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So far, only a few reports about reinfections with SARS-CoV-2 have been published, and they often lack detailed immunological and virological data. We report about a SARS-CoV-2 reinfection with a genetically distinct SARS-CoV-2 variant in an immunocompetent female healthcare worker that has led to a mild disease course. No obvious viral escape mutations were observed in the second virus variant. The infectious virus was shed from the patient during the second infection episode despite the presence of neutralizing antibodies in her blood. Our data indicate that a moderate immune response after the first infection, but not a viral escape, did allow for reinfection and live virus shedding.
Thomas Brehm; Susanne Pfefferle; Ronald von Possel; Robin Kobbe; Dominik Nörz; Stefan Schmiedel; Adam Grundhoff; Flaminia Olearo; Petra Emmerich; Alexis Robitaille; Thomas Günther; Platon Braun; Gabriele Andersen; Johannes Knobloch; Marylyn Addo; Ansgar Lohse; Martin Aepfelbacher; Nicole Fischer; Julian Schulze Zur Wiesch; Marc Lütgehetmann. SARS-CoV-2 Reinfection in a Healthcare Worker Despite the Presence of Detectable Neutralizing Antibodies. Viruses 2021, 13, 661 .
AMA StyleThomas Brehm, Susanne Pfefferle, Ronald von Possel, Robin Kobbe, Dominik Nörz, Stefan Schmiedel, Adam Grundhoff, Flaminia Olearo, Petra Emmerich, Alexis Robitaille, Thomas Günther, Platon Braun, Gabriele Andersen, Johannes Knobloch, Marylyn Addo, Ansgar Lohse, Martin Aepfelbacher, Nicole Fischer, Julian Schulze Zur Wiesch, Marc Lütgehetmann. SARS-CoV-2 Reinfection in a Healthcare Worker Despite the Presence of Detectable Neutralizing Antibodies. Viruses. 2021; 13 (4):661.
Chicago/Turabian StyleThomas Brehm; Susanne Pfefferle; Ronald von Possel; Robin Kobbe; Dominik Nörz; Stefan Schmiedel; Adam Grundhoff; Flaminia Olearo; Petra Emmerich; Alexis Robitaille; Thomas Günther; Platon Braun; Gabriele Andersen; Johannes Knobloch; Marylyn Addo; Ansgar Lohse; Martin Aepfelbacher; Nicole Fischer; Julian Schulze Zur Wiesch; Marc Lütgehetmann. 2021. "SARS-CoV-2 Reinfection in a Healthcare Worker Despite the Presence of Detectable Neutralizing Antibodies." Viruses 13, no. 4: 661.
Congenital human cytomegalovirus (cHCMV) infection of the brain is associated with a wide range of neurocognitive sequelae. Using infection of newborn mice with mouse cytomegalovirus (MCMV) as a reliable model that recapitulates many aspects of cHCMV infection, including disseminated infection, CNS infection, altered neurodevelopment, and sensorineural hearing loss, we have previously shown that mitigation of inflammation prevented alterations in cerebellar development, suggesting that host inflammatory factors are key drivers of neurodevelopmental defects. Here, we show that MCMV infection causes a dramatic increase in the expression of the microglia-derived chemokines CXCL9/CXCL10, which recruit NK and ILC1 cells into the brain in a CXCR3-dependent manner. Surprisingly, brain-infiltrating innate immune cells not only were unable to control virus infection in the brain but also orchestrated pathological inflammatory responses, which lead to delays in cerebellar morphogenesis. Our results identify NK and ILC1 cells as the major mediators of immunopathology in response to virus infection in the developing CNS, which can be prevented by anti–IFN-γ antibodies.
Daria Kveštak; Vanda Juranić Lisnić; Berislav Lisnić; Jelena Tomac; Mijo Golemac; Ilija Brizić; Daniela Indenbirken; Maja Cokarić Brdovčak; Giovanni Bernardini; Fran Krstanović; Carmen Rožmanić; Adam Grundhoff; Astrid Krmpotić; William J. Britt; Stipan Jonjić. NK/ILC1 cells mediate neuroinflammation and brain pathology following congenital CMV infection. Journal of Experimental Medicine 2021, 218, 1 .
AMA StyleDaria Kveštak, Vanda Juranić Lisnić, Berislav Lisnić, Jelena Tomac, Mijo Golemac, Ilija Brizić, Daniela Indenbirken, Maja Cokarić Brdovčak, Giovanni Bernardini, Fran Krstanović, Carmen Rožmanić, Adam Grundhoff, Astrid Krmpotić, William J. Britt, Stipan Jonjić. NK/ILC1 cells mediate neuroinflammation and brain pathology following congenital CMV infection. Journal of Experimental Medicine. 2021; 218 (5):1.
Chicago/Turabian StyleDaria Kveštak; Vanda Juranić Lisnić; Berislav Lisnić; Jelena Tomac; Mijo Golemac; Ilija Brizić; Daniela Indenbirken; Maja Cokarić Brdovčak; Giovanni Bernardini; Fran Krstanović; Carmen Rožmanić; Adam Grundhoff; Astrid Krmpotić; William J. Britt; Stipan Jonjić. 2021. "NK/ILC1 cells mediate neuroinflammation and brain pathology following congenital CMV infection." Journal of Experimental Medicine 218, no. 5: 1.
We describe a multifactorial investigation of a SARS-CoV-2 outbreak in a large meat processing complex in Germany. Infection event timing, spatial, climate and ventilation conditions in the processing plant, sharing of living quarters and transport, and viral genome sequences were analyzed. Our results suggest that a single index case transmitted SARS-CoV-2 to co-workers over distances of more than 8 m, within a confined work area in which air is constantly recirculated and cooled. Viral genome sequencing shows that all cases share a set of mutations representing a novel sub-branch in the SARS-CoV-2 C20 clade. We identified the same set of mutations in samples collected in the time period between this initial infection cluster and a subsequent outbreak within the same factory, with the largest number of confirmed SARS-CoV-2 cases in a German meat processing facility reported so far. Our results indicate climate conditions, fresh air exchange rates, and airflow as factors that can promote efficient spread of SARS-CoV-2 via long distances and provide insights into possible requirements for pandemic mitigation strategies in industrial workplace settings.
Thomas Günther; Manja Czech‐Sioli; Daniela Indenbirken; Alexis Robitaille; Peter Tenhaken; Martin Exner; Matthias Ottinger; Nicole Fischer; Adam Grundhoff; Melanie M Brinkmann. SARS‐CoV‐2 outbreak investigation in a German meat processing plant. EMBO Molecular Medicine 2020, 12, e13296 .
AMA StyleThomas Günther, Manja Czech‐Sioli, Daniela Indenbirken, Alexis Robitaille, Peter Tenhaken, Martin Exner, Matthias Ottinger, Nicole Fischer, Adam Grundhoff, Melanie M Brinkmann. SARS‐CoV‐2 outbreak investigation in a German meat processing plant. EMBO Molecular Medicine. 2020; 12 (12):e13296.
