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Thomas Günther
Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Martinistrasse 52, 20251 Hamburg, Germany

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Communication
Published: 12 April 2021 in Viruses
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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.

ACS Style

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 Style

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 (4):661.

Chicago/Turabian Style

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. 2021. "SARS-CoV-2 Reinfection in a Healthcare Worker Despite the Presence of Detectable Neutralizing Antibodies." Viruses 13, no. 4: 661.

Preprint content
Published: 12 October 2020
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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.

ACS Style

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 Style

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.

Chicago/Turabian Style

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. 2020. "SARS-CoV-2 infects carotid arteries: implications for vascular disease and organ injury in COVID-19." , no. : 1.

Journal article
Published: 27 August 2020 in Viruses
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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.

ACS Style

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 Style

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 (9):952.

Chicago/Turabian Style

Endrit 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.

Journal article
Published: 25 August 2020 in mBio
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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.

ACS Style

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 Style

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 (4):1.

Chicago/Turabian Style

Mark 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.

Research article
Published: 24 August 2020 in PLOS Pathogens
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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.

ACS Style

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 Style

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 (8):e1008562.

Chicago/Turabian Style

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. 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.

Journal article
Published: 16 June 2020 in Journal of Virology
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DNA viruses have evolved complex strategies to gain control over the cell cycle. Several of them target APC/C, a key cellular machinery that controls the timely progression of the cell cycle, by either blocking or enhancing its activity. Here, we investigated the activity of APC/C during the lytic replication cycle of KSHV and found that, in contrast to that of KSHV's close relatives EBV and HCMV, KSHV lytic replication occurs while the APC/C is active. Perturbing APC/C activity by depleting a core protein or the adaptor proteins of the catalytic domain, and hence interfering with normal cell-cycle progression, did not affect virus replication. This suggests that KSHV has evolved to replicate independently of the activity of APC/C and in various cell cycle conditions.

ACS Style

Endrit Elbasani; Silvia Gramolelli; Thomas Günther; Ildar Gabaev; Adam Grundhoff; Päivi M. Ojala. Kaposi’s Sarcoma-Associated Herpesvirus Lytic Replication Is Independent of Anaphase-Promoting Complex Activity. Journal of Virology 2020, 94, 1 .

AMA Style

Endrit Elbasani, Silvia Gramolelli, Thomas Günther, Ildar Gabaev, Adam Grundhoff, Päivi M. Ojala. Kaposi’s Sarcoma-Associated Herpesvirus Lytic Replication Is Independent of Anaphase-Promoting Complex Activity. Journal of Virology. 2020; 94 (13):1.

Chicago/Turabian Style

Endrit Elbasani; Silvia Gramolelli; Thomas Günther; Ildar Gabaev; Adam Grundhoff; Päivi M. Ojala. 2020. "Kaposi’s Sarcoma-Associated Herpesvirus Lytic Replication Is Independent of Anaphase-Promoting Complex Activity." Journal of Virology 94, no. 13: 1.

Other
Published: 16 June 2020
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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.

ACS Style

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 Style

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.

Chicago/Turabian Style

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. 2020. "Low and high infection dose transmissions of SARS-CoV-2 in the first COVID-19 clusters in Northern Germany." , no. : 1.

Other
Published: 09 June 2020 in Cancer Research
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Kaposi sarcoma (KS) is a tumor caused by KS herpesvirus (KSHV) infection and is thought to originate from lymphatic endothelial cells (LEC). While KSHV establishes latency in virtually all susceptible cell types, LEC support spontaneous expression of oncogenic lytic genes, high viral genome copies, and release of infectious virus. It remains unknown the contribution of spontaneous virus production to the expansion of KSHV-infected tumor cells and the cellular factors that render the lymphatic environment unique to KSHV life cycle. We show here that expansion of the infected cell population, observed in LEC but not in blood EC, is dependent on the spontaneous virus production from infected LEC. The drivers of lymphatic endothelium development, SOX18 and PROX1, regulated different steps of the KSHV life cycle. SOX18 enhanced the number of intracellular viral genome copies and bound to the viral origins of replication. Genetic depletion or chemical inhibition of SOX18 caused a decrease of KSHV genome copy numbers. PROX1 interacted with ORF50, the viral initiator of lytic replication, and bound to the KSHV genome in the promoter region of ORF50, increasing its transactivation activity and KSHV spontaneous lytic gene expression and infectious virus release. In KS tumors, SOX18 and PROX1 expression correlated with latent and lytic KSHV protein expression. These results demonstrate the importance of two key transcriptional drivers of LEC fate in the regulation of the tumorigenic KSHV life cycle. Moreover, they introduce molecular targeting of SOX18 as a potential novel therapeutic avenue in KS.

