} {Recombinant} {Rhesus} {Monkey} {Rhadinovirus} {Deleted} of {Glycoprotein} {L} {Establishes} {Persistent} {Infection} of {Rhesus} {Macaques} and {Elicits} {Conventional} {T} {Cell} {Responses}},
volume = {94},
year = {2020}
}
@article{faucris.121149644,
abstract = {Transcription of herpesvirus late genes depends on several virus-encoded proteins whose function is not completely understood. Here, we identify a viral trimeric complex of Kaposi's sarcoma-associated herpesvirus (KSHV) open reading frame 31 (ORF31), ORF24, and ORF34 that is required for late gene expression but not viral DNA replication. We found that (i) ORF34 bridges the interaction between ORF31 and ORF24, (ii) the amino-terminal cysteine-rich and carboxyl-terminal basic domains of ORF31 mediate the ORF31-ORF34 interaction required for late gene expression, and (iii) a complex consisting of ORF24, ORF31, and ORF34 specifically binds to the K8.1 late promoter. Together, our results support the model that a subset of lytic viral proteins assembles into a transcriptional activator complex to induce expression of late genes.},
author = {Brulois, Kevin and Wong, Lai-Yee and Lee, Hye-Ra and Sivadas, Priyanka and Enßer, Armin and Feng, Pinghui and Gao, Shou-Jiang and Toth, Zsolt and Jung, Jae U.},
doi = {10.1128/JVI.00272-15},
faupublication = {yes},
journal = {Journal of Virology},
note = {EVALuna2:8281},
pages = {6148-54},
peerreviewed = {Yes},
title = {{Association} of {Kaposi}'s {Sarcoma}-{Associated} {Herpesvirus} {ORF31} with {ORF34} and {ORF24} {Is} {Critical} for {Late} {Gene} {Expression}},
volume = {89},
year = {2015}
}
@article{faucris.279557593,
abstract = {The SARS-CoV-2 infection cycle is a multistage process that relies on functional interactions between the host and the pathogen. Here, we repurposed antiviral drugs against both viral and host enzymes to pharmaceutically block methylation of the viral RNA 2'-O-ribose cap needed for viral immune escape. We find that the host cap 2'-O-ribose methyltransferase MTr1 can compensate for loss of viral NSP16 methyltransferase in facilitating virus replication. Concomitant inhibition of MTr1 and NSP16 efficiently suppresses SARS-CoV-2 replication. Using in silico target-based drug screening, we identify a bispecific MTr1/NSP16 inhibitor with anti-SARS-CoV-2 activity in vitro and in vivo but with unfavorable side effects. We further show antiviral activity of inhibitors that target independent stages of the host SAM cycle providing the methyltransferase co-substrate. In particular, the adenosylhomocysteinase (AHCY) inhibitor DZNep is antiviral in in vitro, in ex vivo, and in a mouse infection model and synergizes with existing COVID-19 treatments. Moreover, DZNep exhibits a strong immunomodulatory effect curbing infection-induced hyperinflammation and reduces lung fibrosis markers ex vivo. Thus, multispecific and metabolic MTase inhibitors constitute yet unexplored treatment options against COVID-19.},
author = {Bergant, Valter and Yamada, Shintaro and Grass, Vincent and Tsukamoto, Yuta and Lavacca, Teresa and Krey, Karsten and Muhlhofer, Maria-Teresa and Wittmann, Sabine and Enßer, Armin and Herrmann, Alexandra and Vom Hemdt, Anja and Tomita, Yuriko and Matsuyama, Shutoku and Hirokawa, Takatsugu and Huang, Yiqi and Piras, Antonio and Jakwerth, Constanze A. and Oelsner, Madlen and Thieme, Susanne and Graf, Alexander and Krebs, Stefan and Blum, Helmut and Kuemmerer, Beate M. and Stukalov, Alexey and Schmidt-Weber, Carsten B. and Igarashi, Manabu and Gramberg, Thomas and Pichlmair, Andreas and Kato, Hiroki},
doi = {10.15252/embj.2022111608},
faupublication = {yes},
journal = {EMBO Journal},
note = {CRIS-Team WoS Importer:2022-08-05},
peerreviewed = {Yes},
title = {{Attenuation} of {SARS}-{CoV}-2 replication and associated inflammation by concomitant targeting of viral and host cap 2'-{O}-ribose methyltransferases},
year = {2022}
}
@article{faucris.264553330,
abstract = {The life span of dendritic cells (DCs) is determined by the balance of pro- and antiapoptotic proteins. In this study, we report that serum-free cultured human monocyte-derived DCs after TLR stimulation with polyinosinic acid-polycytidylic acid or LPS underwent apoptosis, which was correlated with low TNF production. Apoptosis was prevented by the addition of exogenous TNF or by concomitant stimulation with R-848, which strongly amplified endogenous TNF production. Neutralization of TNF confirmed that DC survival was mediated by autocrine TNF induced either by stimulation with R-848 or by ligation of CD40. DCs stimulated by polyinosinic acid-polycytidylic acid or IFN-β, another known inducer of DC apoptosis, were characterized by high levels and activation of the proapoptotic protein BAK. The ratio of antiapoptotic BCL-2 to BAK correlated best with the survival of activated DCs. Addition of TNF increased this ratio but had little effect on BAX and XIAP. Knockdown experiments using small interfering RNAs confirmed that the survival of activated and also of immature DCs was regulated by BAK and showed that TNF was protective only in the presence of FLIP L. Together, our data demonstrate that the survival of DCs during differentiation and activation depends on autocrine TNF and that the inhibition of BAK plays an important role in this process. Copyright © 2012 by The American Association of Immunologists, Inc.},
author = {Lehner, Manfred and Kellert, Beate and Proff, Julia and Schmid, Martina A. and Diessenbacher, Philip and Enßer, Armin and Dörrie, Jan and Schaft, Niels and Leverkus, Martin and Kämpgen, Eckhart and Holter, Wolfgang},
doi = {10.4049/jimmunol.1101610},
faupublication = {yes},
journal = {Journal of Immunology},
note = {CRIS-Team Scopus Importer:2021-10-01},
pages = {4810-4818},
peerreviewed = {Yes},
title = {{Autocrine} {TNF} is critical for the survival of human dendritic cells by regulating {BAK}, {BCL}-2, and {FLIP} {L}},
volume = {188},
year = {2012}
}
@article{faucris.268453366,
author = {Meier, H. and Bauer, C. and Finkenzeller, W. and Nentwich, J. and Staedt, M. and Steininger, Philipp and Korn, Klaus and Enßer, Armin and Erbguth, F.},
doi = {10.1007/s00115-021-01259-x},
faupublication = {yes},
journal = {Der Nervenarzt},
month = {Jan},
note = {CRIS-Team WoS Importer:2022-01-28},
peerreviewed = {Yes},
title = {{Bornavirus} encephalitis as a differential diagnosis to seronegative autoimmune encephalitis},
year = {2022}
}
@article{faucris.262970247,
abstract = {Human cytomegalovirus (HCMV), by primary infection or reactivation, represents a great risk for immune-suppressed or compromised patients. In immunocompetent humans, the immune system suppresses the spread of HCMV during an infection, resulting in a mostly asymptomatic or mild course of the disease, whereas in immune suppressed patients, the compromised host immune response cannot control the viral infection. Multiple viral immunomodulatory mechanisms additionally contribute to immune evasion. Use of chimeric antigen receptors (CARs), a treatment strategy adapted from cancer immunotherapy, is investigated for possible application to combat HCMV and other infections in immunocompromised patients. The administration of CAR+ T-cells directed against HCMV antigens can bypass viral immune evasion and may complement existing treatment methods. This review gives a short overview of HCMV, the obstacles of current treatment options as well as a brief introduction to CARs and the current research situation on CAR+ T-cells against HCMV.},
author = {Bednar, Christopher and Enßer, Armin},
doi = {10.3390/v13081563},
faupublication = {yes},
journal = {Viruses},
keywords = {Adoptive T-cell therapy; Antiviral immunotherapy; Chimeric antigen receptor (CAR); Cytotoxic T-lymphocytes; Human cytomegalovirus (HCMV)},
note = {CRIS-Team Scopus Importer:2021-08-20},
peerreviewed = {Yes},
title = {{Cars}—a new perspective to hcmv treatment},
volume = {13},
year = {2021}
}
@article{faucris.210556447,
abstract = {Tripartite motif (TRIM) proteins mediate antiviral host defences by either directly targeting viral components or modulating innate immune responses. Here we identify a mechanism of antiviral restriction in which a TRIM E3 ligase controls viral replication by regulating the structure of host cell centrosomes and thereby nuclear lamina integrity. Through RNAi screening we identified several TRIM proteins, including TRIM43, that control the reactivation of Kaposi's sarcoma-associated herpesvirus. TRIM43 was distinguished by its ability to restrict a broad range of herpesviruses and its profound upregulation during herpesvirus infection as part of a germline-specific transcriptional program mediated by the transcription factor DUX4. TRIM43 ubiquitinates the centrosomal protein pericentrin, thereby targeting it for proteasomal degradation, which subsequently leads to alterations of the nuclear lamina that repress active viral chromatin states. Our study identifies a role of the TRIM43-pericentrin-lamin axis in intrinsic immunity, which may be targeted for therapeutic intervention against herpesviral infections.},
author = {Full, Florian and Van Gent, Michiel and Sparrer, Konstantin M. J. and Chiang, Cindy and Zurenski, Matthew A. and Scherer, Myriam and Brockmeyer, Norbert H. and Heinzerling, Lucie and Stürzl, Michael and Korn, Klaus and Stamminger, Thomas and Enßer, Armin and Gack, Michaela U.},
doi = {10.1038/s41564-018-0285-5},
faupublication = {yes},
journal = {Nature Microbiology},
note = {EVALuna2:35255},
pages = {164-+},
peerreviewed = {Yes},
title = {{Centrosomal} protein {TRIM43} restricts herpesvirus infection by regulating nuclear lamina integrity},
volume = {4},
year = {2019}
}
@article{faucris.280960441,
abstract = {Mutations in the spike protein of SARS-CoV-2 can lead to evasion from neutralizing antibodies and affect the efficacy of passive and active immunization strategies. Immunization of mice harboring an entire set of human immunoglobulin variable region gene segments allowed to identify nine neutralizing monoclonal antibodies, which either belong to a cluster of clonally related RBD or NTD binding antibodies. To better understand the genetic barrier to emergence of SARS-CoV-2 variants resistant to these antibodies, escape mutants were selected in cell culture to one antibody from each cluster and a combination of the two antibodies. Three independently derived escape mutants to the RBD antibody harbored mutations in the RBD at the position T478 or S477. These mutations impaired the binding of the RBD antibodies to the spike protein and conferred resistance in a pseudotype neutralization assay. Although the binding of the NTD cluster antibodies were not affected by the RBD mutations, the RBD mutations also reduced the neutralization efficacy of the NTD cluster antibodies. The mutations found in the escape variants to the NTD antibody conferred resistance to the NTD, but not to the RBD cluster antibodies. A variant resistant to both antibodies was more difficult to select and only emerged after longer passages and higher inoculation volumes. VOC carrying the same mutations as the ones identified in the escape variants were also resistant to neutralization. This study further underlines the rapid emergence of escape mutants to neutralizing monoclonal antibodies in cell culture and indicates the need for thorough investigation of escape mutations to select the most potent combination of monoclonal antibodies for clinical use.},
author = {Peter, Antonia Sophia and Grüner, Eva and Socher, Eileen and Fraedrich, Kirsten and Richel, Elie and Müller-Schmucker, Sandra and Cordsmeier, Arne and Enßer, Armin and Sticht, Heinrich and Überla, Klaus},
doi = {10.3390/ijms23158177},
faupublication = {yes},
journal = {International Journal of Molecular Sciences},
note = {CRIS-Team WoS Importer:2022-08-26},
peerreviewed = {Yes},
title = {{Characterization} of {SARS}-{CoV}-2 {Escape} {Mutants} to a {Pair} of {Neutralizing} {Antibodies} {Targeting} the {RBD} and the {NTD}},
volume = {23},
year = {2022}
}
@article{faucris.264564466,
abstract = {The ongoing pandemic coronavirus (CoV) disease 2019 (COVID-19) by severe acute respiratory syndrome CoV-2 (SARS-CoV-2) has already caused substantial morbidity, mortality, and economic devastation. Reverse genetic approaches to generate recombinant viruses are a powerful tool to characterize and understand newly emerging viruses. To contribute to the global efforts for countermeasures to control the spread of SARS-CoV-2, we developed a passage-free SARS-CoV-2 clone based on a bacterial artificial chromosome (BAC). Moreover, using a Lambda-based Red recombination, we successfully generated different reporter and marker viruses, which replicated similar to a clinical isolate in a cell culture. Moreover, we designed a full-length reporter virus encoding an additional artificial open reading frame with wild-type-like replication features. The virus-encoded reporters were successfully applied to ease antiviral testing in cell culture models. Furthermore, we designed a new marker virus encoding 3xFLAG-tagged nucleocapsid that allows the detection of incoming viral particles and, in combination with bio-orthogonal labeling for the visualization of viral RNA synthesis via click chemistry, the spatiotemporal tracking of viral replication on the single-cell level. In summary, by applying BAC-based Red recombination, we developed a powerful, reliable, and convenient platform that will facilitate studies answering numerous questions concerning the biology of SARS-CoV-2.},