Chicago/Turabian StyleThomas Günther; Manja Czech‐Sioli; Daniela Indenbirken; Alexis Robitaille; Peter Tenhaken; Martin Exner; Matthias Ottinger; Nicole Fischer; Adam Grundhoff; Melanie M Brinkmann. 2020. "SARS‐CoV‐2 outbreak investigation in a German meat processing plant." EMBO Molecular Medicine 12, no. 12: e13296.
Stroke and central nervous system dysfunction are cardinal symptoms in critically ill corona virus disease 19 (COVID-19) patients. In an autopsy series of 32 COVID-19 patients, we investigated whether carotid arteries were infected with SARS-CoV-2 by employing genomic, virologic, histochemical and transcriptomic analyses. We show that SARS-CoV-2 productively infects and modulates vascular responses in carotid arteries. This finding has far reaching implications for the understanding and clinical treatment of COVID-19.
Susanne Pfefferle; Thomas Guenther; Victor Puelles; Fabian Heinrich; Dominik Noerz; Manja Czech-Sioli; Alexander Carstens; Susanne Krasemann; Milagros Wong; Lisa Oestereich; Tim Magnus; Lena Allweiss; Caroline Edler; Ann-Sophie Schroeder; Maura Dandri; Tobias Huber; Markus Glatzel; Klaus Pueschel; Adam Grundhoff; Marc Luetgehetmann; Martin Aepfelbacher; Nicole Fischer. SARS-CoV-2 infects carotid arteries: implications for vascular disease and organ injury in COVID-19. 2020, 1 .
AMA StyleSusanne Pfefferle, Thomas Guenther, Victor Puelles, Fabian Heinrich, Dominik Noerz, Manja Czech-Sioli, Alexander Carstens, Susanne Krasemann, Milagros Wong, Lisa Oestereich, Tim Magnus, Lena Allweiss, Caroline Edler, Ann-Sophie Schroeder, Maura Dandri, Tobias Huber, Markus Glatzel, Klaus Pueschel, Adam Grundhoff, Marc Luetgehetmann, Martin Aepfelbacher, Nicole Fischer. SARS-CoV-2 infects carotid arteries: implications for vascular disease and organ injury in COVID-19. . 2020; ():1.
Chicago/Turabian StyleSusanne Pfefferle; Thomas Guenther; Victor Puelles; Fabian Heinrich; Dominik Noerz; Manja Czech-Sioli; Alexander Carstens; Susanne Krasemann; Milagros Wong; Lisa Oestereich; Tim Magnus; Lena Allweiss; Caroline Edler; Ann-Sophie Schroeder; Maura Dandri; Tobias Huber; Markus Glatzel; Klaus Pueschel; Adam Grundhoff; Marc Luetgehetmann; Martin Aepfelbacher; Nicole Fischer. 2020. "SARS-CoV-2 infects carotid arteries: implications for vascular disease and organ injury in COVID-19." , no. : 1.
CRISPR activation (CRISPRa) has revealed great potential as a tool to modulate the expression of targeted cellular genes. Here, we successfully applied the CRISPRa system to trigger the Kaposi’s sarcoma-associated herpesvirus (KSHV) reactivation in latently infected cells by selectively activating ORF50 gene directly from the virus genome. We found that a nuclease-deficient Cas9 (dCas9) fused to a destabilization domain (DD) and 12 copies of the VP16 activation domain (VP192) triggered a more efficient KSHV lytic cycle and virus production when guided to two different sites on the ORF50 promoter, instead of only a single site. To our surprise, the virus reactivation induced by binding of the stable DD-dCas9-VP192 on the ORF50 promoter was even more efficient than reactivation induced by ectopic expression of ORF50. This suggests that recruitment of additional transcriptional activators to the ORF50 promoter, in addition to ORF50 itself, are needed for the efficient virus production. Further, we show that CRISPRa can be applied to selectively express the early lytic gene, ORF57, without disturbing the viral latency. Therefore, CRISPRa-based systems can be utilized to facilitate virus–host interaction studies by controlling the expression of not only cellular but also of specific KSHV genes.
Endrit Elbasani; Francesca Falasco; Silvia Gramolelli; Veijo Nurminen; Thomas Günther; Jere Weltner; Diego Balboa; Adam Grundhoff; Timo Otonkoski; Päivi M. Ojala. Kaposi’s Sarcoma-Associated Herpesvirus Reactivation by Targeting of a dCas9-Based Transcription Activator to the ORF50 Promoter. Viruses 2020, 12, 952 .
AMA StyleEndrit Elbasani, Francesca Falasco, Silvia Gramolelli, Veijo Nurminen, Thomas Günther, Jere Weltner, Diego Balboa, Adam Grundhoff, Timo Otonkoski, Päivi M. Ojala. Kaposi’s Sarcoma-Associated Herpesvirus Reactivation by Targeting of a dCas9-Based Transcription Activator to the ORF50 Promoter. Viruses. 2020; 12 (9):952.
Chicago/Turabian StyleEndrit Elbasani; Francesca Falasco; Silvia Gramolelli; Veijo Nurminen; Thomas Günther; Jere Weltner; Diego Balboa; Adam Grundhoff; Timo Otonkoski; Päivi M. Ojala. 2020. "Kaposi’s Sarcoma-Associated Herpesvirus Reactivation by Targeting of a dCas9-Based Transcription Activator to the ORF50 Promoter." Viruses 12, no. 9: 952.
Kaposi’s sarcoma-associated herpesvirus (KSHV) causes the aggressive disease primary effusion lymphoma (PEL). Here, we show that a viral transcription factor (vIRF3) cooperates with the cellular transcription factor IRF4 to control an oncogenic gene expression program in PEL cells. These proteins promote KSHV-mediated B cell transformation by activating the expression of prosurvival genes through super-enhancers. Our report thus demonstrates that this DNA tumor virus encodes a transcription factor that functions with cellular IRF4 to drive oncogenic transcriptional reprogramming.
Mark Manzano; Thomas Günther; Hyunwoo Ju; John Nicholas; Elizabeth T. Bartom; Adam Grundhoff; Eva Gottwein. Kaposi’s Sarcoma-Associated Herpesvirus Drives a Super-Enhancer-Mediated Survival Gene Expression Program in Primary Effusion Lymphoma. mBio 2020, 11, 1 .
AMA StyleMark Manzano, Thomas Günther, Hyunwoo Ju, John Nicholas, Elizabeth T. Bartom, Adam Grundhoff, Eva Gottwein. Kaposi’s Sarcoma-Associated Herpesvirus Drives a Super-Enhancer-Mediated Survival Gene Expression Program in Primary Effusion Lymphoma. mBio. 2020; 11 (4):1.
Chicago/Turabian StyleMark Manzano; Thomas Günther; Hyunwoo Ju; John Nicholas; Elizabeth T. Bartom; Adam Grundhoff; Eva Gottwein. 2020. "Kaposi’s Sarcoma-Associated Herpesvirus Drives a Super-Enhancer-Mediated Survival Gene Expression Program in Primary Effusion Lymphoma." mBio 11, no. 4: 1.