ACS Style

Silvia Gramolelli; Endrit Elbasani; Krista Tuohinto; Veijo Nurminen; Thomas Günther; Riikka E. Kallinen; Seppo P. Kaijalainen; Raquel Diaz; Adam Grundhoff; Caj Haglund; Joseph M. Ziegelbauer; Teijo Pellinen; Mark Bower; Mathias Francois; Päivi M. Ojala. Oncogenic Herpesvirus Engages Endothelial Transcription Factors SOX18 and PROX1 to Increase Viral Genome Copies and Virus Production. Cancer Research 2020, 80, 3116 -3129.

AMA Style

Silvia Gramolelli, Endrit Elbasani, Krista Tuohinto, Veijo Nurminen, Thomas Günther, Riikka E. Kallinen, Seppo P. Kaijalainen, Raquel Diaz, Adam Grundhoff, Caj Haglund, Joseph M. Ziegelbauer, Teijo Pellinen, Mark Bower, Mathias Francois, Päivi M. Ojala. Oncogenic Herpesvirus Engages Endothelial Transcription Factors SOX18 and PROX1 to Increase Viral Genome Copies and Virus Production. Cancer Research. 2020; 80 (15):3116-3129.

Chicago/Turabian Style

Silvia Gramolelli; Endrit Elbasani; Krista Tuohinto; Veijo Nurminen; Thomas Günther; Riikka E. Kallinen; Seppo P. Kaijalainen; Raquel Diaz; Adam Grundhoff; Caj Haglund; Joseph M. Ziegelbauer; Teijo Pellinen; Mark Bower; Mathias Francois; Päivi M. Ojala. 2020. "Oncogenic Herpesvirus Engages Endothelial Transcription Factors SOX18 and PROX1 to Increase Viral Genome Copies and Virus Production." Cancer Research 80, no. 15: 3116-3129.

Journal article
Published: 04 June 2020 in Microbiology Resource Announcements
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Here, we describe the complete genome sequence of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain isolated from an oropharyngeal swab sample from a female patient with COVID-19 who was infected in Hamburg, northern Germany.

ACS Style

Susanne Pfefferle; Jiabin Huang; Dominik Nörz; Daniela Indenbirken; Marc Lütgehetmann; Lisa Oestereich; Thomas Günther; Adam Grundhoff; Martin Aepfelbacher; Nicole Fischer. Complete Genome Sequence of a SARS-CoV-2 Strain Isolated in Northern Germany. Microbiology Resource Announcements 2020, 9, 1 .

AMA Style

Susanne Pfefferle, Jiabin Huang, Dominik Nörz, Daniela Indenbirken, Marc Lütgehetmann, Lisa Oestereich, Thomas Günther, Adam Grundhoff, Martin Aepfelbacher, Nicole Fischer. Complete Genome Sequence of a SARS-CoV-2 Strain Isolated in Northern Germany. Microbiology Resource Announcements. 2020; 9 (23):1.

Chicago/Turabian Style

Susanne Pfefferle; Jiabin Huang; Dominik Nörz; Daniela Indenbirken; Marc Lütgehetmann; Lisa Oestereich; Thomas Günther; Adam Grundhoff; Martin Aepfelbacher; Nicole Fischer. 2020. "Complete Genome Sequence of a SARS-CoV-2 Strain Isolated in Northern Germany." Microbiology Resource Announcements 9, no. 23: 1.

Preprint content
Published: 23 April 2020
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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.

ACS Style

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 Style

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.

Chicago/Turabian Style

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. 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.

Research article
Published: 31 October 2019 in PLOS Pathogens
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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.

ACS Style

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 Style

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 (10):e1007838.

Chicago/Turabian Style

Thomas 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.

Preprint content
Published: 27 August 2019
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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.

ACS Style

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 Style

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.

Chicago/Turabian Style

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. 2019. "Oncogenic herpesvirus engages the endothelial transcription factors SOX18 and PROX1 to increase viral genome copies and virus production." , no. : 742932.

Preprint
Published: 24 May 2019
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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.

ACS Style

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 Style

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.

Chicago/Turabian Style

Felix 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.

Preprint
Published: 15 May 2019
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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.

ACS Style

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 Style

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.

Chicago/Turabian Style

Thomas 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.

Journal article
Published: 26 February 2019 in mBio
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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.

ACS Style

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 Style

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 (1):e02323-18.

Chicago/Turabian Style

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. 2019. "Repression of Human Papillomavirus Oncogene Expression under Hypoxia Is Mediated by PI3K/mTORC2/AKT Signaling." mBio 10, no. 1: e02323-18.