author = {Herrmann, Alexandra and Jungnickl, Doris and Cordsmeier, Arne and Peter, Antonia Sophia and Überla, Klaus and Enßer, Armin},
doi = {10.3390/ijms221910188},
faupublication = {yes},
journal = {International Journal of Molecular Sciences},
keywords = {Bacterial artificial chromosome; COVID-19 pandemic; Incoming viral particles; Recombinant virus; Red recombination; Reporter virus; Reverse genetics; SARS-CoV-2},
note = {CRIS-Team Scopus Importer:2021-10-01},
peerreviewed = {Yes},
title = {{Cloning} of a passage-free {SARS}-{CoV}-2 genome and mutagenesis using red recombination},
volume = {22},
year = {2021}
}
@article{faucris.291589956,
abstract = {Foamy viruses (FVs) are naturally found in many different animals and also in primates with the notable exception of humans, but zoonotic infections are common. In several species, two different envelope (env) gene sequence clades or genotypes exist. We constructed a simian FV (SFV) clone containing a reporter gene cassette. In this background, we compared the env genes of the SFVmmu-DPZ9524 (genotype 1) and of the SFVmmu{\_}R289hybAGM (genotype 2) isolates. SFVmmu{\_}R289hybAGM env-driven infection was largely resistant to neutralization by SFVmmu-DPZ9524-neutralizing sera. While SFVmmu{\_}R289hybAGM env consistently effected higher infectivity and cell-cell fusion, we found no differences in the cell tropism conferred by either env across a range of different cells. Infection by both viruses was weakly and non-significantly enhanced by simultaneous knockout of interferon-induced transmembrane proteins (IFITMs) 1, 2, and 3 in A549 cells, irrespective of prior interferon stimulation. Infection was modestly reduced by recombinant overexpression of IFITM3, suggesting that the SFV entry step might be weakly restricted by IFITM3 under some conditions. Overall, our results suggest that the different env gene clades in macaque foamy viruses induce genotype-specific neutralizing antibodies without exhibiting overt differences in cell tropism, but individual env genes may differ significantly with regard to fitness.},
author = {Fricke, Thomas and Schlagowski, Sarah and Liu, Shanchuan and Yang, Xiaoliang and Fiebig, Uwe and Kaul, Artur and Enßer, Armin and Hahn, Alexander S.},
doi = {10.3390/v15020262},
faupublication = {yes},
journal = {Viruses},
keywords = {envelope; foamy virus; fusion; interferon-induced transmembrane proteins; virus entry},
month = {Jan},
note = {CRIS-Team Scopus Importer:2023-03-10},
peerreviewed = {Yes},
title = {{Comparison} of a {Genotype} 1 and a {Genotype} 2 {Macaque} {Foamy} {Virus} env {Gene} {Indicates} {Distinct} {Infectivity} and {Cell}-{Cell} {Fusion} but {Similar} {Tropism} and {Restriction} of {Cell} {Entry} by {Interferon}-{Induced} {Transmembrane} {Proteins}},
volume = {15},
year = {2023}
}
@article{faucris.218988789,
abstract = {The original version of this Article contained an error in the presentation of the author Armin Ensser, which was incorrectly given as Ensser Armin. The correct author list is as follows: Annemieke Smet, Koji Yahara, Mirko Rossi, Alfred Tay, Steffen Backert, Armin Ensser, James G. Fox, Bram Flahou, Richard Ducatelle, Freddy Haesebrouck, Jukka Corander The authors apologise for any inconvenience caused.},
author = {Smet, Annemieke and Yahara, Koji and Rossi, Mirko and Tay, Alfred and Backert, Steffen and Enßer, Armin and Fox, James G. and Flahou, Bram and Ducatelle, Richard and Haesebrouck, Freddy and Corander, Jukka},
doi = {10.1038/s41396-019-0380-5},
faupublication = {yes},
journal = {Isme Journal},
note = {CRIS-Team Scopus Importer:2019-05-28},
pages = {1890-1890},
peerreviewed = {unknown},
title = {{Correction}: {Macroevolution} of gastric {Helicobacter} species unveils interspecies admixture and time of divergence ({The} {ISME} {Journal}, (2018), 12, 10, (2518-2531), 10.1038/s41396-018-0199-5)},
volume = {13},
year = {2019}
}
@article{faucris.249338209,
abstract = {The HIV-1 Rev protein is a nuclear export factor for unspliced and incom-pletely spliced HIV-1 RNAs. Without Rev, these intron-retaining RNAs are trapped in the nucleus. A genome-wide screen identified nine proteins of the spliceosome, which all enhanced expression from the HIV-1 unspliced RNA after CRISPR/Cas knockdown. Depletion of DHX38, WDR70, and four proteins of the Prp19-associated complex (ISY1, BUD31, XAB2, and CRNKL1) resulted in a more than 20-fold enhancement of unspliced HIV-1 RNA levels in the cytoplasm. Targeting of CRNKL1, DHX38, and BUD31 affected nuclear export efficiencies of the HIV-1 unspliced RNA to a much larger extent than splicing. Transcriptomic analyses further revealed that CRNKL1 also suppresses cyto-plasmic levels of a subset of cellular mRNAs, including some with selectively retained introns. Thus, CRNKL1-dependent nuclear retention is a novel cellular mechanism for the regulation of cytoplasmic levels of intron-retaining HIV-1 mRNAs, which HIV-1 may have harnessed to direct its complex splicing pattern. IMPORTANCE To regulate its complex splicing pattern, HIV-1 uses the adaptor protein Rev to shuttle unspliced or partially spliced mRNA from the nucleus to the cyto-plasm. In the absence of Rev, these RNAs are retained in the nucleus, but it is unclear why. Here we identify cellular proteins whose depletion enhances cytoplas-mic levels of the HIV-1 unspliced RNA. Depletion of one of them, CRNKL1, also increases cytoplasmic levels of a subset of intron-retaining cellular mRNA, suggesting that CRNKL1-dependent nuclear retention may be a basic cellular mechanism exploited by HIV-1.},
author = {Xiao, Han and Wyler, Emanuel and Milek, Miha and Grewe, Bastian and Kirchner, Philipp and Ekici, Arif Bülent and Silva, Ana Beatriz Oliveira Villela and Jungnickl, Doris and Full, Florian and Thomas, Marco and Landthaler, Markus and Enßer, Armin and Überla, Klaus},
doi = {10.1128/mBio.02525-20},
faupublication = {yes},
journal = {mBio},
keywords = {Association; CRNKL1; Human immunodeficiency virus; Intron-retaining RNA; Nuclear retention; RNA splicing},
month = {Jan},
note = {CRIS-Team Scopus Importer:2021-02-12},
pages = {1-24},
peerreviewed = {Yes},
title = {{Crnkl1} is a highly selective regulator of intron-retaining {HIV}-1 and cellular mrnas},
volume = {12},
year = {2021}
}
@article{faucris.109472924,
abstract = {In order to explore the potential of HLA-independent T cell therapy for human cytomegalovirus (HCMV) infections, we developed a chimeric antigen receptor (CAR) directed against the HCMV encoded glycoprotein B (gB), which is expressed at high levels on the surface of infected cells. T cells engineered with this anti-gB CAR recognized HCMV-infected cells and released cytokines and cytotoxic granules. Unexpectedly, and in contrast to analogous approaches for HIV, Hepatitis B or Hepatitis C virus, we found that HCMV-infected cells were resistant to killing by the CAR-modified T cells. In order to elucidate whether this phenomenon was restricted to the use of CARs, we extended our experiments to T cell receptor (TCR)-mediated recognition of infected cells. To this end we infected fibroblasts with HCMV-strains deficient in viral inhibitors of antigenic peptide presentation and targeted these HLA-class I expressing peptide-loaded infected cells with peptide-specific cytotoxic T cells (CTLs). Despite strong degranulation and cytokine production by the T cells, we again found significant inhibition of lysis of HCMV-infected cells. Impairment of cell lysis became detectable 1 day after HCMV infection and gradually increased during the following 3 days. We thus postulate that viral anti-apoptotic factors, known to inhibit suicide of infected host cells, have evolved additional functions to directly abrogate T cell cytotoxicity. In line with this hypothesis, CAR-T cell cytotoxicity was strongly inhibited in non-infected fibroblasts by expression of the HCMV-protein UL37x1, and even more so by additional expression of UL36. Our data extend the current knowledge on Betaherpesviral evasion from T cell immunity and show for the first time that, beyond impaired antigen presentation, infected cells are efficiently protected by direct blockade of cytotoxic effector functions through viral proteins.},
author = {Proff, Julia and Walterskirchen, Christian and Brey, Charlotte and Geyeregger, Rene and Full, Florian and Enßer, Armin and Lehner, Manfred and Holter, Wolfgang},
doi = {10.3389/fmicb.2016.00844},
faupublication = {yes},
journal = {Frontiers in Microbiology},
note = {EVALuna2:8321},
pages = {844},
peerreviewed = {unknown},
title = {{Cytomegalovirus}-{Infected} {Cells} {Resist} {T} {Cell} {Mediated} {Killing} in an {HLA}-{Recognition} {Independent} {Manner}},
volume = {7},
year = {2016}
}
@article{faucris.228293891,
abstract = {Herpesviruses are important pathogens that can cause significant morbidity and mortality in the human population. Herpesviruses have a double-stranded DNA genome, and viral genome replication takes place inside the nucleus. Upon entering the nucleus, herpesviruses have to overcome the obstacle of cellular proteins in order to enable viral gene expression and genome replication. In this review, we want to highlight cellular proteins that sense incoming viral genomes of the DNA-damage repair (DDR) pathway and of PML-nuclear bodies (PML-NBs) that all can act as antiviral restriction factors within the first hours after the viral genome is released into the nucleus. We show the function and significance of both nuclear DNA sensors, the DDR and PML-NBs, and demonstrate for three human herpesviruses of the alpha-, beta- and gamma-subfamilies, HSV-1, HCMV and KSHV respectively, how viral tegument proteins antagonize these pathways.},
author = {Full, Florian and Enßer, Armin},
doi = {10.3390/jcm8091408},
faupublication = {yes},
journal = {Journal of Clinical Medicine},
note = {CRIS-Team WoS Importer:2019-10-25},
peerreviewed = {Yes},
title = {{Early} {Nuclear} {Events} after {Herpesviral} {Infection}},
volume = {8},
year = {2019}
}
@article{faucris.118005404,
author = {Vogel, Benjamin and Tennert, K. and Full, F. and Enßer, Armin},
doi = {10.1038/leu.2013.188},
faupublication = {yes},
journal = {Leukemia},
note = {EVALuna2:8207},
pages = {192-5},
peerreviewed = {Yes},
title = {{Efficient} generation of human natural killer cell lines by viral transformation},
volume = {28},
year = {2014}
}
@article{faucris.274473001,
author = {Meier, H. and Bauer, C. and Finkenzeller, W. and Nentwich, J. and Städt, M. and Steininger, Philipp and Korn, Klaus and Enßer, Armin and Erbguth, F.},
doi = {10.1007/s00115-022-01281-7},
faupublication = {yes},
journal = {Der Nervenarzt},
note = {CRIS-Team Scopus Importer:2022-05-06},
peerreviewed = {Yes},
title = {{Erratum} to: {Bornavirus} encephalitis as a differential diagnosis to seronegative autoimmune encephalitis ({Der} {Nervenarzt}, (2022), 10.1007/s00115-021-01259-x) {Erratum} zu: {Die} {Borna}-{Virus}-{Enzephalitis} als {Differenzialdiagnose} zur seronegativen {Autoimmunenzephalitis} ({Der} {Nervenarzt}, (2022), 10.1007/s00115-021-01259-x)},
year = {2022}
}
@article{faucris.208677431,
author = {Korn, Klaus and Coras, Roland and Bobinger, Tobias and Herzog, Sibylle M. and Lücking, Hannes and Stoehr, Roland and Huttner, Hagen and Hartmann, Arndt and Enßer, Armin},
doi = {10.1056/NEJMc1800724},
faupublication = {yes},
journal = {New England Journal of Medicine},
note = {EVALuna2:34851},
pages = {1375-1377},
peerreviewed = {Yes},
title = {{Fatal} {Encephalitis} {Associated} with {Borna} {Disease} {Virus} 1},
volume = {379},
year = {2018}
}
@article{faucris.205207197,
abstract = {Gammaherpesviruses like Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) subvert the ubiquitin proteasome system for their own benefit in order to facilitate viral gene expression and replication. In particular, viral tegument proteins that share sequence homology to the formylglycineamide ribonucleotide amidotransferase (FGARAT, or PFAS), an enzyme in the cellular purine biosynthesis, are important for disrupting the intrinsic antiviral response associated with Promyelocytic Leukemia (PML) protein-associated nuclear bodies (PML-NBs) by proteasome-dependent and independent mechanisms. In addition, all herpesviruses encode for a potent ubiquitin protease that can efficiently remove ubiquitin chains from proteins and thereby interfere with several different cellular pathways. In this review, we discuss mechanisms and functional consequences of virus-induced ubiquitination and deubiquitination for early events in gammaherpesviral infection.},
author = {Full, Florian and Hahn, Alexander S. and Grosskopf, Anna K. and Enßer, Armin},
doi = {10.3390/v9100308},
faupublication = {yes},
journal = {Viruses},
note = {EVALuna2:33753},
peerreviewed = {Yes},
title = {{Gammaherpesviral} {Tegument} {Proteins}, {PML}-{Nuclear} {Bodies} and the {Ubiquitin}-{Proteasome} {System}},
volume = {9},
year = {2017}
}
@article{faucris.211692286,
abstract = {The complete genome sequence of the alcelaphine gammaherpesvirus 1 (AIHV-1) attenuated laboratory strain WC11 was determined from purified virion DNA. The viral light DNA (L-DNA) genome of 127,215 bp is mostly conserved compared to the pathogenic strain C500; however, 3.3 kb is deleted in two regions, affecting 4 of 10 AIHV-1-specific open reading frames.