Merkel Cell Polyomavirus (MCPyV) is the etiological agent of the majority of Merkel Cell Carcinomas (MCC). MCPyV positive MCCs harbor integrated, defective viral genomes that constitutively express viral oncogenes. Which molecular mechanisms promote viral integration, if distinct integration patterns exist, and if integration occurs preferentially at loci with specific chromatin states is unknown. We here combined short and long-read (nanopore) next-generation sequencing and present the first high-resolution analysis of integration site structure in MCC cell lines as well as primary tumor material. We find two main types of integration site structure: Linear patterns with chromosomal breakpoints that map closely together, and complex integration loci that exhibit local amplification of genomic sequences flanking the viral DNA. Sequence analysis suggests that linear patterns are produced during viral replication by integration of defective/linear genomes into host DNA double strand breaks via non-homologous end joining, NHEJ. In contrast, our data strongly suggest that complex integration patterns are mediated by microhomology-mediated break-induced replication, MMBIR. Furthermore, we show by ChIP-Seq and RNA-Seq analysis that MCPyV preferably integrates in open chromatin and provide evidence that viral oncogene expression is driven by the viral promoter region, rather than transcription from juxtaposed host promoters. Taken together, our data explain the characteristics of MCPyV integration and may also provide a model for integration of other oncogenic DNA viruses such as papillomaviruses. Integration of viral DNA into the host genome is a key event in the pathogenesis of many virus-induced cancers. One such cancer is Merkel cell carcinoma (MCC), a highly malignant tumor that harbors monoclonally integrated and replication-defective Merkel cell polyomavirus (MCPyV) genomes. Although MCPyV integration sites have been analyzed before, there is very little knowledge of the mechanisms that lead to mutagenesis and integration of viral genomes. We used multiple sequencing technologies and interrogation of chromatin states to perform a comprehensive characterization of MCPyV integration loci. This analysis allowed us to deduce the events that likely precede viral integration. We provide evidence that the mutations which result in the replication defective phenotype are acquired prior to integration and propose that the cellular DNA repair pathways non-homologous end joining (NHEJ) and microhomology-mediated break-induced replication (MMBIR) produce two principal MCPyV integration patterns (simple and complex, respectively). We show that, although MCPyV integrates predominantly in open chromatin regions, viral oncogene expression is independent of host promoters and driven by the viral promotor region. Our findings are important since they can explain the mechanisms of MCPyV integration. Furthermore, our model may also apply to papillomaviruses, another clinically important family of oncogenic DNA viruses.
Manja Czech-Sioli; Thomas Günther; Marlin Therre; Michael Spohn; Daniela Indenbirken; Juliane Theiss; Sabine Riethdorf; Minyue Qi; Malik Alawi; Corinna Wülbeck; Irene Fernandez-Cuesta; Franziska Esmek; Jürgen C. Becker; Adam Grundhoff; Nicole Fischer. High-resolution analysis of Merkel Cell Polyomavirus in Merkel Cell Carcinoma reveals distinct integration patterns and suggests NHEJ and MMBIR as underlying mechanisms. PLOS Pathogens 2020, 16, e1008562 .
AMA StyleManja Czech-Sioli, Thomas Günther, Marlin Therre, Michael Spohn, Daniela Indenbirken, Juliane Theiss, Sabine Riethdorf, Minyue Qi, Malik Alawi, Corinna Wülbeck, Irene Fernandez-Cuesta, Franziska Esmek, Jürgen C. Becker, Adam Grundhoff, Nicole Fischer. High-resolution analysis of Merkel Cell Polyomavirus in Merkel Cell Carcinoma reveals distinct integration patterns and suggests NHEJ and MMBIR as underlying mechanisms. PLOS Pathogens. 2020; 16 (8):e1008562.
Chicago/Turabian StyleManja Czech-Sioli; Thomas Günther; Marlin Therre; Michael Spohn; Daniela Indenbirken; Juliane Theiss; Sabine Riethdorf; Minyue Qi; Malik Alawi; Corinna Wülbeck; Irene Fernandez-Cuesta; Franziska Esmek; Jürgen C. Becker; Adam Grundhoff; Nicole Fischer. 2020. "High-resolution analysis of Merkel Cell Polyomavirus in Merkel Cell Carcinoma reveals distinct integration patterns and suggests NHEJ and MMBIR as underlying mechanisms." PLOS Pathogens 16, no. 8: e1008562.
ObjectivesWe used viral genomics to deeply analyze the first SARS-CoV-2 infection clusters in the metropolitan region of Hamburg, Germany. Epidemiological analysis and contact tracing together with a thorough investigation of virus variant patterns revealed low and high infection dose transmissions to be involved in transmission events.MethodsInfection control measures were applied to follow up contract tracing. Metagenomic RNA- and SARS-CoV-2 amplicon sequencing was performed from 25 clinical samples for sequence analysis and variant calling.ResultsThe index patient acquired SARS-CoV-2 in Italy and after his return to Hamburg transmitted it to 2 out of 132 contacts. Virus genomics and variant pattern clearly confirms the initial local cluster. We identify frequent single nucleotide polymorphisms at positions 241, 3037, 14408, 23403 and 28881 previously described in Italian sequences and now considered as one major genotype in Europe. While the index patient showed a single nucleotide polymorphism only one variant was transmitted to the recipients. Different to the initial cluster, we observed in household clusters occurring at the time in Hamburg also intra-host viral species transmission events.ConclusionsSARS-CoV-2 variant tracing highlights both, low infection dose transmissions suggestive of fomites as route of infection in the initial cluster and high and low infection dose transmissions in family clusters indicative of fomites and droplets as infection routes. This suggests (1) single viral particle infection can be sufficient to initiate SARS-CoV-2 infection and (2) household/family members are exposed to high virus loads and therefore have a high risk to acquire SARS-CoV-2.
Susanne Pfefferle; Thomas Guenther; Robin Kobbe; Manja Czech-Sioli; Dominic Nörz; René Santer; Jun Oh; Stefan Kluge; Lisa Oestereich; Kersten Peldschus; Daniela Indenbirken; Jiabin Huang; Adam Grundhoff; Martin Aepfelbacher; Johannes K. Knobloch; Marc Luetgehetmann; Nicole Fischer. Low and high infection dose transmissions of SARS-CoV-2 in the first COVID-19 clusters in Northern Germany. 2020, 1 .
AMA StyleSusanne Pfefferle, Thomas Guenther, Robin Kobbe, Manja Czech-Sioli, Dominic Nörz, René Santer, Jun Oh, Stefan Kluge, Lisa Oestereich, Kersten Peldschus, Daniela Indenbirken, Jiabin Huang, Adam Grundhoff, Martin Aepfelbacher, Johannes K. Knobloch, Marc Luetgehetmann, Nicole Fischer. Low and high infection dose transmissions of SARS-CoV-2 in the first COVID-19 clusters in Northern Germany. . 2020; ():1.
Chicago/Turabian StyleSusanne Pfefferle; Thomas Guenther; Robin Kobbe; Manja Czech-Sioli; Dominic Nörz; René Santer; Jun Oh; Stefan Kluge; Lisa Oestereich; Kersten Peldschus; Daniela Indenbirken; Jiabin Huang; Adam Grundhoff; Martin Aepfelbacher; Johannes K. Knobloch; Marc Luetgehetmann; Nicole Fischer. 2020. "Low and high infection dose transmissions of SARS-CoV-2 in the first COVID-19 clusters in Northern Germany." , no. : 1.