Journal article
Published: 01 October 2017 in Current Opinion in Virology
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ACS Style

Thomas Günther; Adam Grundhoff. Epigenetic manipulation of host chromatin by Kaposi sarcoma-associated herpesvirus: a tumor-promoting factor? Current Opinion in Virology 2017, 26, 104 -111.

AMA Style

Thomas Günther, Adam Grundhoff. Epigenetic manipulation of host chromatin by Kaposi sarcoma-associated herpesvirus: a tumor-promoting factor? Current Opinion in Virology. 2017; 26 ():104-111.

Chicago/Turabian Style

Thomas Günther; Adam Grundhoff. 2017. "Epigenetic manipulation of host chromatin by Kaposi sarcoma-associated herpesvirus: a tumor-promoting factor?" Current Opinion in Virology 26, no. : 104-111.

Journal article
Published: 16 June 2017 in Scientific Reports
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We recovered the first full-length poxvirus genome, including the terminal hairpin region, directly from complex clinical material using a combination of second generation short read and third generation nanopore sequencing technologies. The complete viral genome sequence was directly recovered from a skin lesion of a grey seal thereby preventing sequence changes due to in vitro passaging of the virus. Subsequent analysis of the proteins encoded by this virus identified genes specific for skin adaptation and pathogenesis of parapoxviruses. These data warrant the classification of seal parapoxvirus, tentatively designated SePPV, as a new species within the genus Parapoxvirus.

ACS Style

Thomas Günther; Ludwig Haas; Malik Alawi; Peter Wohlsein; Jerzy Marks; Adam Grundhoff; Paul Becher; Nicole Fischer. Recovery of the first full-length genome sequence of a parapoxvirus directly from a clinical sample. Scientific Reports 2017, 7, 1 -8.

AMA Style

Thomas Günther, Ludwig Haas, Malik Alawi, Peter Wohlsein, Jerzy Marks, Adam Grundhoff, Paul Becher, Nicole Fischer. Recovery of the first full-length genome sequence of a parapoxvirus directly from a clinical sample. Scientific Reports. 2017; 7 (1):1-8.

Chicago/Turabian Style

Thomas Günther; Ludwig Haas; Malik Alawi; Peter Wohlsein; Jerzy Marks; Adam Grundhoff; Paul Becher; Nicole Fischer. 2017. "Recovery of the first full-length genome sequence of a parapoxvirus directly from a clinical sample." Scientific Reports 7, no. 1: 1-8.

Journal article
Published: 15 March 2017 in Journal of Virology
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KS-Bcl-2 is a Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded viral Bcl-2 (vBcl-2) homolog which has apoptosis- and autophagy-inhibiting activity when expressed in transfected cells. However, little is known about its function during viral infection. As KS-Bcl-2 is expressed during the lytic replication cycle, we used constitutively lytic and inducibly lytic KSHV mutants to investigate the role of KS-Bcl-2 during the lytic cycle. We show that KSHV cannot complete the lytic replication cycle and produce infectious progeny in the absence of KS-Bcl-2, indicating that the protein is essential for KSHV replication. Replacement of the KS-Bcl-2 coding sequence, ORF16, by sequences encoding a potent cellular apoptosis and autophagy inhibitor, Bcl-XL, or the cytomegalovirus mitochondrial inhibitor of apoptosis, vMIA, did not rescue KSHV replication, suggesting that KS-Bcl-2 has a function that goes beyond apoptosis and autophagy inhibition. Strikingly, the vBcl-2 proteins of the related γ 2 -herpesviruses murine herpesvirus 68 and herpesvirus saimiri did not rescue the replication of a KS-Bcl-2 deletion mutant, but rhesus rhadinovirus (RRV) vBcl-2 did. Deletion of ORF16 from the RRV genome abrogated viral replication, but its replacement by KSHV ORF16 rescued RRV replication, indicating that the essential vBcl-2 function is conserved between these two primate rhadinoviruses. We further show that the KSHV and RRV Bcl-2 homologs localize to the mitochondria and nuclei of infected cells. Deletion of 17 amino acids from the N terminus of KS-Bcl-2 abrogates nuclear localization and KSHV replication, suggesting that KS-Bcl-2 might execute its essential function in the nuclei of infected cells. IMPORTANCE Several viruses express proteins homologous to cellular Bcl-2. Viral Bcl-2 proteins have functions similar to those of cellular Bcl-2: they can inhibit apoptosis, a form of programmed cell death, and autophagy, a self-degradative process for the disposal of dysfunctional or unwanted components. This study shows that the vBcl-2 proteins of KSHV and RRV differ from other vBcl-2 proteins in that they are essential for viral replication. The essential function is separate from the apoptosis- and autophagy-inhibiting activity but correlates with an unusual localization within the cell nucleus, suggesting that these proteins exert a novel function in the nucleus.