},
author = {Enßer, Armin},
doi = {10.1128/genomeA.01219-17},
faupublication = {yes},
journal = {Genome Announcements},
note = {EVALuna2:35814},
peerreviewed = {Yes},
title = {{Genome} {Sequence} of the {Alcelaphine} {Gammaherpesvirus} 1 {Attenuated} {Laboratory} {Strain} {WC11}},
volume = {5},
year = {2017}
}
@article{faucris.312955078,
abstract = {Neutralizing antibodies targeting HIV-1 Env have been shown to protect from systemic infection. To explore whether these antibodies can inhibit infection of the first cells, challenge viruses based on simian immunodeficiency virus (SIV) were developed that use HIV-1 Env for entry into target cells during the first replication cycle, but then switch to SIV Env usage. Antibodies binding to Env of HIV-1, but not SIV, block HIV-1 Env-mediated infection events after rectal exposure of non-human primates to the switching challenge virus. After natural exposure to HIV-1, such a reduction of the number of first infection events should be sufficient to provide sterilizing immunity in the strictest sense in most of the exposed individuals. Since blocking infection of the first cells avoids the formation of latently infected cells and reduces the risk of emergence of antibody-resistant mutants, it may be the best mode of protection.},
author = {Stab, Viktoria and Stahl-Hennig, Christiane and Enßer, Armin and Richel, Elie and Fraedrich, Kirsten and Sauermann, Ulrike and Tippler, Bettina and Klein, Florian and Burton, Dennis R. and Tenbusch, Matthias and Überla, Klaus},
doi = {10.1016/j.xcrm.2023.101201},
faupublication = {yes},
journal = {Cell Reports Medicine},
keywords = {AIDS; Fc-effector function; HIV; mucosal immunity; neutralizing antibody; sterilizing immunity},
note = {CRIS-Team Scopus Importer:2023-10-20},
peerreviewed = {Yes},
title = {{HIV}-1 neutralizing antibodies provide sterilizing immunity by blocking infection of the first cells},
volume = {4},
year = {2023}
}
@article{faucris.123948704,
author = {Ott, Lisa and Scholz, Brigitte and Höller, Martina and Hasselt, Kristin and Enßer, Armin and Burkovski, Andreas},
doi = {10.1099/mic.0.061879-0},
faupublication = {yes},
journal = {Microbiology},
pages = {126-135},
peerreviewed = {Yes},
title = {{Induction} of the {NF}-kb signal transduction pathway in response to {Corynebacterium} diphtheriae infection},
volume = {159},
year = {2013}
}
@article{faucris.207767219,
author = {Bartenhagen, Christoph and Fischer, Ute and Korn, Klaus and Pfister, Stefan M. and Gombert, Michael and Chen, Cai and Okpanyi, Vera and Hauer, Julia and Rinaldi, Anna and Bourquin, Jean-Pierre and Eckert, Cornelia and Hu, Jianda and Enßer, Armin and Dugas, Martin and Borkhardt, Arndt},
doi = {10.3324/haematol.2016.155382},
faupublication = {yes},
journal = {Haematologica},
note = {EVALuna2:33763},
pages = {e179-e183},
peerreviewed = {No},
title = {{Infection} as a cause of childhood leukemia: virus detection employing whole genome sequencing},
volume = {102},
year = {2017}
}
@article{faucris.211683207,
abstract = {SFVmmu-DPZ9524 represents the third completely sequenced rhesus macaque simian foamy virus (SFV) isolate, alongside SFVmmu{\_}K3T with a similar SFV-1-type env, and R289HybAGM with a SFV-2-like env. Sequence analysis demonstrates that, in gag and pol, SFVmmu-DPZ9524 is more closely related to R289HybAGM than to SFVmmu{\_}K3T, which, outside of env, is more similar to a Japanese macaque isolate than to the other two rhesus macaque isolates SFVmmu-DPZ9524 and R289HybAGM. Further, we identify bel as another recombinant locus in R289HybAGM, confirming that recombination contributes to sequence diversity in SFV.
},
author = {Enßer, Armin and Grosskopf, Anna K. and Maetz-Rensing, Kerstin and Roos, Christian and Hahn, Alexander S.},
doi = {10.1007/s00705-018-3892-9},
faupublication = {yes},
journal = {Archives of Virology},
note = {EVALuna2:35813},
pages = {2507-2512},
peerreviewed = {Yes},
title = {{Isolation} and sequence analysis of a novel rhesus macaque foamy virus isolate with a serotype-1-like env},
volume = {163},
year = {2018}
}
@article{faucris.314054893,
abstract = {Kaposi’s sarcoma-associated herpesvirus (KSHV) is associated with Kaposi’s sarcoma and B cell malignancies. K8.1, the major antigenic component of the KSHV virion, has been reported to play a critical role in the infection of B cells, but otherwise its function remains enigmatic. We created a K8.1 knockout virus (KSHVΔK8.1) in the BAC16 genetic background and analyzed its infectivity on a range of adherent cells. We observed a strong defect on several epithelial cells, such as the HaCaT keratinocyte cell line, human embryonic kidney (HEK) 293T, and A549 lung epithelial cells. However, we did not observe such a defect in other cells, including lymphatic and blood endothelial cells. Mechanistically, we found that reduced infectivity of the K8.1 knockout virus correlated with reduced attachment to HaCaT cells. The defect in infectivity of KSHVΔK8.1 could be rescued by complementation through expression of K8.1 in KSHVΔK8.1 producing cells by means of a lentiviral vector. In a coculture infection model with iSLK producer cells, KSHVΔK8.1 was highly efficient at infecting the BJAB B cell line but was significantly impaired at infecting the MC116 B cell line, in line with a previous report. In fusion assays together with the gH/gL glycoprotein complex and gB, the components of the conserved herpesviral core fusion machinery, we did not observe activation of membrane fusion by K8.1 or its R8.1 homolog of the rhesus monkey rhadinovirus. In summary, we found K8.1 to function in a highly cell-specific manner during KSHV entry at the attachment step, playing an important role in the infection of epithelial cells. IMPORTANCE Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of several B cell malignancies and Kaposi’s sarcoma. We analyzed the function of K8.1, the major antigenic component of the KSHV virion in the infection of different cells. To do this, we deleted K8.1 from the viral genome. It was found that K8.1 is critical for the infection of certain epithelial cells, e.g., a skin model cell line but not for infection of many other cells. K8.1 was found to mediate attachment of the virus to cells where it plays a role in infection. In contrast, we did not find K8.1 or a related protein from a closely related monkey virus to activate fusion of the viral and cellular membranes, at least not under the conditions tested. These findings suggest that K8.1 functions in a highly cell-specific manner during KSHV entry, playing a crucial role in the attachment of KSHV to, e.g., skin epithelial cells.},
author = {Liu, Shanchuan and Großkopf, Anna K. and Yang, Xiaoliang and Mannheim, Maximilian E. and Backovic, Marija and Scribano, Stefano and Schlagowski, Sarah and Enßer, Armin and Hahn, Alexander S.},
doi = {10.1128/jvi.00832-23},
faupublication = {yes},
journal = {Journal of Virology},
keywords = {attachment; entry; glycoproteins; Kaposi's sarcoma; Kaposi's sarcoma-associated herpesvirus; KSHV; virus},
note = {CRIS-Team Scopus Importer:2023-11-17},
peerreviewed = {Yes},
title = {{Kaposi}’s sarcoma-associated herpesvirus glycoprotein {K8}.1 is critical for infection in a cell-specific manner and functions at the attachment step on keratinocytes},
volume = {97},
year = {2023}
}
@article{faucris.111519804,
abstract = {The downregulation of immune synapse components such as major histocompatibility complex class I (MHC-I) and ICAM-1 is a common viral immune evasion strategy that protects infected cells from targeted elimination by cytolytic effector functions of the immune system. Kaposi's sarcoma-associated herpesvirus (KSHV) encodes two membrane-bound ubiquitin E3 ligases, called K3 and K5, which share the ability to induce internalization and degradation of MHC-I molecules. Although individual functions of K3 and K5 outside the viral genome are well characterized, their roles during the KSHV life cycle are still unclear. In this study, we individually introduced the amino acid-coding sequences of K3 or K5 into a ?K3 ?K5 recombinant virus, at either original or interchanged genomic positions. Recombinants harboring coding sequences within the K5 locus showed higher K3 and K5 protein expression levels and more rapid surface receptor downregulation than cognate recombinants in which coding sequences were introduced into the K3 locus. To identify infected cells undergoing K3-mediated downregulation of MHC-I, we employed a novel reporter virus, called red-green-blue-BAC16 (RGB-BAC16), which was engineered to harbor three fluorescent protein expression cassettes: EF1?-monomeric red fluorescent protein 1 (mRFP1), polyadenylated nuclear RNA promoter (pPAN)-enhanced green fluorescent protein (EGFP), and pK8.1-monomeric blue fluorescent protein (tagBFP), marking latent, immediate early, and late viral gene expression, respectively. Analysis of RGB-derived K3 and K5 deletion mutants showed that while the K5-mediated downregulation of MHC-I was concomitant with pPAN induction, the reduction of MHC-I surface expression by K3 was evident in cells that were enriched for pPAN-driven EGFP(high) and pK8.1-driven blue fluorescent protein-positive (BFP(+)) populations. These data support the notion that immunoreceptor downregulation occurs by a sequential process wherein K5 is critical during the immediately early phase and K3 plays a significant role during later stages.Although the roles of K3 and K5 outside the viral genome are well characterized, the function of these proteins in the context of the KSHV life cycle has remained unclear, particularly in the case of K3. This study examined the relative contributions of K3 and K5 to the downregulation of MHC-I during the lytic replication of KSHV. We show that while K5 acts immediately upon entry into the lytic phase, K3-mediated downregulation of MHC-I was evident during later stages of lytic replication. The identification of distinctly timed K3 and K5 activities significantly advances our understanding of KSHV-mediated immune evasion. Crucial to this study was the development of a novel recombinant KSHV, called RGB-BAC16, which facilitated the delineation of stage-specific phenotypes.},
author = {Brulois, Kevin and Toth, Zsolt and Wong, Lai-Yee and Feng, Pinghui and Gao, Shou-Jiang and Enßer, Armin and Jung, Jae U.},
doi = {10.1128/JVI.00873-14},
faupublication = {yes},
journal = {Journal of Virology},
note = {EVALuna2:8234},
pages = {9335-49},
peerreviewed = {Yes},
title = {{Kaposi}'s sarcoma-associated herpesvirus {K3} and {K5} ubiquitin {E3} ligases have stage-specific immune evasion roles during lytic replication},
volume = {88},
year = {2014}
}
@article{faucris.107453324,
abstract = {Nuclear domain 10 (ND10) components are restriction factors that inhibit herpesviral replication. Effector proteins of different herpesviruses can antagonize this restriction by a variety of strategies, including degradation or relocalization of ND10 proteins. We investigated the interplay of Kaposi's Sarcoma-Associated Herpesvirus (KSHV) infection and cellular defense by nuclear domain 10 (ND10) components. Knock-down experiments in primary human cells show that KSHV-infection is restricted by the ND10 components PML and Sp100, but not by ATRX. After KSHV infection, ATRX is efficiently depleted and Daxx is dispersed from ND10, indicating that these two ND10 components can be antagonized by KSHV. We then identified the ORF75 tegument protein of KSHV as the viral factor that induces the disappearance of ATRX and relocalization of Daxx. ORF75 belongs to a viral protein family (viral FGARATs) that has homologous proteins in all gamma-herpesviruses. Isolated expression of ORF75 in primary cells induces a relocalization of PML and dispersal of Sp100, indicating that this viral effector protein is able to influence multiple ND10 components. Moreover, by constructing a KSHV mutant harboring a stop codon at the beginning of ORF75, we could demonstrate that ORF75 is absolutely essential for viral replication and the initiation of viral immediate-early gene expression. Using recombinant viruses either carrying Flag- or YFP-tagged variants of ORF75, we could further corroborate the role of ORF75 in the antagonization of ND10-mediated intrinsic immunity, and show that it is independent of the PML antagonist vIRF3. Members of the viral FGARAT family target different ND10 components, suggesting that the ND10 targets of viral FGARAT proteins have diversified during evolution. We assume that overcoming ND10 intrinsic defense constitutes a critical event in the replication of all herpesviruses; on the other hand, restriction of herpesviral replication by ND10 components may also promote latency as the default outcome of infection.},