Merkel Cell Polyomavirus (MCPyV) is the etiological agent of the majority of Merkel Cell Carcinomas (MCC). MCPyV positive MCCs harbor integrated, defective viral genomes that constitutively express viral oncogenes. Which molecular mechanisms promote viral integration, if distinct integration patterns exist, and if integration occurs preferentially at loci with specific chromatin states is unknown.We here combined short and long-read (nanopore) next-generation sequencing and present the first high-resolution analysis of integration site structure in MCC cell lines as well as primary tumor material. We find two main types of integration site structure: Linear patterns with chromosomal breakpoints that map closely together, and complex integration loci that exhibit local amplification of genomic sequences flanking the viral DNA. Sequence analysis suggests that linear patterns are produced during viral replication by integration of defective/linear genomes into host DNA double strand breaks via non-homologous end joining, NHEJ. In contrast, our data strongly suggest that complex integration patterns are mediated by microhomology-mediated break-induced replication, MMBIR.Furthermore, we show by ChIP-Seq and RNA-Seq analysis that MCPyV preferably integrates in open chromatin and provide evidence that viral oncogene expression is driven by the viral promoter region, rather than transcription from juxtaposed host promoters. Taken together, our data explain the characteristics of MCPyV integration and may also provide a model for integration of other oncogenic DNA viruses such as papillomaviruses.Author summaryIntegration of viral DNA into the host genome is a key event in the pathogenesis of many virus-induced cancers. One such cancer is Merkel cell carcinoma (MCC), a highly malignant tumor that harbors monoclonally integrated and replication-defective Merkel cell polyomavirus (MCPyV) genomes. Although MCPyV integration sites have been analyzed before, there is very little knowledge of the mechanisms that lead to mutagenesis and integration of viral genomes. We used multiple sequencing technologies and interrogation of chromatin states to perform a comprehensive characterization of MCPyV integration loci. This analysis allowed us to deduce the events that likely precede viral integration. We provide evidence that the mutations which result in the replication defective phenotype are acquired prior to integration and propose that the cellular DNA repair pathways non-homologous end joining (NHEJ) and microhomology-mediated break-induced replication (MMBIR) produce two principal MCPyV integration patterns (simple and complex, respectively). We show that, although MCPyV integrates predominantly in open chromatin regions, viral oncogene expression is independent of host promoters and driven by the viral promotor region. Our findings are important since they can explain the mechanisms of MCPyV integration. Furthermore, our model may also apply to papillomaviruses, another clinically important family of oncogenic DNA viruses.
Manja Czech-Sioli; Thomas Günther; Marlin Therre; Michael Spohn; Daniela Indenbirken; Juliane Theiss; Sabine Riethdorf; Minyue Qi; Malik Alawi; Corinna Wülbeck; Irene Fernandez-Cuesta; Franziska Esmek; Jürgen C. Becker; Adam Grundhoff; Nicole Fischer. High-resolution analysis of Merkel Cell Polyomavirus in Merkel Cell Carcinoma reveals distinct integration patterns and suggests NHEJ and MMBIR as underlying mechanisms. 2020, 1 .
AMA StyleManja Czech-Sioli, Thomas Günther, Marlin Therre, Michael Spohn, Daniela Indenbirken, Juliane Theiss, Sabine Riethdorf, Minyue Qi, Malik Alawi, Corinna Wülbeck, Irene Fernandez-Cuesta, Franziska Esmek, Jürgen C. Becker, Adam Grundhoff, Nicole Fischer. High-resolution analysis of Merkel Cell Polyomavirus in Merkel Cell Carcinoma reveals distinct integration patterns and suggests NHEJ and MMBIR as underlying mechanisms. . 2020; ():1.
Chicago/Turabian StyleManja Czech-Sioli; Thomas Günther; Marlin Therre; Michael Spohn; Daniela Indenbirken; Juliane Theiss; Sabine Riethdorf; Minyue Qi; Malik Alawi; Corinna Wülbeck; Irene Fernandez-Cuesta; Franziska Esmek; Jürgen C. Becker; Adam Grundhoff; Nicole Fischer. 2020. "High-resolution analysis of Merkel Cell Polyomavirus in Merkel Cell Carcinoma reveals distinct integration patterns and suggests NHEJ and MMBIR as underlying mechanisms." , no. : 1.
Kaposi sarcoma-associated herpesvirus (KSHV) is the etiologic agent of several malignancies of endothelial and B-cell origin. The fact that latently infected tumor cells in these malignancies do not express classical viral oncogenes suggests that pathogenesis of KSHV-associated disease results from multistep processes that, in addition to constitutive viral gene expression, may require accumulation of cellular alterations. Heritable changes of the epigenome have emerged as an important co-factor that contributes to the pathogenesis of many non-viral cancers. Since KSHV encodes a number of factors that directly or indirectly manipulate host cell chromatin, it is an intriguing possibility that epigenetic reprogramming also contributes to the pathogenesis of KSHV-associated tumors. The fact that heritable histone modifications have also been shown to regulate viral gene expression programs in KSHV-infected tumor cells underlines the importance of epigenetic control during latency and tumorigenesis. We here review what is presently known about the role of epigenetic regulation of viral and host chromatin in KSHV infection and discuss how viral manipulation of these processes may contribute to the development of KSHV-associated disease.
Jacqueline Fröhlich; Adam Grundhoff. Epigenetic control in Kaposi sarcoma-associated herpesvirus infection and associated disease. Seminars in Immunopathology 2020, 42, 143 -157.
AMA StyleJacqueline Fröhlich, Adam Grundhoff. Epigenetic control in Kaposi sarcoma-associated herpesvirus infection and associated disease. Seminars in Immunopathology. 2020; 42 (2):143-157.
Chicago/Turabian StyleJacqueline Fröhlich; Adam Grundhoff. 2020. "Epigenetic control in Kaposi sarcoma-associated herpesvirus infection and associated disease." Seminars in Immunopathology 42, no. 2: 143-157.
Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, for which whole-genome and—for a subset—whole-transcriptome sequencing data from 2,658 cancers across 38 tumor types was aggregated, we systematically investigated potential viral pathogens using a consensus approach that integrated three independent pipelines. Viruses were detected in 382 genome and 68 transcriptome datasets. We found a high prevalence of known tumor-associated viruses such as Epstein–Barr virus (EBV), hepatitis B virus (HBV) and human papilloma virus (HPV; for example, HPV16 or HPV18). The study revealed significant exclusivity of HPV and driver mutations in head-and-neck cancer and the association of HPV with APOBEC mutational signatures, which suggests that impaired antiviral defense is a driving force in cervical, bladder and head-and-neck carcinoma. For HBV, HPV16, HPV18 and adeno-associated virus-2 (AAV2), viral integration was associated with local variations in genomic copy numbers. Integrations at the TERT promoter were associated with high telomerase expression evidently activating this tumor-driving process. High levels of endogenous retrovirus (ERV1) expression were linked to a worse survival outcome in patients with kidney cancer.