ACS Style

Antonio Gallo; Melanie Lampe; Thomas Günther; Wolfram Brune. The Viral Bcl-2 Homologs of Kaposi's Sarcoma-Associated Herpesvirus and Rhesus Rhadinovirus Share an Essential Role for Viral Replication. Journal of Virology 2017, 91, e01875-16 .

AMA Style

Antonio Gallo, Melanie Lampe, Thomas Günther, Wolfram Brune. The Viral Bcl-2 Homologs of Kaposi's Sarcoma-Associated Herpesvirus and Rhesus Rhadinovirus Share an Essential Role for Viral Replication. Journal of Virology. 2017; 91 (6):e01875-16.

Chicago/Turabian Style

Antonio Gallo; Melanie Lampe; Thomas Günther; Wolfram Brune. 2017. "The Viral Bcl-2 Homologs of Kaposi's Sarcoma-Associated Herpesvirus and Rhesus Rhadinovirus Share an Essential Role for Viral Replication." Journal of Virology 91, no. 6: e01875-16.

Case reports
Published: 16 September 2016 in Diagnostic Microbiology and Infectious Disease
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Recently Gram-negative bacteria co-producing multiple carbapenemases have emerged in different parts of the world. We report the first isolation of an Escherichia coli strain co-producing the carbapenemases NDM-1 and OXA-232.

ACS Style

Anna Both; Jiabin Huang; Martin Kaase; Julia Hezel; Daniel Wertheimer; Ines Fenner; Thomas Günther; Adam Grundhoff; Henning Büttner; Martin Aepfelbacher; Holger Rohde; Moritz Hentschke. First report of Escherichia coli co-producing NDM-1 and OXA-232. Diagnostic Microbiology and Infectious Disease 2016, 86, 437 -438.

AMA Style

Anna Both, Jiabin Huang, Martin Kaase, Julia Hezel, Daniel Wertheimer, Ines Fenner, Thomas Günther, Adam Grundhoff, Henning Büttner, Martin Aepfelbacher, Holger Rohde, Moritz Hentschke. First report of Escherichia coli co-producing NDM-1 and OXA-232. Diagnostic Microbiology and Infectious Disease. 2016; 86 (4):437-438.

Chicago/Turabian Style

Anna Both; Jiabin Huang; Martin Kaase; Julia Hezel; Daniel Wertheimer; Ines Fenner; Thomas Günther; Adam Grundhoff; Henning Büttner; Martin Aepfelbacher; Holger Rohde; Moritz Hentschke. 2016. "First report of Escherichia coli co-producing NDM-1 and OXA-232." Diagnostic Microbiology and Infectious Disease 86, no. 4: 437-438.

Journal article
Published: 13 February 2016 in Current Protocols in Microbiology
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Complex regulation of viral transcription patterns and DNA replication levels is a feature of many DNA viruses. This is especially true for those viruses which establish latent or persistent infections (e.g., herpesviruses, papillomaviruses, polyomaviruses, or adenovirus), as long-term persistence often requires adaptation of gene expression programs and/or replication levels to the cellular milieu. A key factor in the control of such processes is the establishment of a specific chromatin state on promoters or replication origins, which in turn will determine whether or not the underlying DNA is accessible for other factors that mediate downstream processes. Chromatin immunoprecipitation (ChIP) is a powerful technique to investigate viral chromatin, in particular to study binding patterns of modified histones, transcription factors or other DNA-/chromatin-binding proteins that regulate the viral lifecycle. Here, we provide protocols that are suitable for performing ChIP-PCR and ChIP-Seq studies on chromatin of large and small viral genomes.

ACS Style

Thomas Günther; Juliane Theiss; Nicole Fischer; Adam Grundhoff. Investigation of Viral and Host Chromatin by ChIP‐PCR or ChIP‐Seq Analysis. Current Protocols in Microbiology 2016, 40, 1E.10.1 -1E.10.21.

AMA Style

Thomas Günther, Juliane Theiss, Nicole Fischer, Adam Grundhoff. Investigation of Viral and Host Chromatin by ChIP‐PCR or ChIP‐Seq Analysis. Current Protocols in Microbiology. 2016; 40 (1):1E.10.1-1E.10.21.

Chicago/Turabian Style

Thomas Günther; Juliane Theiss; Nicole Fischer; Adam Grundhoff. 2016. "Investigation of Viral and Host Chromatin by ChIP‐PCR or ChIP‐Seq Analysis." Current Protocols in Microbiology 40, no. 1: 1E.10.1-1E.10.21.