author = {Full, Florian and Jungnickl, Doris and Reuter, Nina and Bogner, Elke and Brulois, Kevin and Scholz, Brigitte and Stürzl, Michael and Myoung, Jinjong and Jung, Jae U. and Stamminger, Thomas and Enßer, Armin},
doi = {10.1371/journal.ppat.1003863},
faupublication = {yes},
journal = {PLoS Pathogens},
note = {EVALuna2:8222},
pages = {e1003863},
peerreviewed = {Yes},
title = {{Kaposi}'s sarcoma associated herpesvirus tegument protein {ORF75} is essential for viral lytic replication and plays a critical role in the antagonization of {ND10}-instituted intrinsic immunity},
volume = {10},
year = {2014}
}
@article{faucris.211803507,
abstract = {Since the discovery of the human pathogen Helicobacter pylori, various other Helicobacter species have been identified in the stomach of domesticated and wild mammals. To better understand the evolutionary history of these ecologically similar but genetically distinct species, we analyzed 108 gastric Helicobacter genomes and included 54 enterohepatic Helicobacter genomes for comparison purposes. An admixture analysis supported the presence of an ecological barrier, preventing the genetic exchange between the gastric and enterohepatic Helicobacter species, and unraveled many gene flow events within and across species residing in the stomach. As pets can be colonized by multiple gastric Helicobacter species, the genetic exchange between the canine and feline strains was evident, with H. heilmannii and H. bizzozeronii showing the highest interspecies recombination. An admixture between H. pylori (in particular, the ancestral African strains), H. acinonychis from wild felines and H. cetorum from marine mammals was also identified. Because these latter species do not share the same host, this phenomenon is most likely a remaining signal of shared ancestry. A reconstruction of the time of divergence of the gastric Helicobacter spp. revealed that the domestic animal-related Helicobacter species evolved in parallel with H. pylori and its two closest relatives (H. acinonychis and H. cetorum), rather than together.},
author = {Smet, Annemieke and Yahara, Koji and Rossi, Mirko and Tay, Alfred and Backert, Steffen and Enßer, Armin and Fox, James G. and Flahou, Bram and Ducatelle, Richard and Haesebrouck, Freddy and Corander, Jukka},
doi = {10.1038/s41396-018-0199-5},
faupublication = {yes},
journal = {Isme Journal},
note = {EVALuna2:35812},
pages = {2518-2531},
peerreviewed = {Yes},
title = {{Macroevolution} of gastric {Helicobacter} species unveils interspecies admixture and time of divergence},
volume = {12},
year = {2018}
}
@article{faucris.234698617,
author = {Smet, Annemieke and Yahara, Koji and Rossi, Mirko and Tay, Alfred and Backert, Steffen and Enßer, Armin and Fox, James G. and Flahou, Bram and Ducatelle, Richard and Haesebrouck, Freddy and Corander, Jukka},
doi = {10.1038/s41396-019-0380-5},
faupublication = {yes},
journal = {Isme Journal},
pages = {1890-1890},
peerreviewed = {Yes},
title = {{Macroevolution} of gastric {Helicobacter} species unveils interspecies admixture and time of divergence (vol 12, pg 2518, 2018)},
volume = {13},
year = {2019}
}
@article{faucris.263729786,
abstract = {Currently, human infections with the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) are accelerating the ongoing spread of the pandemic. Several innovative types of vaccines have already been developed, whereas effective options of antiviral treatments still await a scientific implementation. The development of novel anti-SARS-CoV-2 drug candidates demands skillful strategies and analysis systems. Promising results have been achieved with first generation direct-acting antivirals targeting the viral polymerase RdRp or the protease 3CLpro . Such recently approved or investigational drugs like remdesivir and GC376 represent a basis for further development and optimization. Here, we establish a multi-readout assay (MRA) system that enables the antiviral assessment and mechanistic characterization of novel test compounds, drug repurposing and combination treatments. Our SARS-CoV-2-specific MRA combines the quantitative measurement of several parameters of virus infection, such as the intracellular production of proteins and genomes, enzymatic activities and virion release, as well as the use of reporter systems. In this regard, the antiviral efficacy of remdesivir and GC376 has been investigated in human Caco-2 cells. The readouts included the use of spike-and double-strand RNA-specific monoclonal antibodies for in-cell fluorescence imaging, a newly generated recombinant SARS-CoV-2 reporter virus d6YFP, the novel 3CLpro-based FRET CFP::YFP and the previously reported FlipGFP reporter assays, as well as viral genome-specific RT-qPCR. The data produced by our MRA confirm the high antiviral potency of these two drugs in vitro. Combined, this MRA approach may be applied for broader analyses of SARS-CoV-2-specific antivirals, including compound screenings and the characterization of selected drug candidates.},
author = {Hahn, Friedrich and Häge, Sigrun and Herrmann, Alexandra and Wangen, Christina and Kicuntod, Jintawee and Jungnickl, Doris and Tillmanns, Julia and Müller, Regina and Fraedrich, Kirsten and Überla, Klaus and Kohlhof, Hella and Enßer, Armin and Marschall, Manfred},
doi = {10.3390/pathogens10091076},
faupublication = {yes},
journal = {Pathogens},
keywords = {Anti-coronaviral treatment; Antiviral drug assessment; Candidate drugs; COVID-19 pandemic; Cultured human cells; Methodological development; Multi-readout assay (MRA); SARS-CoV-2 infection},
note = {CRIS-Team Scopus Importer:2021-09-10},
peerreviewed = {Yes},
title = {{Methodological} development of a multi-readout assay for the assessment of antiviral drugs against sars-cov-2},
volume = {10},
year = {2021}
}
@article{faucris.237818828,
abstract = {Objectives: Brain abscesses lead to high mortality despite antibiotic and surgical treatment. Identification of causative bacteria is important to guide antibiotic therapy, but culture-based methods and molecular diagnostics by Sanger sequencing of 16S PCR products are hampered by antibiotic treatment and the often polymicrobial nature of brain abscesses. We have applied 16S-rRNA-based next-generation sequencing (NGS) for metagenomic analysis of intracranial abscess (brain and epidural) and meningitis samples. Methods: Seventy-nine samples from 54 patients with intracranial abscesses or meningitis were included. DNA was subjected to 16S PCR. Amplicons were analysed with the Illumina MiSeq system, sequence reads were blasted versus the NCBI 16S bacterial database and analysed using MEGAN software. Results were compared to those of gram-staining, culture and Sanger sequencing. Results: The NGS workflow was successful for 51 intracranial abscesses (46 brain and five epidural) and nine meningitis samples. Inclusion of (mono)bacterial meningitis samples allowed us to establish a cut-off criterion for the exclusion of contaminating sequences. In total 86 bacterial taxa were identified in brain abscesses by NGS, with Streptococcus intermedius and Fusobacterium nucleatum as most prevalent species; Propionibacterium and Staphylococcus spp. were associated with epidural abscesses. NGS identified two or more bacterial taxa in 31/51 intracranial abscesses, revealing the polymicrobial nature of these infections and allowing the discrimination of up to 16 bacterial taxa per sample. Conclusion: These results extend earlier studies showing that NGS methods expand the spectrum of bacteria detected in brain abscesses and demonstrate that the MiSeq platform is suitable for metagenomic diagnostics of this severe infection.},
author = {Stebner, Alexander and Enßer, Armin and Geißdörfer, Walter and Bozhkov, Yavor and Lang, Roland},
doi = {10.1016/j.cmi.2020.03.028},
faupublication = {yes},
journal = {Clinical Microbiology and Infection},
keywords = {16S rDNA; Brain abscess; Metagenome; Next-generation sequencing; Polymicrobial infection},
note = {CRIS-Team Scopus Importer:2020-04-28},
peerreviewed = {Yes},
title = {{Molecular} diagnosis of polymicrobial brain abscesses with {16S}-{rDNA}-based next-generation sequencing},
year = {2020}
}
@article{faucris.284510110,
abstract = {Methylation of the mRNA 5′ cap by cellular methyltransferases enables efficient translation and avoids recognition by innate immune factors. Coronaviruses encode viral 2′-O-methyltransferases to shield their RNA from host factors. Here, we generate recombinant SARS–CoV-2 harboring a catalytically inactive 2′-O-methyltransferase Nsp16, Nsp16mut, and analyze viral replication in human lung epithelial cells. Although replication is only slightly attenuated, we find SARS–CoV-2 Nsp16mut to be highly immunogenic, resulting in a strongly enhanced release of type I interferon upon infection. The elevated immunogenicity of Nsp16mut is absent in cells lacking the RNA sensor MDA5. In addition, we report that Nsp16mut is highly sensitive to type I IFN treatment and demonstrate that this strong antiviral effect of type I IFN is mediated by the restriction factor IFIT1. Together, we describe a dual role for the 2′-O-methyltransferase Nsp16 during SARS–CoV-2 replication in avoiding efficient recognition by MDA5 and in shielding its RNA from interferon-induced antiviral responses, thereby identifying Nsp16 as a promising target for generating attenuated and highly immunogenic SARS–CoV-2 strains and as a potential candidate for therapeutic intervention.},
author = {Ruß, Alina and Wittmann, Sabine and Tsukamoto, Yuta and Herrmann, Alexandra and Deutschmann, Janina and Lagisquet, Justine and Enßer, Armin and Kato, Hiroki and Gramberg, Thomas},
doi = {10.15252/embr.202255648},
faupublication = {yes},
journal = {EMBO Reports},
keywords = {2′-O-methyltransferase; IFIT1; MDA5; Nsp16; SARS–CoV-2},
note = {CRIS-Team Scopus Importer:2022-11-04},
pages = {e55648},
peerreviewed = {Yes},
title = {{Nsp16} shields {SARS}–{CoV}-2 from efficient {MDA5} sensing and {IFIT1}-mediated restriction},
volume = {23},
year = {2022}
}
@article{faucris.313477188,
abstract = {Most SARS-CoV-2 proteins are translated from subgenomic RNAs (sgRNAs). While the majority of these sgRNAs are monocistronic, some viral mRNAs encode more than one protein. One example is the ORF3a sgRNA that also encodes ORF3c, an enigmatic 41-amino-acid peptide. Here, we show that ORF3c is expressed in SARS-CoV-2-infected cells and suppresses RIG-I- and MDA5-mediated IFN-β induction. ORF3c interacts with the signaling adaptor MAVS, induces its C-terminal cleavage, and inhibits the interaction of RIG-I with MAVS. The immunosuppressive activity of ORF3c is conserved among members of the subgenus sarbecovirus, including SARS-CoV and coronaviruses isolated from bats. Notably, however, the SARS-CoV-2 delta and kappa variants harbor premature stop codons in ORF3c, demonstrating that this reading frame is not essential for efficient viral replication in vivo and is likely compensated by other viral proteins. In agreement with this, disruption of ORF3c does not significantly affect SARS-CoV-2 replication in CaCo-2, CaLu-3, or Rhinolophus alcyone cells. In summary, we here identify ORF3c as an immune evasion factor of SARS-CoV-2 that suppresses innate sensing in infected cells.},
author = {Müller, Martin and Herrmann, Alexandra and Fujita, Shigeru and Uriu, Keiya and Kruth, Carolin and Strange, Adam and Kolberg, Jan E. and Schneider, Markus and Ito, Jumpei and Müller, Marcel A. and Drosten, Christian and Enßer, Armin and Sato, Kei and Sauter, Daniel},
doi = {10.15252/embr.202357137},
faupublication = {yes},
journal = {EMBO Reports},
keywords = {cryptic open reading frames; IFN antagonist; immune evasion; ORF3c; SARS-CoV-2},
note = {CRIS-Team Scopus Importer:2023-11-03},
peerreviewed = {Yes},
title = {{ORF3c} is expressed in {SARS}-{CoV}-2-infected cells and inhibits innate sensing by targeting {MAVS}},
year = {2023}
}
@article{faucris.252986798,
author = {Steininger, Philipp and Seifert, Frank and Balk, Stefanie and Kuramatsu, Joji and Kremer, Andreas and Coras, Roland and Engelhorn, Tobias and Maier, Clara and Tenbusch, Matthias and Korn, Klaus and Enßer, Armin},
doi = {10.1212/WNL.0000000000011357},
faupublication = {yes},
journal = {Neurology},
note = {CRIS-Team Scopus Importer:2021-03-26},
pages = {496-499},
peerreviewed = {Yes},
title = {{Pearls} & {Oy}-sters: {SARS}-{CoV}-2 {Infection} of the {CNS} in a {Patient} {With} {Meningeosis} {Carcinomatosa}},
volume = {96},
year = {2021}
}
@article{faucris.255365545,