Marc Zapatka; Pcawg Pathogens; Ivan Borozan; Daniel S. Brewer; Murat Iskar; Adam Grundhoff; Malik Alawi; Nikita Desai; Holger Sültmann; Holger Moch; Colin S. Cooper; Roland Eils; Vincent Ferretti; Peter Lichter; PCAWG Consortium. The landscape of viral associations in human cancers. Nature Structural Biology 2020, 52, 320 -330.
AMA StyleMarc Zapatka, Pcawg Pathogens, Ivan Borozan, Daniel S. Brewer, Murat Iskar, Adam Grundhoff, Malik Alawi, Nikita Desai, Holger Sültmann, Holger Moch, Colin S. Cooper, Roland Eils, Vincent Ferretti, Peter Lichter, PCAWG Consortium. The landscape of viral associations in human cancers. Nature Structural Biology. 2020; 52 (3):320-330.
Chicago/Turabian StyleMarc Zapatka; Pcawg Pathogens; Ivan Borozan; Daniel S. Brewer; Murat Iskar; Adam Grundhoff; Malik Alawi; Nikita Desai; Holger Sültmann; Holger Moch; Colin S. Cooper; Roland Eils; Vincent Ferretti; Peter Lichter; PCAWG Consortium. 2020. "The landscape of viral associations in human cancers." Nature Structural Biology 52, no. 3: 320-330.
We describe DAMIAN, an open source bioinformatics tool designed for the identification of pathogenic microorganisms in diagnostic samples. By using authentic clinical samples and comparing our results to those from established analysis pipelines as well as conventional diagnostics, we demonstrate that DAMIAN rapidly identifies pathogens in different diagnostic entities, and accurately classifies viral agents down to the strain level. We furthermore show that DAMIAN is able to assemble full-length viral genomes even in samples co-infected with multiple virus strains, an ability which is of considerable advantage for the investigation of outbreak scenarios. While DAMIAN, similar to other pipelines, analyzes single samples to perform classification of sequences according to their likely taxonomic origin, it also includes a tool for cohort-based analysis. This tool uses cross-sample comparisons to identify sequence signatures that are frequently present in a sample group of interest (e.g., a disease-associated cohort), but occur less frequently in control cohorts. As this approach does not require homology searches in databases, it principally allows the identification of not only known, but also completely novel pathogens. Using samples from a meningitis outbreak, we demonstrate the feasibility of this approach in identifying enterovirus as the causative agent.
Malik Alawi; Lia Burkhardt; Daniela Indenbirken; Kerstin Reumann; Maximilian Christopeit; Nicolaus Kröger; Marc Lütgehetmann; Martin Aepfelbacher; Nicole Fischer; Adam Grundhoff. DAMIAN: an open source bioinformatics tool for fast, systematic and cohort based analysis of microorganisms in diagnostic samples. Scientific Reports 2019, 9, 16841 -17.
AMA StyleMalik Alawi, Lia Burkhardt, Daniela Indenbirken, Kerstin Reumann, Maximilian Christopeit, Nicolaus Kröger, Marc Lütgehetmann, Martin Aepfelbacher, Nicole Fischer, Adam Grundhoff. DAMIAN: an open source bioinformatics tool for fast, systematic and cohort based analysis of microorganisms in diagnostic samples. Scientific Reports. 2019; 9 (1):16841-17.
Chicago/Turabian StyleMalik Alawi; Lia Burkhardt; Daniela Indenbirken; Kerstin Reumann; Maximilian Christopeit; Nicolaus Kröger; Marc Lütgehetmann; Martin Aepfelbacher; Nicole Fischer; Adam Grundhoff. 2019. "DAMIAN: an open source bioinformatics tool for fast, systematic and cohort based analysis of microorganisms in diagnostic samples." Scientific Reports 9, no. 1: 16841-17.
Latent Kaposi sarcoma-associated herpesvirus (KSHV) genomes rapidly acquire distinct patterns of the activating histone modification H3K4-me3 as well as repressive H3K27-me3 marks, a modification linked to transcriptional silencing by polycomb repressive complexes (PRC). Interestingly, PRCs have recently been reported to restrict viral gene expression in a number of other viral systems, suggesting they may play a broader role in controlling viral chromatin. If so, it is an intriguing possibility that latency establishment may result from viral subversion of polycomb-mediated host responses to exogenous DNA. To investigate such scenarios we sought to establish whether rapid repression by PRC constitutes a general hallmark of herpesvirus latency. For this purpose, we performed a comparative epigenome analysis of KSHV and the related murine gammaherpesvirus 68 (MHV-68). We demonstrate that, while latently replicating MHV-68 genomes readily acquire distinct patterns of activation-associated histone modifications upon de novo infection, they fundamentally differ in their ability to efficiently attract H3K27-me3 marks. Statistical analyses of ChIP-seq data from in vitro infected cells as well as in vivo latency reservoirs furthermore suggest that, whereas KSHV rapidly attracts PRCs in a genome-wide manner, H3K27-me3 acquisition by MHV-68 genomes may require spreading from initial seed sites to which PRC are recruited as the result of an inefficient or stochastic recruitment, and that immune pressure may be needed to select for latency pools harboring PRC-silenced episomes in vivo. Using co-infection experiments and recombinant viruses, we also show that KSHV’S ability to rapidly and efficiently acquire H3K27-me3 marks does not depend on the host cell environment or unique properties of the KSHV-encoded LANA protein, but rather requires specific cis-acting sequence features. We show that the non-canonical PRC1.1 component KDM2B, a factor which binds to unmethylated CpG motifs, is efficiently recruited to KSHV genomes, indicating that CpG island characteristics may constitute these features. In accord with the fact that, compared to MHV-68, KSHV genomes exhibit a fundamentally higher density of CpG motifs, we furthermore demonstrate efficient acquisition of H2AK119-ub by KSHV and H3K36-me2 by MHV-68 (but not vice versa), furthermore supporting the notion that KSHV genomes rapidly attract PRC1.1 complexes in a genome-wide fashion. Collectively, our results suggest that rapid PRC silencing is not a universal feature of viral latency, but that some viruses may rather have adopted distinct genomic features to specifically exploit default host pathways that repress epigenetically naive, CpG-rich DNA. During herpesvirus latency, viral genomes persist as partially repressed nuclear episomes which do not express genes required for progeny production. Latently infected cells not only form a reservoir of lifelong persistence but also represent the driving force in cancers associated with tumorigenic herpesviruses such as KSHV. Hence, it is fundamentally important to understand the mechanisms controlling latency. We have shown previously that latent KSHV episomes rapidly acquire H3K27-me3, a histone mark associated with polycomb repressive complexes (PRC). PRCs play a pivotal role in the control of developmental genes but are also involved in the pathogenesis of several tumors. We here investigated whether PRC-repression represents a general feature of herpesvirus latency. By performing side-by-side analyses of KSHV and the related MHV-68 we show that the latter indeed has a fundamentally lower propensity to acquire H3K27-me3, and that KSHV’S ability to rapidly attract this mark is most likely the result of a specific sequence composition that promotes recruitment of non-canonical PRC1 (a complex which is important for the regulation of cellular CpG islands). Our results have widespread implications for nuclear DNA viruses and suggest that some viruses have specifically evolved to exploit common host responses to epigenetically naive DNA.
Thomas Günther; Jacqueline Fröhlich; Christina Herrde; Shinji Ohno; Lia Burkhardt; Heiko Adler; Adam Grundhoff. A comparative epigenome analysis of gammaherpesviruses suggests cis-acting sequence features as critical mediators of rapid polycomb recruitment. PLOS Pathogens 2019, 15, e1007838 .
AMA StyleThomas Günther, Jacqueline Fröhlich, Christina Herrde, Shinji Ohno, Lia Burkhardt, Heiko Adler, Adam Grundhoff. A comparative epigenome analysis of gammaherpesviruses suggests cis-acting sequence features as critical mediators of rapid polycomb recruitment. PLOS Pathogens. 2019; 15 (10):e1007838.
Chicago/Turabian StyleThomas Günther; Jacqueline Fröhlich; Christina Herrde; Shinji Ohno; Lia Burkhardt; Heiko Adler; Adam Grundhoff. 2019. "A comparative epigenome analysis of gammaherpesviruses suggests cis-acting sequence features as critical mediators of rapid polycomb recruitment." PLOS Pathogens 15, no. 10: e1007838.
Kaposi sarcoma (KS) is a tumour of endothelial origin caused by KS herpesvirus (KSHV) infection and suggested to originate from lymphatic endothelial cells (LECs). While KSHV establishes latency in virtually all susceptible cell types, LECs support a spontaneous lytic gene expression program with high viral genome copies and release of infectious virus. Here, we investigated the role of PROX1, SOX18 and COUPTF2, drivers of lymphatic endothelial fate during embryogenesis, in this unique KSHV infection program. We found that these factors were co-expressed in KS tumours with the viral lytic marker K8.1, and that SOX18 and PROX1 regulate KSHV infection via two independent mechanisms. SOX18 binds to the viral origins of replication and its depletion or chemical inhibition significantly reduced the KSHV genome copies in LECs. PROX1 interacts with ORF50, the initiator of the lytic cascade, increases lytic gene expression and virus production and its depletion reduces KSHV spontaneous lytic reactivation. Upon lytic replication, PROX1 binds to the KSHV genome in the promoter region of ORF50 and enhances its transactivation activity. These results demonstrate the importance of two endothelial transcription factors in the regulation of the KSHV life cycle and introduce SOX18 inhibition as a potential, novel therapeutic modality for KS.
Silvia Gramolelli; Endrit Elbasani; Veijo Nurminen; Krista Tuohinto; Thomas Günther; Riikka E. Kallinen; Seppo P. Kaijalainen; Raquel Diaz; Adam Grundhoff; Caj Haglund; Joseph M. Ziegelbauer; Mark Bower; Mathias Francois; Päivi M. Ojala. Oncogenic herpesvirus engages the endothelial transcription factors SOX18 and PROX1 to increase viral genome copies and virus production. 2019, 742932 .
AMA StyleSilvia Gramolelli, Endrit Elbasani, Veijo Nurminen, Krista Tuohinto, Thomas Günther, Riikka E. Kallinen, Seppo P. Kaijalainen, Raquel Diaz, Adam Grundhoff, Caj Haglund, Joseph M. Ziegelbauer, Mark Bower, Mathias Francois, Päivi M. Ojala. Oncogenic herpesvirus engages the endothelial transcription factors SOX18 and PROX1 to increase viral genome copies and virus production. . 2019; ():742932.
Chicago/Turabian StyleSilvia Gramolelli; Endrit Elbasani; Veijo Nurminen; Krista Tuohinto; Thomas Günther; Riikka E. Kallinen; Seppo P. Kaijalainen; Raquel Diaz; Adam Grundhoff; Caj Haglund; Joseph M. Ziegelbauer; Mark Bower; Mathias Francois; Päivi M. Ojala. 2019. "Oncogenic herpesvirus engages the endothelial transcription factors SOX18 and PROX1 to increase viral genome copies and virus production." , no. : 742932.
Herpesvirus genome replication, capsid assembly and packaging take place in the host cell nucleus. Matured capsids leave the nucleus through a unique envelopment-de-envelopment process at the nuclear membranes called nuclear egress. How assembled and DNA-containing herpesvirus capsids reach the sites of nuclear egress is however still controversially discussed, as host chromatin that marginalizes during infection might constitute a major barrier. For alphaherpesviruses, previous work has suggested that nuclear capsids use active transport mediated by nuclear filamentous actin (F-actin). However, direct evidence for nuclear capsid motility on nuclear F-actin was missing. Our subsequent work did not detect nuclear F-actin associated with motile capsids, but instead found evidence for chromatin remodeling to facilitate passive capsid diffusion. A recent report described that human cyto-megalovirus, a betaherpesvirus, induces nuclear F-actin and that the motor protein myosin V localizes to these structures. Direct evidence of capsid recruitment to these structures and motility on them was however missing. In this study, we tested the functional role of HCMV-induced, nuclear actin assemblies for capsid transport. We did not observe transport events along nuclear F-actin. Instead, reproduction of nuclear F-actin was only possible using strong overexpression of the fluorescent marker LifeAct-mCherry-NLS. Also, two alternative fluo-rescent F-actin markers did not detect F-actin in HCMV-infected cells. Furthermore, single particle tracking of nuclear HCMV capsids showed no indication for active transport, which is in line with previous work on alphaherpesviruses.
Felix Flomm; Eva Maria Borst; Thomas Günther; Rudolph Reimer; Laura De Vries; Carola Schneider; Adam Grundhoff; Kay Grünewald; Martin Messerle; Jens Bern-Hard Bosse. Human cytomegalovirus nuclear capsid motility is non-directed and independent of nuclear actin bundles. 2019, 641266 .
AMA StyleFelix Flomm, Eva Maria Borst, Thomas Günther, Rudolph Reimer, Laura De Vries, Carola Schneider, Adam Grundhoff, Kay Grünewald, Martin Messerle, Jens Bern-Hard Bosse. Human cytomegalovirus nuclear capsid motility is non-directed and independent of nuclear actin bundles. . 2019; ():641266.
Chicago/Turabian StyleFelix Flomm; Eva Maria Borst; Thomas Günther; Rudolph Reimer; Laura De Vries; Carola Schneider; Adam Grundhoff; Kay Grünewald; Martin Messerle; Jens Bern-Hard Bosse. 2019. "Human cytomegalovirus nuclear capsid motility is non-directed and independent of nuclear actin bundles." , no. : 641266.