abstract = {The rhesus monkey rhadinovirus (RRV), a gamma 2-herpesvirus of rhesus macaques, shares many biological features with the human pathogenic Kaposi's sarcoma-associated herpesvirus (KSHV). Both viruses, as well as the more distantly related Epstein-Barr virus, engage cellular receptors from the Eph family of receptor tyrosine kinases (Ephs). However, the importance of the Eph interaction for RRV entry varies between cell types suggesting the existence of Eph-independent entry pathways. We therefore aimed to identify additional cellular receptors for RRV by affinity enrichment and mass spectrometry. We identified an additional receptor family, the Plexin domain containing proteins 1 and 2 (Plxdc1/2) that bind the RRV gH/gL glycoprotein complex. Preincubation of RRV with soluble Plxdc2 decoy receptor reduced infection by similar to 60%, while overexpression of Plxdc1 and 2 dramatically enhanced RRV susceptibility and cell-cell fusion of otherwise marginally permissive Raji cells. While the Plxdc2 interaction is conserved between two RRV strains, 26-95 and 17577, Plxdc1 specifically interacts with RRV 26-95 gH. The Plxdc interaction is mediated by a short motif at the N-terminus of RRV gH that is partially conserved between isolate 26-95 and isolate 17577, but absent in KSHV gH. Mutation of this motif abrogated the interaction with Plxdc1/2 and reduced RRV infection in a cell type-specific manner. Taken together, our findings characterize Plxdc1/2 as novel interaction partners and entry receptors for RRV and support the concept of the N-terminal domain of the gammaherpesviral gH/gL complex as a multifunctional receptor-binding domain. Further, Plxdc1/2 usage defines an important biological difference between KSHV and RRV.},
author = {Grosskopf, Anna K. and Schlagowski, Sarah and Fricke, Thomas and Enßer, Armin and Desrosiers, Ronald C. and Hahn, Alexander S.},
doi = {10.1371/journal.ppat.1008979},
faupublication = {yes},
journal = {PLoS Pathogens},
note = {CRIS-Team WoS Importer:2021-04-16},
peerreviewed = {Yes},
title = {{Plxdc} family members are novel receptors for the rhesus monkey rhadinovirus ({RRV})},
volume = {17},
year = {2021}
}
@article{faucris.267063908,
abstract = {Several effective SARS-CoV-2 vaccines are currently in use, but effective boosters are needed to maintain or increase immunity due to waning responses and the emergence of novel variants. Here we report that intranasal vaccinations with adenovirus 5 and 19a vectored vaccines following a systemic plasmid DNA or mRNA priming result in systemic and mucosal immunity in mice. In contrast to two intramuscular applications of an mRNA vaccine, intranasal boosts with adenoviral vectors induce high levels of mucosal IgA and lung-resident memory T cells (TRM); mucosal neutralization of virus variants of concern is also enhanced. The mRNA prime provokes a comprehensive T cell response consisting of circulating and lung TRM after the boost, while the plasmid DNA prime induces mostly mucosal T cells. Concomitantly, the intranasal boost strategies lead to complete protection against a SARS-CoV-2 infection in mice. Our data thus suggest that mucosal booster immunizations after mRNA priming is a promising approach to establish mucosal immunity in addition to systemic responses.},
author = {Lapuente, Dennis and Fuchs, Jana and Willar, Jonas and Vieira Antao, Ana Isabel and Eberlein, Valentina and Uhlig, Nadja and Issmail, Leila and Schmidt, Anna and Oltmanns, Friederike and Peter, Antonia Sophia and Müller-Schmucker, Sandra and Irrgang, Pascal and Fraedrich, Kirsten and Cara, Andrea and Hoffmann, Markus and Poehlmann, Stefan and Enßer, Armin and Pertl, Cordula and Willert, Torsten and Thirion, Christian and Grunwald, Thomas and Überla, Klaus and Tenbusch, Matthias},
doi = {10.1038/s41467-021-27063-4},
faupublication = {yes},
journal = {Nature Communications},
note = {CRIS-Team Scopus Importer:2021-12-10},
peerreviewed = {Yes},
title = {{Protective} mucosal immunity against {SARS}-{CoV}-2 after heterologous systemic prime-mucosal boost immunization},
volume = {12},
year = {2021}
}
@inproceedings{faucris.288302469,
address = {HOBOKEN},
author = {Lapuente, Dennis and Fuchs, Julian and Willar, J. and Antao, A. and Eberlein, V. and Uhlig, N. and Issmail, L. and Schmidt, Anna and Oltmanns, Friederike and Peter, Anne and Müller-Schmucker, Sandra and Irrgang, P. and Fraedrich, Kirsten and Cara, A. and Hoffmann, M. and Poehlmann, S. and Enßer, Armin and Pertl, C. and Willert, T. and Thirion, C. and Grunwald, T. and Überla, Klaus and Tenbusch, Matthias},
booktitle = {EUROPEAN JOURNAL OF IMMUNOLOGY},
doi = {10.1101/2021.08.03.454858},
faupublication = {yes},
note = {CRIS-Team WoS Importer:2023-01-27},
pages = {56-57},
peerreviewed = {unknown},
publisher = {WILEY},
title = {{Protective} mucosal immunity against {SARS}-{CoV}-2 after heterologous systemic {RNA}-mucosal adenoviral vector immunization},
year = {2022}
}
@article{faucris.244605490,
abstract = {SARS-CoV-2 has emerged as a previously unknown zoonotic coronavirus that spread worldwide causing a serious pandemic. While reliable nucleic acid–based diagnostic assays were rapidly available, only a limited number of validated serological assays were available in the early phase of the pandemic. Here, we evaluated a novel flow cytometric approach to assess spike-specific antibody responses.HEK 293T cells expressing SARS-CoV-2 spike protein in its natural confirmation on the surface were used to detect specific IgG and IgM antibody responses in patient sera by flow cytometry. A soluble angiotensin-converting-enzyme 2 (ACE-2) variant was developed as external standard to quantify spike-specific antibody responses on different assay platforms. Analyses of 201 pre-COVID-19 sera proved a high assay specificity in comparison to commercially available CLIA and ELISA systems, while also revealing the highest sensitivity in specimens from PCR-confirmed SARS-CoV-2-infected patients. The external standard allowed robust quantification of antibody responses among different assay platforms. In conclusion, our newly established flow cytometric assay allows sensitive and quantitative detection of SARS-CoV-2-specific antibodies, which can be easily adopted in different laboratories and does not rely on external supply of assay kits. The flow cytometric assay also provides a blueprint for rapid development of serological tests to other emerging viral infections},
author = {Lapuente, Dennis and Maier, Clara and Irrgang, Pascal and Hübner, Julian and Peter, Antonia Sophia and Hoffmann, Markus and Enßer, Armin and Ziegler, Katharina and Winkler, Thomas and Birkholz, Torsten and Kremer, Andreas and Steininger, Philipp and Korn, Klaus and Neipel, Frank and Überla, Klaus and Tenbusch, Matthias},
doi = {10.1007/s10096-020-04072-7},
faupublication = {yes},
journal = {European Journal of Clinical Microbiology & Infectious Diseases},
keywords = {Antibodies; Coronavirus; Flow cytometry; SARS-CoV-2; Serology},
note = {CRIS-Team Scopus Importer:2020-10-30},
peerreviewed = {Yes},
title = {{Rapid} response flow cytometric assay for the detection of antibody responses to {SARS}-{CoV}-2},
year = {2020}
}
@article{faucris.311725567,
abstract = {Murine cytomegalovirus (MCMV), and, in particular, recombinant virus derived from MCMV-bacmid pSM3fr, is widely used as the small animal infection model for human cytomegalovirus (HCMV). We sequenced the complete genomes of MCMV strains and recombinants for quality control. However, we noticed deviances from the deposited reference sequences of MCMV-bacmid pSM3fr. This prompted us to re-analyze pSM3fr and reannotate the reference sequence, as well as that for the commonly used MCMV-m157luc reporter virus. A correct reference sequence for this frequently used pSM3fr, containing a repaired version of m129 (MCK-2) and the luciferase gene instead of ORF m157, was constructed. The new reference also contains the original bacmid sequence, and it has a hybrid origin from MCMV strains Smith and K181.},
author = {Cordsmeier, Arne and Bednar, Christopher and Kübel, Sabrina and Bauer, Larissa and Enßer, Armin},
doi = {10.3390/ijms241814102},
faupublication = {yes},
journal = {International Journal of Molecular Sciences},
keywords = {MCMV; MCMV bacmid reference; MCMV-m157lucMCK-2 repair; pSM3fr},
note = {CRIS-Team Scopus Importer:2023-10-06},
peerreviewed = {Yes},
title = {{Re}-{Analysis} of the {Widely} {Used} {Recombinant} {Murine} {Cytomegalovirus} {MCMV}-m157luc {Derived} from the {Bacmid} {pSM3fr} {Confirms} {Its} {Hybrid} {Nature}},
volume = {24},
year = {2023}
}
@article{faucris.264553582,
abstract = {We explored the possibility to target Ewing's sarcoma family of tumors (ESFT) by redirecting T cells. To this aim, we considered NKG2D-ligands (NKG2D-Ls) as possible target antigens. Detailed analysis of the expression of MICA, MICB, ULBP-1, -2, and -3 in fourteen ESFT cell lines revealed consistent expression of at least one NKG2D-L. Thus, for redirecting T cells, we fused a CD3ζ/CD28-derived signaling domain to the ectodomain of NKG2D, however, opposite transmembrane orientation of this signaling domain and NKG2D required inverse orientation fusion of either of them. We hypothesized that the particularly located C-terminus of the NKG2D ectodomain should allow reengineering of the membrane anchoring from a native N-terminal to an artificial C-terminal linkage. Indeed, the resulting chimeric NKG2D receptor (chNKG2D) was functional and efficiently mediated ESFT cell death triggered by activated T cells. Notably, ESFT cells with even low NKG2D-L expression were killed by CD8 pos and also CD4 pos cells. Both, mRNA transfection and lentiviral transduction resulted in high level surface expression of chNKG2D. However, upon target-cell recognition receptor surface levels were maintained by tranfected RNA only during the first couple of hours after transfection. Later, target-cell contact resulted in strong and irreversible receptor down-modulation, whereas lentivirally mediated expression of chNKG2D remained constant under these conditions. Together, our study defines NKG2D-Ls as targets for a CAR-mediated T cell based immunotherapy of ESFT. A comparison of two different methods of gene transfer reveals strong differences in the susceptibility to ligand-induced receptor down-modulation with possible implications for the applicability of RNA transfection. © 2012 Lehner et al.},
author = {Lehner, Manfred and Goetz, Gabriel and Proff, Julia and Schaft, Niels and Dörrie, Jan and Full, Florian and Enßer, Armin and Muller, Yves and Cerwenka, Adelheid and Abken, Hinrich and Parolini, Ornella and Ambros, Peter F. and Kovar, Heinrich and Holter, Wolfgang},
doi = {10.1371/journal.pone.0031210},
faupublication = {yes},
journal = {PLoS ONE},
note = {CRIS-Team Scopus Importer:2021-10-01},
peerreviewed = {Yes},
title = {{Redirecting} {T} cells to ewing's sarcoma family of tumors by a chimeric {NKG2D} receptor expressed by lentiviral transduction or {mRNA} transfection},
volume = {7},
year = {2012}
}
@article{faucris.316123479,
abstract = {Tick-borne encephalitis virus (TBEV) is the most important tick-transmitted neurotropic flavivirus in Europe and Asia. Our analysis aimed to investigate the contribution of TBEV-specific antibody detection by serological assays and TBEV RNA detection by real-time PCR to the diagnosis of tick-borne encephalitis (TBE). We analyzed data from 3713 patients from 16 years of laboratory TBEV diagnostics in an endemic area in Southern Germany. During this period, 126 cases of TBE were diagnosed. TBEV-specific IgM ELISA tests showed a high clinical sensitivity (96.8%) and a very high clinical specificity (99.7%). In immunocompetent patients, TBE was reliably diagnosed by detection of TBEV IgM antibodies in serum. Intrathecal TBEV IgG antibody synthesis was detected in 46 of 84 (55%) cases by analysis of paired serum and cerebrospinal fluid (CSF) samples. None of the 87 immunocompetent TBE patients tested had detectable TBEV RNA in serum or CSF. In contrast, in two TBE patients without TBEV-specific antibodies, diagnosis could only be made by the detection of TBEV RNA in CSF. Both patients had previously been treated with the B cell-depleting antibody rituximab. Therefore, in patients with CNS infection and humoral immunodeficiency, it is necessary to include TBEV PCR in the diagnostic approach.},
author = {Steininger, Philipp and Enßer, Armin and Knöll, Antje and Korn, Klaus},
doi = {10.3390/v15122357},
faupublication = {yes},
journal = {Viruses},
note = {EVALuna2:545508},
peerreviewed = {Yes},
title = {{Results} of {Tick}-{Borne} {Encephalitis} {Virus} ({TBEV}) {Diagnostics} in an {Endemic} {Area} in {Southern} {Germany}, 2007 to 2022.},