Latent Kaposi sarcoma-associated herpesvirus (KSHV) genomes rapidly acquire distinct patterns of the activating histone modification H3K4-me3 as well as repressive H3K27-me3 marks, a modification linked to transcriptional silencing by polycomb repressive complexes (PRC). Interestingly, PRCs have recently been reported to restrict viral gene expression in a number of other viral systems, suggesting they may play a broader role in controlling viral chromatin. If so, it is an intriguing possibility that latency establishment may result from viral subversion of polycomb-mediated host responses to exogenous DNA.To investigate such scenarios we sought to establish whether rapid repression by PRC constitutes a general hallmark of herpesvirus latency. For this purpose, we performed a comparative epigenome analysis of KSHV and the related murine gammaherpesvirus 68 (MHV-68). We demonstrate that, while latently replicating MHV-68 genomes readily acquire distinct patterns of activation-associated histone modifications uponde novoinfection, they fundamentally differ in their ability to efficiently attract H3K27-me3 marks. Statistical analyses of ChIP-seq data fromin vitroinfected cells as well asin vivolatency reservoirs furthermore suggest that, whereas KSHV rapidly attracts PRCs in a genome-wide manner, H3K27-me3 acquisition by MHV-68 genomes may require spreading from initial seed sites to which PRC are recruited as the result of an inefficient or stochastic recruitment, and that immune pressure may be needed to select for latency pools harboring PRC-silenced episomesin vivo.Using co-infection experiments and recombinant viruses, we also show that KSHV’S ability to rapidly and efficiently acquire H3K27-me3 marks does not depend on the host cell environment or unique properties of the KSHV-encoded LANA protein, but rather requires specific cis-acting sequence features. We show that the non-canonical PRC1.1 component KDM2B, a factor which binds to unmethylated CpG motifs, is efficiently recruited to KSHV genomes, indicating that CpG island characteristics may constitute these features. In accord with the fact that, compared to MHV-68, KSHV genomes exhibit a fundamentally higher density of CpG motifs, we furthermore demonstrate efficient acquisition of H2AK119-ub by KSHV and H3K36-me2 by MHV-68 (but not vice versa), furthermore supporting the notion that KSHV genomes rapidly attract PRC1.1 complexes in a genome-wide fashion. Collectively, our results suggest that rapid PRC silencing is not a universal feature of viral latency, but that some viruses may rather have adopted distinct genomic features to specifically exploit default host pathways that repress epigenetically naive, CpG-rich DNA.Author SummaryDuring herpesvirus latency, viral genomes persists as partially repressed nuclear episomes which do not express genes required for progeny production. Latently infected cells not only form a reservoir of lifelong persistence but also represent the driving force in cancers associated with tumorigenic herpesviruses such as KSHV. Hence, it is fundamentally important to understand the mechanisms controlling latency. We have shown previously that latent KSHV episomes rapidly acquire H3K27-me3, a histone mark associated with polycomb repressive complexes (PRC). PRCs play a pivotal role in the control of developmental genes but are also involved in the pathogenesis of several tumors. We here investigated whether PRC-repression represents a general feature of herpesvirus latency. By performing side-by-side analyses of KSHV and the related MHV-68 we show that the latter indeed has a fundamentally lower propensity to acquire H3K27-me3, and that KSHV’S ability to rapidly attract this mark is most likely the result of a specific sequence composition that promotes recruitment of non-canonical PRC1 (a complex which is important for the regulation of cellular CpG islands). Our results have widespread implications for nuclear DNA viruses and suggest that some viruses have specifically evolved to exploit common host responses to epigenetically naive DNA.
Thomas Günther; Jacqueline Fröhlich; Christina Herrde; Shinji Ohno; Lia Burkhardt; Heiko Adler; Adam Grundhoff. A comparative epigenome analysis of gammaherpesviruses suggests cis-acting sequence features as critical mediators of rapid polycomb recruitment. 2019, 639898 .
AMA StyleThomas Günther, Jacqueline Fröhlich, Christina Herrde, Shinji Ohno, Lia Burkhardt, Heiko Adler, Adam Grundhoff. A comparative epigenome analysis of gammaherpesviruses suggests cis-acting sequence features as critical mediators of rapid polycomb recruitment. . 2019; ():639898.
Chicago/Turabian StyleThomas Günther; Jacqueline Fröhlich; Christina Herrde; Shinji Ohno; Lia Burkhardt; Heiko Adler; Adam Grundhoff. 2019. "A comparative epigenome analysis of gammaherpesviruses suggests cis-acting sequence features as critical mediators of rapid polycomb recruitment." , no. : 639898.
ANP32B belongs to a family of evolutionary conserved acidic nuclear phosphoproteins (ANP32A-H). Family members have been described as multifunctional regulatory proteins and proto-oncogenic factors affecting embryonic development, cell proliferation, apoptosis, and gene expression at various levels. Involvement of ANP32B in multiple processes of cellular life is reflected by the previous finding that systemic gene knockout (KO) of Anp32b leads to embryonic lethality in mice. Here, we demonstrate that a conditional KO of Anp32b is well tolerated in adult animals. However, after immune activation splenocytes isolated from Anp32b KO mice showed a strong commitment towards Th17 immune responses. Therefore, we further analyzed the respective animals in vivo using an experimental autoimmune encephalomyelitis (EAE) model. Interestingly, an exacerbated clinical score was observed in the Anp32b KO mice. This was accompanied by the finding that animal-derived T lymphocytes were in a more activated state, and RNA sequencing analyses revealed hyperactivation of several T lymphocyte-associated immune modulatory pathways, attended by significant upregulation of Tfh cell numbers that altogether might explain the observed strong autoreactive processes. Therefore, Anp32b appears to fulfill a role in regulating adequate adaptive immune responses and, hence, may be involved in dysregulation of pathways leading to autoimmune disorders and/or immune deficiencies.
Jan Chemnitz; Dorothea Pieper; Lena Stich; Udo Schumacher; Stefan Balabanov; Michael Spohn; Adam Grundhoff; Alexander Steinkasserer; Joachim Hauber; Elisabeth Zinser. The acidic protein rich in leucines Anp32b is an immunomodulator of inflammation in mice. Scientific Reports 2019, 9, 4853 .
AMA StyleJan Chemnitz, Dorothea Pieper, Lena Stich, Udo Schumacher, Stefan Balabanov, Michael Spohn, Adam Grundhoff, Alexander Steinkasserer, Joachim Hauber, Elisabeth Zinser. The acidic protein rich in leucines Anp32b is an immunomodulator of inflammation in mice. Scientific Reports. 2019; 9 (1):4853.
Chicago/Turabian StyleJan Chemnitz; Dorothea Pieper; Lena Stich; Udo Schumacher; Stefan Balabanov; Michael Spohn; Adam Grundhoff; Alexander Steinkasserer; Joachim Hauber; Elisabeth Zinser. 2019. "The acidic protein rich in leucines Anp32b is an immunomodulator of inflammation in mice." Scientific Reports 9, no. 1: 4853.
Oncogenic HPV types are major human carcinogens. Under hypoxia, HPV-positive cancer cells can repress the viral E6/E7 oncogenes and induce a reversible growth arrest. This response could contribute to therapy resistance, immune evasion, and tumor recurrence upon reoxygenation. Here, we uncover evidence that HPV oncogene repression is mediated by hypoxia-induced activation of canonical PI3K/mTORC2/AKT signaling. AKT-dependent downregulation of E6/E7 is only observed under hypoxia and occurs, at least in part, at the transcriptional level. Quantitative proteome analyses identify additional factors as candidates to be involved in AKT-dependent E6/E7 repression and/or hypoxic PI3K/mTORC2/AKT activation. These results connect PI3K/mTORC2/AKT signaling with HPV oncogene regulation, providing new mechanistic insights into the cross talk between oncogenic HPVs and their host cells.