volume = {15},
year = {2023}
}
@article{faucris.237015494,
abstract = {We isolated a rhesus monkey rhadinovirus, isolate RRVmmu 209-07, from hemangioma tissue. The virion DNA was sequenced by Illumina-based sequencing. Isolate RRVmmu 209-07 is highly similar overall to RRV 26-95, but considerable differences exist in the 3= region of the genome.},
author = {Enßer, Armin and Yasuda, Koji and Lauer, William and Desrosiers, Ronald C. and Hahn, Alexander S.},
doi = {10.1128/MRA.01347-19},
faupublication = {yes},
journal = {Microbiology Resource Announcements},
note = {CRIS-Team Scopus Importer:2020-04-07},
peerreviewed = {Yes},
title = {{Rhesus} monkey rhadinovirus isolated from hemangioma tissue},
volume = {9},
year = {2020}
}
@article{faucris.238498886,
abstract = {In December 2019, cases of pneumonia of unknown cause first started to appear in Wuhan in China; subsequently, a new coronavirus was soon identified as the cause of the illness, now known as Coronavirus Disease 2019 (COVID-19). Since then, infections have been confirmed worldwide in numerous countries, with the number of cases steadily rising. The aim of the present review is to provide an overview of the new severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) and, in particular, to deduce from it potential risks and complications for pregnant patients. For this purpose, the available literature on cases of infection in pregnancy during the SARS epidemic of 2002/2003, the MERS (Middle East respiratory syndrome) epidemic ongoing since 2012, as well as recent publications on cases infected with SARS-CoV-2 in pregnancy are reviewed and reported. Based on the literature available at the moment, it can be assumed that the clinical course of COVID-19 disease may be complicated by pregnancy which could be associated with a higher mortality rate. It may also be assumed at the moment that transmission from mother to child in utero is unlikely. Breastfeeding is possible once infection has been excluded or the disease declared cured.},
author = {Stumpfe, Florian and Titzmann, Adriana and Schneider, Michael and Stelzl, Patrick and Kehl, Sven and Fasching, Peter and Beckmann, Matthias and Enßer, Armin},
doi = {10.1055/a-1134-5951},
faupublication = {yes},
journal = {Geburtshilfe und Frauenheilkunde},
keywords = {2019-nCoV; coronavirus; COVID-19; pregnancy; SARS-CoV-2},
note = {CRIS-Team Scopus Importer:2020-05-19},
pages = {380-390},
peerreviewed = {Yes},
title = {{SARS}-{CoV}-2 {Infection} in {Pregnancy} - a {Review} of the {Current} {Literature} and {Possible} {Impact} on {Maternal} and {Neonatal} {Outcome}},
volume = {80},
year = {2020}
}
@article{faucris.261055391,
abstract = {Objectives: Detection and surveillance of SARS-CoV-2 is of eminent importance, particularly due to the rapid emergence of variants of concern (VOCs). In this study we evaluated if a commercially available quantitative real-time PCR (qRT-PCR) assay can identify SARS-CoV-2 B.1.1.7 lineage samples by a specific N gene dropout or Ct value shift compared with the S or RdRp gene. Methods: VOC B.1.1.7 and non-B.1.1.7 SARS-CoV-2-positive patient samples were identified via whole-genome sequencing and variant-specific PCR. Confirmed B.1.1.7 (n = 48) and non-B.1.1.7 samples (n = 58) were analysed using the Allplex™ SARS-CoV-2/FluA/FluB/RSV™ PCR assay for presence of SARS-CoV-2 S, RdRp and N genes. The N gene coding sequence of SARS-CoV-2 with and without the D3L mutation (specific for B.1.1.7) was cloned into pCR™II-TOPO™ vectors to validate polymorphism-dependent N gene dropout with the Allplex™ SARS-CoV-2/FluA/FluB/RSV™ PCR assay. Results: All studied B.1.1.7-positive patient samples showed significantly higher Ct values in qRT-PCR (Δ6–10, N gene dropout on Ct values > 29) of N gene than the corresponding values of S (p ≤ 0.0001) and RdRp (p ≤ 0.0001) genes. The assay reliably discriminated B.1.1.7 and non-B.1.1.7 positive samples (area under the curve = 1) in a receiver operating characteristic curve analysis. Identical Ct value shifts (Δ7–10) were detected in reverse genetic experiments, using isolated plasmids containing N gene coding sequences corresponding to D3 or 3L variants. Discussion: An N gene dropout or Ct value shift is shown for B.1.1.7-positive samples in the Allplex™ SARS-CoV-2/FluA/FluB/RSV™ PCR assay. This approach can be used as a rapid tool for B.1.1.7 detection in single assay high throughput diagnostics.},
author = {Wollschläger, Paul and Todt, Daniel and Gerlitz, Nadja and Pfaender, Stephanie and Bollinger, Thomas and Sing, Andreas and Dangel, Alexandra and Ackermann, Nickolaus and Korn, Klaus and Enßer, Armin and Steinmann, Eike and Buhl, Michael and Steinmann, Joerg},
doi = {10.1016/j.cmi.2021.05.025},
faupublication = {yes},
journal = {Clinical Microbiology and Infection},
keywords = {B.1.1.7; Diagnostic quantitative RT-PCR; Mutation; SARS-CoV-2; VOC},
note = {CRIS-Team Scopus Importer:2021-07-02},
peerreviewed = {Yes},
title = {{SARS}-{CoV}-2 {N} gene dropout and {N} gene {Ct} value shift as indicator for the presence of {B}.1.1.7 lineage in a commercial multiplex {PCR} assay},
year = {2021}
}
@article{faucris.244300317,
abstract = {We found that a single nucleotide polymorphism (SNP) in the nucleoprotein gene of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from a patient interfered with detection in a widely used commercial assay. Some 0.2% of the isolates in the EpiCoV database contain this SNP. Although SARS-CoV-2 was still detected by the other probe in the assay, this underlines the necessity of targeting two independent essential regions of a pathogen for reliable detection.},
author = {Ziegler, Katharina and Steininger, Philipp and Ziegler, Renate and Steinmann, Jörg and Korn, Klaus and Enßer, Armin},
doi = {10.2807/1560-7917.ES.2020.25.39.2001650},
faupublication = {yes},
journal = {Eurosurveillance},
note = {CRIS-Team Scopus Importer:2020-10-23},
peerreviewed = {Yes},
title = {{SARS}-{CoV}-2 samples may escape detection because of a single point mutation in the {N} gene},
volume = {25},
year = {2020}
}
@article{faucris.310442864,
abstract = {With the emergence of multiple predominant SARS-CoV-2 variants, it becomes important to have a comprehensive assessment of their viral fitness and transmissibility. Here, we demonstrate that natural temperature differences between the upper (33°C) and lower (37°C) respiratory tract have profound effects on SARS-CoV-2 replication and transmissibility. Specifically, SARS-CoV-2 variants containing the NSP12 mutations P323L or P323L/G671S exhibit enhanced RNA-dependent RNA polymerase (RdRp) activity at 33°C compared with 37°C and high transmissibility. Molecular dynamics simulations and microscale thermophoresis demonstrate that the NSP12 P323L and P323L/G671S mutations stabilize the NSP12-NSP7-NSP8 complex through hydrophobic effects, leading to increased viral RdRp activity. Furthermore, competitive transmissibility assay reveals that reverse genetic (RG)-P323L or RG-P323L/G671S NSP12 outcompetes RG-WT (wild-type) NSP12 for replication in the upper respiratory tract, allowing markedly rapid transmissibility. This suggests that NSP12 P323L or P323L/G671S mutation of SARS-CoV-2 is associated with increased RdRp complex stability and enzymatic activity, promoting efficient transmissibility.},
author = {Kim, Se Mi and Kim, Eun Ha and Casel, Mark Anthony B. and Kim, Young Il and Sun, Rong and Kwak, Mi Jeong and Yoo, Ji Seung and Yu, Mina and Yu, Kwang Min and Jang, Seung Gyu and Rollon, Rare and Choi, Jeong Ho and Gil, Juryeon and Eun, Kiyoung and Kim, Hyunggee and Enßer, Armin and Hwang, Jungwon and Song, Min Suk and Kim, Myung Hee and Jung, Jae U. and Choi, Young Ki},
doi = {10.1016/j.celrep.2023.113077},
faupublication = {yes},
journal = {Cell Reports},
keywords = {CP: Immunology; ferret; NSP12 mutation; RNA-dependent RNA polymerase; SARS-CoV-2; transmissibility},
note = {CRIS-Team Scopus Importer:2023-09-15},
peerreviewed = {Yes},
title = {{SARS}-{CoV}-2 variants with {NSP12} {P323L}/{G671S} mutations display enhanced virus replication in ferret upper airways and higher transmissibility},
volume = {42},
year = {2023}
}
@article{faucris.219404598,
author = {Coras, Roland and Korn, Klaus and Kürten, Stefanie and Huttner, Hagen and Enßer, Armin},
doi = {10.1007/s00401-019-02005-z},
faupublication = {yes},
journal = {Acta Neuropathologica},
note = {CRIS-Team Scopus Importer:2019-06-04},
pages = {1017-1019},
peerreviewed = {Yes},
title = {{Severe} bornavirus-encephalitis presenting as {Guillain}–{Barré}-syndrome},
volume = {137},
year = {2019}
}
@article{faucris.273936642,
abstract = {The COVID-19 pandemic caused by SARS-CoV-2 has lasted for more than two years. Despite the presence of very effective vaccines, the number of virus variants that escape neutralizing antibodies is growing. Thus, there is still a need for effective antiviral treatments that target virus replication independently of the circulating variant. Here, we show for the first time that deficiency or pharmacological inhibition of the cellular lysine-methyltransferase SMYD2 decreases TMPRSS2 expression on both mRNA and protein levels. SARS-CoV-2 uses TMPRSS2 for priming its spike protein to infect target cells. Treatment of cultured cells with the SMYD2 inhibitors AZ505 or BAY598 significantly inhibited viral replication. In contrast, treatment of Vero E6 cells, which do not express detectable amounts of TMPRSS2, had no effect on SARS-CoV-2 infection. Moreover, by generating a recombinant reporter virus that expresses the spike protein of the Delta variant of SARS-CoV-2, we demonstrate that BAY598 exhibits similar antiviral activity against this variant of concern. In summary, SMYD2 inhibition downregulates TMPRSS2 and blocks viral replication. Targeting cellular SMYD2 represents a promising tool to curtail SARS-CoV-2 infection.},
author = {Yu, Yidong and Herrmann, Alexandra and Thonn, Veronika and Cordsmeier, Arne and Neurath, Markus and Enßer, Armin and Becker, Christoph},
doi = {10.3390/cells11081262},
faupublication = {yes},
journal = {Cells},
keywords = {antiviral treatment; AZ505; BAY598; COVID-19; SARS-CoV-2; SMYD2; TMPRSS2},
note = {CRIS-Team Scopus Importer:2022-04-29},
peerreviewed = {Yes},
title = {{SMYD2} {Inhibition} {Downregulates} {TMPRSS2} and {Decreases} {SARS}-{CoV}-2 {Infection} in {Human} {Intestinal} and {Airway} {Epithelial} {Cells}},
volume = {11},
year = {2022}
}
@article{faucris.289685097,
abstract = {The SARS-CoV-2 Omicron variant is more immune evasive and less virulent than other major viral variants that have so far been recognized1–12. The Omicron spike (S) protein, which has an unusually large number of mutations, is considered to be the main driver of these phenotypes. Here we generated chimeric recombinant SARS-CoV-2 encoding the S gene of Omicron (BA.1 lineage) in the backbone of an ancestral SARS-CoV-2 isolate, and compared this virus with the naturally circulating Omicron variant. The Omicron S-bearing virus robustly escaped vaccine-induced humoral immunity, mainly owing to mutations in the receptor-binding motif; however, unlike naturally occurring Omicron, it efficiently replicated in cell lines and primary-like distal lung cells. Similarly, in K18-hACE2 mice, although virus bearing Omicron S caused less severe disease than the ancestral virus, its virulence was not attenuated to the level of Omicron. Further investigation showed that mutating non-structural protein 6 (nsp6) in addition to the S protein was sufficient to recapitulate the attenuated phenotype of Omicron. This indicates that although the vaccine escape of Omicron is driven by mutations in S, the pathogenicity of Omicron is determined by mutations both in and outside of the S protein.},
author = {Chen, Da Yuan and Chin, Chue Vin and Kenney, Devin and Tavares, Alexander H. and Khan, Nazimuddin and Conway, Hasahn L. and Liu, Guan Qun and Choudhary, Manish C. and Gertje, Hans P. and O’Connell, Aoife K. and Adams, Scott and Kotton, Darrell N. and Herrmann, Alexandra and Enßer, Armin and Connor, John H. and Bosmann, Markus and Li, Jonathan Z. and Gack, Michaela U. and Baker, Susan C. and Kirchdoerfer, Robert N. and Kataria, Yachana and Crossland, Nicholas A. and Douam, Florian and Saeed, Mohsan},
doi = {10.1038/s41586-023-05697-2},
faupublication = {yes},
journal = {Nature},
note = {CRIS-Team Scopus Importer:2023-02-24},
peerreviewed = {Yes},
title = {{Spike} and nsp6 are key determinants of {SARS}-{CoV}-2 {Omicron} {BA}.1 attenuation},
year = {2023}
}
@article{faucris.267064412,
abstract = {The bat sarbecovirus RaTG13 is a close relative of SARS-CoV-2, the cause of the COVID-19 pandemic. However, this bat virus was most likely unable to directly infect humans since its Spike (S) protein does not interact efficiently with the human ACE2 receptor. Here, we show that a single T403R mutation increases binding of RaTG13 S to human ACE2 and allows VSV pseudoparticle infection of human lung cells and intestinal organoids. Conversely, mutation of R403T in the SARS-CoV-2 S reduces pseudoparticle infection and viral replication. The T403R RaTG13 S is neutralized by sera from individuals vaccinated against COVID-19 indicating that vaccination might protect against future zoonoses. Our data suggest that a positively charged amino acid at position 403 in the S protein is critical for efficient utilization of human ACE2 by S proteins of bat coronaviruses. This finding could help to better predict the zoonotic potential of animal coronaviruses.},
author = {Zech, Fabian and Schniertshauer, Daniel and Jung, Christoph and Herrmann, Alexandra and Cordsmeier, Arne and Xie, Qinya and Nchioua, Rayhane and Bozzo, Caterina Prelli and Volcic, Meta and Koepke, Lennart and Mueller, Janis A. and Krueger, Jana and Heller, Sandra and Stenger, Steffen and Hoffmann, Markus and Poehlmann, Stefan and Kleger, Alexander and Jacob, Timo and Conzelmann, Karl-Klaus and Enßer, Armin and Sparrer, Konstantin M. J. and Kirchhoff, Frank},
doi = {10.1038/s41467-021-27180-0},
faupublication = {yes},
journal = {Nature Communications},
note = {CRIS-Team Scopus Importer:2021-12-10},
peerreviewed = {Yes},
title = {{Spike} residue 403 affects binding of coronavirus spikes to human {ACE2}},
volume = {12},
year = {2021}
}
@article{faucris.230059380,
abstract = {Infections with Clostridioides difficile (formerly Clostridium difficile) have increased in incidence, morbidity, and mortality over the past decade. Preventing infections is becoming increasingly important, as frontline antibiotics become less effective and frequently induce recurrence by disrupting intestinal microbiota. The clinically most advanced vaccine approaches prevent symptoms once C. difficile infection is established by inducing immunity to secreted clostridial cytotoxins. However, they do not inhibit bacterial colonization and thereby favor asymptomatic carriage. Synthetic oligosaccharides resembling the C. difficile surface glycans PS-I, PS-II, and PS-III are immunogenic and serve as basis for colonization-preventing vaccines. Here, we demonstrate that glycoconjugate vaccine candidates based on synthetic oligosaccharides protected mice from infections with two different C. difficile strains. Four synthetic antigens, ranging in size from disaccharides to hexasaccharides, were conjugated to CRM197, which is a carrier protein used in commercial vaccines. The vaccine candidates induced glycan-specific antibodies in mice and substantially limited C. difficile colonization and colitis after experimental infection. The glycoconjugates ameliorated intestinal pathology more substantially than a toxin-targeting vaccine. Colonization of the gut by C. difficile was selectively inhibited while intestinal microbiota remained preserved. Passive transfer experiments with anti-PS-I serum revealed that protection is mediated by specific antiglycan antibodies; however, cell-mediated immunity likely also contributed to protection in vivo. Thus, glycoconjugate vaccines against C. difficile are a complementary approach to toxin-targeting strategies and are advancing through preclinical work.},
author = {Broecker, Felix and Wegner, Erik and Seco, Bruna M.S. and Kaplonek, Paulina and Bräutigam, Maria and Enßer, Armin and Pfister, Frederick and Daniel, Christoph and Martin, Christopher E. and Mattner, Jochen and Seeberger, Peter H.},
doi = {10.1021/acschembio.9b00642},
faupublication = {yes},
journal = {ACS Chemical Biology},
note = {CRIS-Team Scopus Importer:2019-12-03},
peerreviewed = {Yes},
title = {{Synthetic} {Oligosaccharide}-{Based} {Vaccines} {Protect} {Mice} from {Clostridioides} difficile {Infections}},
year = {2019}
}
@inproceedings{faucris.227608551,
address = {HOBOKEN},
author = {Mattner, Jochen and Enßer, Armin and Seeberger, P.},
booktitle = {EUROPEAN JOURNAL OF IMMUNOLOGY},
date = {2019-09-10/2019-09-13},
faupublication = {yes},
note = {CRIS-Team WoS Importer:2019-10-08},
pages = {101-101},
peerreviewed = {unknown},
publisher = {WILEY},
title = {{Synthetic} oligosaccharide-based vaccines protect mice from {Clostridium} difficile infections},
venue = {Munich},
year = {2019}
}
@article{faucris.229226247,
abstract = {Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma, a highly vascularized tumor originating from lymphatic endothelial cells, and of at least two different B cell malignancies. A dimeric complex formed by the envelope glycoproteins H and L (gH-gL) is required for entry of herpesviruses into host cells. We show that the ephrin receptor tyrosine kinase A2 (EphA2) is a cellular receptor for KSHV gH-gL. EphA2 co-precipitated with both gH-gL and KSHV virions. Infection of human epithelial cells with a GFP-expressing recombinant KSHV strain, as measured by FACS analysis, was increased upon overexpression of EphA2. Antibodies against EphA2 and siRNAs directed against EphA2 inhibited infection of endothelial cells. Pretreatment of KSHV with soluble EphA2 resulted in inhibition of KSHV infection by up to 90%. This marked reduction of KSHV infection was seen with all the different epithelial and endothelial cells used in this study. Similarly, pretreating epithelial or endothelial cells with the soluble EphA2 ligand ephrinA4 impaired KSHV infection. Deletion of the gene encoding EphA2 essentially abolished KSHV infection of mouse endothelial cells. Binding of gH-gL to EphA2 triggered EphA2 phosphorylation and endocytosis, a major pathway of KSHV entry. Quantitative RT-PCR and in situ histochemistry revealed a close correlation between KSHV infection and EphA2 expression both in cultured cells derived from human Kaposi's sarcoma lesions or unaffected human lymphatic endothelium, and in situ in Kaposi's sarcoma specimens, respectively. Taken together, our results identify EphA2, a tyrosine kinase with known functions in neovascularization and oncogenesis, as an entry receptor for KSHV. © 2012 Nature America, Inc. All rights reserved.},
author = {Hahn, Alexander and Kaufmann, Johanna K. and Wies, Effi and Naschberger, Elisabeth and Panteleev-Ivlev, Julia and Schmidt, Katharina and Holzer, Angela and Schmidt, Martin and Chen, Jin and Koenig, Simone and Enßer, Armin and Myoung, Jinjong and Brockmeyer, Norbert H. and Stürzl, Michael and Fleckenstein, Bernhard and Neipel, Frank},
doi = {10.1038/nm.2805},
faupublication = {yes},
journal = {Nature Medicine},
note = {Created from Fastlane, Scopus look-up},
pages = {961-966},
peerreviewed = {Yes},
title = {{The} ephrin receptor tyrosine kinase {A2} is a cellular receptor for {Kaposi}'s sarcoma-associated herpesvirus},
volume = {18},
year = {2012}
}
@article{faucris.210425012,
abstract = {Patients with epidermodysplasia verruciformis (EV) and biallelic null mutations of TMC6 (encoding EVER1) or TMC8 (EVER2) are selectively prone to disseminated skin lesions due to keratinocyte-tropic human beta-papillomaviruses (beta-HPVs), which lack E5 and E8. We describe EV patients homozygous for null mutations of the CIB1 gene encoding calcium-and integrin-binding protein-1 (CIB1). CIB1 is strongly expressed in the skin and cultured keratinocytes of controls but not in those of patients. CIB1 forms a complex with EVER1 and EVER2, and CIB1 proteins are not expressed in EVER1- or EVER2-deficient cells. The known functions of EVER1 and EVER2 in human keratinocytes are not dependent on CIB1, and CIB1 deficiency does not impair keratinocyte adhesion or migration. In keratinocytes, the CIB1 protein interacts with the HPV E5 and E8 proteins encoded by alpha-HPV16 and gamma-HPV4, respectively, suggesting that this protein acts as a restriction factor against HPVs. Collectively, these findings suggest that the disruption of CIB1-EVER1-EVER2-dependent keratinocyte-intrinsic immunity underlies the selective susceptibility to beta-HPVs of EV patients.},
author = {De Jong, Sarah Jill and Crequer, Amandine and Matos, Irina and Hum, David and Gunasekharan, Vignesh and Lorenzo, Lazaro and Jabot-Hanin, Fabienne and Imahorn, Elias and Arias, Andres A. and Vahidnezhad, Hassan and Youssefian, Leila and Markle, Janet G. and Patin, Etienne and D'Amico, Aurelia and Wang, Claire Q. F. and Full, Florian and Enßer, Armin and Leisner, Tina M. and Parise, Leslie V. and Bouaziz, Matthieu and Portilla Maya, Nataly and Rueda Cadena, Xavier and Saka, Bayaki and Saeidian, Amir Hossein and Aghazadeh, Nessa and Zeinali, Sirous and Itin, Peter and Krueger, James G. and Laimins, Lou and Abel, Laurent and Fuchs, Elaine and Uitto, Jouni and Luis Franco, Jose and Burger, Bettina and Orth, Gerard and Jouanguy, Emmanuelle and Casanova, Jean-Laurent},
doi = {10.1084/jem.20170308},
faupublication = {yes},
journal = {Journal of Experimental Medicine},
note = {EVALuna2:35267},
pages = {2289-2310},
peerreviewed = {Yes},
title = {{The} human {CIB1}-{EVER1}-{EVER2} complex governs keratinocyte-intrinsic immunity to beta-papillomaviruses},
volume = {215},
year = {2018}
}
@article{faucris.316123226,
abstract = {The infection of human cytomegalovirus (HCMV) is strongly determined by the host-cell interaction in a way that the efficiency of HCMV lytic replication is dependent on the regulatory interplay between viral and cellular proteins. In particular, the activities of protein kinases, such as cyclin-dependent kinases (CDKs) and the viral CDK ortholog (vCDK/pUL97), play an important role in both viral reproduction and virus-host interaction. Very recently, we reported on the complexes formed between vCDK/pUL97, human cyclin H, and CDK7. Major hallmarks of this interplay are the interaction between cyclin H and vCDK/pUL97, which is consistently detectable across various conditions and host cell types of infection, the decrease or increase in pUL97 kinase activity resulting from cyclin H knock-down or elevated levels, respectively, and significant trans-stimulation of human CDK7 activity by pUL97 in vitro. Due to the fact that even a ternary complex of vCDK/pUL97-cyclin H-CDK7 can be detected by coimmunoprecipitation and visualized by bioinformatic structural modeling, we postulated a putative impact of the respective kinase activities on the patterns of transcription in HCMV-infected cells. Here, we undertook a first vCDK/pUL97-specific transcriptomic analysis, which combined conditions of fully lytic HCMV replication with those under specific vCDK/pUL97 or CDK7 drug-mediated inhibition or transient cyclin H knockout. The novel results were further strengthened using bioinformatic modeling of the involved multi-protein complexes. Our data underline the importance of these kinase activities for the C-terminal domain (CTD) phosphorylation-driven activation of host RNA polymerase in HCMV-infected cells. The impact of the individual experimental conditions on differentially expressed gene profiles is described in detail and discussed.},
author = {Schütz, Martin and Cordsmeier, Arne and Wangen, Christina and Horn, Anselm and Wyler, Emanuel and Enßer, Armin and Sticht, Heinrich and Marschall, Manfred},
doi = {10.3390/ijms242417421},
faupublication = {yes},
journal = {International Journal of Molecular Sciences},
note = {EVALuna2:545510},
peerreviewed = {Yes},
title = {{The} {Interactive} {Complex} between {Cytomegalovirus} {Kinase} {vCDK}/{pUL97} and {Host} {Factors} {CDK7}-{Cyclin} {H} {Determines} {Individual} {Patterns} of {Transcription} in {Infected} {Cells}.},
volume = {24},
year = {2023}
}
@article{faucris.210421857,
abstract = {Background: During infection with human cytomegalovirus (HCMV) several viral proteins occur on cell surfaces in high quantity. We thus pursue an HLA-independent approach for immunotherapy of HCMV using chimeric antigen receptors (CARs) and bispecific -BiTE (R) antibody constructs. In this context, HCMV-encoded proteins that mediate viral immune evasion and bind human IgG might represent particularly attractive target antigens. Unlike in observations of similar approaches for HIV and hepatitis B and C viruses, however, HCMV-infected cells develop a striking resistance to cytotoxic effector functions at later stages of the replication cycle. In our study we therefore wanted to test two hypotheses: (1) CAR T cells can efficiently inhibit HCMV replication independently from cytotoxic effector functions, and (2) HCMV can be targeted by CH2-CH3 IgG spacer domains that contain mutations previously reported to prevent exhaustion and to rescue CAR T cell function in vivo.