Felicitas Bossler; Bianca J. Kuhn; Thomas Günther; Stephen J. Kraemer; Prajakta Khalkar; Svenja Adrian; Claudia Lohrey; Angela Holzer; Mitsugu Shimobayashi; Matthias Dürst; Arnulf Mayer; Frank Rösl; Adam Grundhoff; Jeroen Krijgsveld; Karin Hoppe-Seyler; Felix Hoppe-Seyler. Repression of Human Papillomavirus Oncogene Expression under Hypoxia Is Mediated by PI3K/mTORC2/AKT Signaling. mBio 2019, 10, e02323-18 .
AMA StyleFelicitas Bossler, Bianca J. Kuhn, Thomas Günther, Stephen J. Kraemer, Prajakta Khalkar, Svenja Adrian, Claudia Lohrey, Angela Holzer, Mitsugu Shimobayashi, Matthias Dürst, Arnulf Mayer, Frank Rösl, Adam Grundhoff, Jeroen Krijgsveld, Karin Hoppe-Seyler, Felix Hoppe-Seyler. Repression of Human Papillomavirus Oncogene Expression under Hypoxia Is Mediated by PI3K/mTORC2/AKT Signaling. mBio. 2019; 10 (1):e02323-18.
Chicago/Turabian StyleFelicitas Bossler; Bianca J. Kuhn; Thomas Günther; Stephen J. Kraemer; Prajakta Khalkar; Svenja Adrian; Claudia Lohrey; Angela Holzer; Mitsugu Shimobayashi; Matthias Dürst; Arnulf Mayer; Frank Rösl; Adam Grundhoff; Jeroen Krijgsveld; Karin Hoppe-Seyler; Felix Hoppe-Seyler. 2019. "Repression of Human Papillomavirus Oncogene Expression under Hypoxia Is Mediated by PI3K/mTORC2/AKT Signaling." mBio 10, no. 1: e02323-18.
The proliferative darkening syndrome (PDS) is a lethal disease of brown trout (Salmo trutta fario) which occurs in several alpine Bavarian limestone rivers. Because mortality can reach 100%, PDS is a serious threat for affected fish populations. Recently, Kuehn and colleagues reported that a high throughput RNA sequencing approach identified a piscine orthoreovirus (PRV) as a causative agent of PDS. We investigated samples from PDS-affected fish obtained from two exposure experiments performed at the river Iller in 2008 and 2009. Using a RT-qPCR and a well-established next-generation RNA sequencing pipeline for pathogen detection, PRV-specific RNA was not detectable in PDS fish from 2009. In contrast, PRV RNA was readily detectable in several organs from diseased fish in 2008. However, similar virus loads were detectable in the control fish which were not exposed to Iller water and did not show any signs of the disease. Therefore, we conclude that PRV is not the causative agent of PDS of brown trout in the rhithral region of alpine Bavarian limestone rivers. The abovementioned study by Kuehn used only samples from the exposure experiment from 2008 and detected a subclinical PRV bystander infection. Work is ongoing to identify the causative agent of PDS.
Robert Fux; Daniela Arndt; Martin C. Langenmayer; Julia Schwaiger; Hermann Ferling; Nicole Fischer; Daniela Indenbirken; Adam Grundhoff; Lars Dölken; Mikolaj Adamek; Dieter Steinhagen; Gerd Sutter. Piscine Orthoreovirus 3 Is Not the Causative Pathogen of Proliferative Darkening Syndrome (PDS) of Brown Trout (Salmo trutta fario). Viruses 2019, 11, 112 .
AMA StyleRobert Fux, Daniela Arndt, Martin C. Langenmayer, Julia Schwaiger, Hermann Ferling, Nicole Fischer, Daniela Indenbirken, Adam Grundhoff, Lars Dölken, Mikolaj Adamek, Dieter Steinhagen, Gerd Sutter. Piscine Orthoreovirus 3 Is Not the Causative Pathogen of Proliferative Darkening Syndrome (PDS) of Brown Trout (Salmo trutta fario). Viruses. 2019; 11 (2):112.
Chicago/Turabian StyleRobert Fux; Daniela Arndt; Martin C. Langenmayer; Julia Schwaiger; Hermann Ferling; Nicole Fischer; Daniela Indenbirken; Adam Grundhoff; Lars Dölken; Mikolaj Adamek; Dieter Steinhagen; Gerd Sutter. 2019. "Piscine Orthoreovirus 3 Is Not the Causative Pathogen of Proliferative Darkening Syndrome (PDS) of Brown Trout (Salmo trutta fario)." Viruses 11, no. 2: 112.
Rotaviruses are well‐known causative agents of enteric disorders in humans and other mammals, but little is known about their virulence and pathogenic role in pigeons and other birds. Starting in summer 2017, a series of outbreaks of an acute disease with high mortalities was reported in domestic pigeons in Germany, Belgium and Denmark. The clinical picture was characterized by diarrhea, vomiting, hepatic necrosis, and sudden fatalities. From these severe outbreaks, we discovered several previously unknown group A rotavirus (RVA) lineages of genotype G18P[17]‐I4‐R4‐C4‐M4‐A4‐T4‐N4‐E19‐H4, which were closely related but not identical to an RVA variant identified in cases of fatal hepatic necrosis in Australian pigeon lofts in 2016. Retrospective analysis demonstrated that the predecessors of the highly virulent variants have circulated in Europe since at least 2010. Our data indicate that reassortment and intercontinental spread has led to the emergence of novel RVA variants, which may constitute a major threat to animal welfare and health of domestic pigeon populations worldwide. This article is protected by copyright. All rights reserved.
Dennis Rubbenstroth; Elisabeth Peus; Eva Schramm; Daniel Kottmann; Hilke Bartels; Christina McCowan; Christoph Schulze; Valerij Akimkin; Nicole Fischer; Claudia Wylezich; Andreas Hlinak; Anja Spadinger; Ernst Großmann; Henning Petersen; Adam Grundhoff; Silke Rautenschlein; Lydia Teske. Identification of a novel clade of group A rotaviruses in fatally diseased domestic pigeons in Europe. Transboundary and Emerging Diseases 2018, 66, 552 -561.
AMA StyleDennis Rubbenstroth, Elisabeth Peus, Eva Schramm, Daniel Kottmann, Hilke Bartels, Christina McCowan, Christoph Schulze, Valerij Akimkin, Nicole Fischer, Claudia Wylezich, Andreas Hlinak, Anja Spadinger, Ernst Großmann, Henning Petersen, Adam Grundhoff, Silke Rautenschlein, Lydia Teske. Identification of a novel clade of group A rotaviruses in fatally diseased domestic pigeons in Europe. Transboundary and Emerging Diseases. 2018; 66 (1):552-561.
Chicago/Turabian StyleDennis Rubbenstroth; Elisabeth Peus; Eva Schramm; Daniel Kottmann; Hilke Bartels; Christina McCowan; Christoph Schulze; Valerij Akimkin; Nicole Fischer; Claudia Wylezich; Andreas Hlinak; Anja Spadinger; Ernst Großmann; Henning Petersen; Adam Grundhoff; Silke Rautenschlein; Lydia Teske. 2018. "Identification of a novel clade of group A rotaviruses in fatally diseased domestic pigeons in Europe." Transboundary and Emerging Diseases 66, no. 1: 552-561.