Methods: Replication of GFP-encoding recombinant HCMV in fibroblasts in the presence and absence of supernatants from T cell co-cultures plus/minus cytokine neutralizing antibodies was analyzed by flow cytometry. CARs with wild type and mutated CH2-CH3 domains were expressed in human T cells by mRNA electroporation, and the function of the CARs was assessed by quantifying T cell cytokine secretion.
Results: We confirm and extend previous evidence of antiviral cytokine effects and demonstrate that CAR T cells strongly block HCMV replication in fibroblasts mainly by combined secretion of IFN-gamma and TNF. Furthermore, we show that fibroblasts infected with HCMV strains AD169 and Towne starting from day 3 have a high capacity for binding of human IgG1 and also strongly activate T cells expressing a CAR with CH2-CH3 domain. Importantly, we further show that mutations in the CH2-CH3 domain of IgG1 and IgG4, which were previously reported to rescue CAR T cell function by abrogating interaction with endogenous Fc receptors (FcRs), still enable recognition of FcRs encoded by HCMV.
Conclusions: Our findings identify HCMV-encoded FcRs as an attractive additional target for HCMV immunotherapy by CARs and possibly bispecific antibodies. The use of specifically mutated IgG domains that bind to HCMV-FcRs without recognizing endogenous FcRs may supersede screening for novel binders directed against individual HCMV-FcRs.},
author = {Proff, Julia and Brey, Charlotte U. and Enßer, Armin and Holter, Wolfgang and Lehner, Manfred},
doi = {10.1186/s12967-018-1394-x},
faupublication = {yes},
journal = {Journal of Translational Medicine},
note = {EVALuna2:35288},
peerreviewed = {Yes},
title = {{Turning} the tables on cytomegalovirus: targeting viral {Fc} receptors by
{CARs} containing mutated {CH2}-{CH3} {IgG} spacer domains},
volume = {16},
year = {2018}
}
@article{faucris.235083887,
abstract = {BK polyomavirus (BKPyV) causes major complications in solid organ transplant recipients but little is known about its role in the development of urothelial carcinoma (UC) during immunosuppression. Immunohistochemistry (IHC) screening for polyomavirus large T antigen (LTag) was performed in 94 micropapillary UC (MPUC), 480 unselected UC, 199 muscle invasive UC (including 83 UC with variant differentiation), 76 cases of plasmocytoid, nested and large nested UC and 15 posttransplant UC. LTag expressing UC were reevaluated regarding their histomorphological features and characterized by IHC for p53 and HER2, chromogenic in situ hybridization for HER2 and SNaPshot analysis of the TERT promoter and HRAS. Real-time PCR and next generation sequencing (NGS) were performed to search for BKPyV-DNA and for variants in the tumor and viral genomes. We detected five LTag expressing UC which were diagnosed between 2 and 18 years after kidney (n = 4) or heart (n = 1) transplantation. 89 MPUC without history of organ transplantation and overall 755 UC (including cases with variant histology) were LTag negative. Of the five LTag expressing UC, three were MPUC, one showed extensive divergent differentiation with Mullerian type clear cell carcinoma, and one displayed focal villoglandular differentiation. All five tumors had aberrant nuclear p53 expression, 2/5 were HER2-amplified, and 3/5 had TERT promoter mutations. Within the 50 most common cancer related genes altered in UC we detected very few alterations and no TP53 mutations. BKPyV-DNA was present in 5/5 UC, chromosomal integration of the BKPyV genome was detectable in 4/5 UC. Two UC with BKPyV integration showed small deletions in the BKPyV noncoding control region (NCCR). The only UC without detectable BKPyV integration had a high viral load of human herpesvirus 6 (HHV-6). Our results suggest that LTag expression of integrated BKPyV genomes and resulting p53 inactivation lead to aggressive high-grade UC with unusual, often micropapillary morphology.},
author = {Bertz, Simone and Enßer, Armin and Stöhr, Robert and Eckstein, Markus and Apel, Hendrik and Mayr, Doris and Büttner-Herold, Maike and Gaisa, Nadine Therese and Comperat, Eva and Wullich, Bernd and Hartmann, Arndt and Knöll, Antje},
doi = {10.1038/s41379-020-0489-0},
faupublication = {yes},
journal = {Modern Pathology},
note = {CRIS-Team WoS Importer:2020-02-28},
peerreviewed = {Yes},
title = {{Variant} morphology and random chromosomal integration of {BK} polyomavirus in posttransplant urothelial carcinomas},
year = {2020}
}
@article{faucris.120898844,
abstract = {Nuclear domain 10 (ND10) components restrict herpesviral infection, and herpesviruses antagonize this restriction by a variety of strategies, including degradation or relocalization of ND10 proteins. The rhesus monkey rhadinovirus (RRV) shares many key biological features with the closely related Kaposi's sarcoma-associated herpesvirus (KSHV; human herpesvirus 8) and readily infects cells of both human and rhesus monkey origin. We used the clustered regularly interspaced short palindromic repeat-Cas9 (CRISPR-Cas9) technique to generate knockout (ko) cells for each of the four ND10 components, PML, SP100, DAXX, and ATRX. These ko cells were analyzed with regard to permissiveness for RRV infection. In addition, we analyzed the fate of the individual ND10 components in infected cells by immunofluorescence and Western blotting. Knockout of the ND10 component DAXX markedly increased RRV infection, while knockout of PML or SP100 had a less pronounced effect. In line with these observations, RRV infection resulted in rapid degradation of SP100, followed by degradation of PML and the loss of ND10 structures, whereas the protein levels of ATRX and DAXX remained constant. Notably, inhibition of the proteasome but not inhibition of de novo gene expression prevented the loss of SP100 and PML in cells that did not support lytic replication, compatible with proteasomal degradation of these ND10 components through the action of a viral tegument protein. Expression of the RRV FGARAT homolog ORF75 was sufficient to effect the loss of SP100 and PML in transfected or transduced cells, implicating ORF75 as the viral effector protein.Our findings highlight the antiviral role of ND10 and its individual components and further establish the viral FGARAT homologs of the gammaherpesviruses to be important viral effectors that counteract ND10-instituted intrinsic immunity. Surprisingly, even closely related viruses like KSHV and RRV evolved to use different strategies to evade ND10-mediated restriction. RRV first targets SP100 for degradation and then targets PML with a delayed kinetic, a strategy which clearly differs from that of other gammaherpesviruses. Despite efficient degradation of these two major ND10 components, RRV is still restricted by DAXX, another abundant ND10 component, as evidenced by a marked increase in RRV infection and replication upon knockout of DAXX. Taken together, our findings substantiate PML, SP100, and DAXX as key antiviral proteins, in that the first two are targeted for degradation by RRV and the last one still potently restricts replication of RRV.},
author = {Hahn, Alexander S. and Grosskopf, Anna K. and Jungnickl, Doris and Scholz, Brigitte and Enßer, Armin},
doi = {10.1128/JVI.01181-16},
faupublication = {yes},
journal = {Journal of Virology},
note = {EVALuna2:8329},
pages = {8013-28},
peerreviewed = {Yes},
title = {{Viral} {FGARAT} {Homolog} {ORF75} of {Rhesus} {Monkey} {Rhadinovirus} {Effects} {Proteasomal} {Degradation} of the {ND10} {Components} {SP100} and {PML}},
volume = {90},
year = {2016}
}
@article{faucris.274938035,
abstract = {Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection triggers cytokine-mediated inflammation, leading to a myriad of clinical presentations in COVID-19. The SARS-CoV-2 open reading frame 8 (ORF8) is a secreted and rapidly evolving glycoprotein. Patients infected with SARS-CoV-2 variants with ORF8 deleted are associated with mild disease outcomes, but the molecular mechanism behind this is unknown. Here, we report that SARS-CoV-2 ORF8 is a viral cytokine that is similar to but distinct from interleukin 17A (IL-17A) as it induces stronger and broader human IL-17 receptor (hIL-17R) signaling than IL-17A. ORF8 primarily targeted blood monocytes and induced the heterodimerization of hIL-17RA and hIL- 17RC, triggering a robust inflammatory response. Transcriptome analysis revealed that besides its activation of the hIL-17R pathway, ORF8 upregulated gene expression for fibrosis signaling and coagulation dysregulation. A naturally occurring ORF8 L84S variant that was highly associated with mild COVID-19 showed reduced hIL- 17RA binding and attenuated inflammatory responses. This study reveals how SARSCoV- 2 ORF8 by a viral mimicry of the IL-17 cytokine contributes to COVID-19 severe inflammation. },
author = {Wu, Xin and Xia, Tian and Shin, Woo-Jin and Yu, Kwang-Min and Jung, Wooram and Herrmann, Alexandra and Foo, Suan-Sin and Chen, Weiqiang and Zhang, Pengfei and Lee, Jong-Soo and Poo, Haryoung and Comhair, Suzy A. A. and Jehi, Lara and Choi, Young Ki and Enßer, Armin and Jung, Jae U.},
doi = {10.1128/mbio.00402-22},
faupublication = {yes},
journal = {Mbio},
keywords = {COVID-19; inflammation; viral IL-17},
note = {CRIS-Team Scopus Importer:2022-05-13},
peerreviewed = {Yes},
title = {{Viral} {Mimicry} of {Interleukin}-{17A} by {SARS}-{CoV}-2 {ORF8}},
volume = {13},
year = {2022}
}
@article{faucris.210423329,
abstract = {Although the majority of cases can still be attributed to travellers returning from epidemic and endemic areas, changes in the distribution of insect vectors will increase the frequency of locally acquired infections and minor outbreaks of "tropical" viruses in Southern and Central Europe. Virus-associated arthritis is a characteristic feature of an acute infection with the Chikungunya virus. A number of other tropical and endemic pathogens as well as early forms of rheumatoid arthritis and other autoimmune diseases should be included in the differential-diagnostic evaluation.},
author = {Enßer, Armin},
faupublication = {yes},
journal = {Aktuelle Rheumatologie},
note = {EVALuna2:35281},
pages = {126-134},
peerreviewed = {Yes},
title = {{Virus}-{Associated} {Arthritis}: {Globalisation} of {Vectors} and {Viruses}},
volume = {43},
year = {2018}
}