John Ziebuhr

John Ziebuhr
Justus-Liebig-Universität Gießen | JLU · Institute of Medical Virology

Doctor of Medicine

About

186
Publications
115,975
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23,002
Citations
Citations since 2017
74 Research Items
16700 Citations
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Introduction

Publications

Publications (186)
Article
Despite the great success of vaccines that protect against RNA virus infections and the development and clinical use of a limited number of RNA virus-specific drugs, there is still an urgent need for new classes of antiviral drugs against circulating or emerging RNA viruses. To date, it has proven difficult to efficiently suppress RNA virus replica...
Chapter
Coronaviruses form a genetically divergent family of enveloped RNA viruses that includes important human and animal pathogens. Coronaviruses have the largest genomes (30 kb) among all known RNA viruses and use complex mechanisms to express and replicate their genome. Seven coronaviruses are known to infect humans. They have been classified as belon...
Article
Full-text available
The Na+/taurocholate co-transporting polypeptide (NTCP, gene symbol SLC10A1) is both a physiological bile acid transporter and the high-affinity hepatic receptor for the hepatitis B and D viruses (HBV/HDV). Virus entry via endocytosis of the virus/NTCP complex involves co-factors, but this process is not fully understood. As part of the innate immu...
Article
Full-text available
Rocaglates are potent broad-spectrum antiviral compounds with a promising safety profile. They inhibit viral protein synthesis for different RNA viruses by clamping the 5′-UTRs of mRNAs onto the surface of the RNA helicase eIF4A. Apart from the natural rocaglate silvestrol, synthetic rocaglates like zotatifin or CR-1-31-B have been developed. Here,...
Article
Full-text available
Zusammenfassung Das Nationale Referenzzentrum (NRZ) für Hepatitis-B-Viren (HBV) und Hepatitis-D-Viren (HDV) befindet sich seit seiner Gründung und Berufung im Jahr 2011 am Institut für Medizinische Virologie der Justus-Liebig-Universität Gießen (JLU). In diesem Beitrag werden die Tätigkeitsbereiche des NRZ und die damit verbundenen Erfahrungen besc...
Article
Full-text available
Circular RNAs (circRNAs) are noncoding RNAs that exist in all eukaryotes investigated and are derived from back-splicing of certain pre-mRNA exons. Here, we report the application of artificial circRNAs designed to act as antisense-RNAs. We systematically tested a series of antisense-circRNAs targeted to the SARS-CoV-2 genome RNA, in particular its...
Article
Full-text available
Coronaviruses (CoVs) are important human pathogens for which no specific treatment is available. Here, we provide evidence that pharmacological reprogramming of ER stress pathways can be exploited to suppress CoV replication. The ER stress inducer thapsigargin efficiently inhibits coronavirus (HCoV-229E, MERS-CoV, SARS-CoV-2) replication in differe...
Article
Full-text available
The global emergence of SARS-CoV-2 urgently requires an in-depth understanding of molecular functions of viral proteins and their interactions with the host proteome. Several individual omics studies have extended our knowledge of COVID-19 pathophysiology1–10. Integration of such datasets to obtain a holistic view of virus-host interactions and to...
Article
A group convened and led by the Virus Evolution Working Group of the World Health Organization reports on its deliberations and announces a naming scheme that will enable clear communication about SARS-CoV-2 variants of interest and concern.
Article
Full-text available
At least six small alternative-frame open reading frames (ORFs) overlapping well-characterized SARS-CoV-2 genes have been hypothesized to encode accessory proteins. Researchers have used different names for the same ORF or the same name for different ORFs, resulting in erroneous homological and functional inferences. We propose standard names for t...
Article
Full-text available
The SARS-CoV-2 virus is the causative agent of the global COVID-19 infectious disease outbreak, which can lead to acute respiratory distress syndrome (ARDS). However, it is still unclear how the virus interferes with immune cell and metabolic functions in the human body. In this study, we investigated the immune response in acute or convalescent CO...
Article
Full-text available
The increase in pandemics caused by RNA viruses of zoonotic origin highlights the urgent need for broad-spectrum antivirals against novel and re-emerging RNA viruses. Broad-spectrum antivirals could be deployed as first-line interventions during an outbreak while virus-specific drugs and vaccines are developed and rolled out. Viruses depend on the...
Article
Full-text available
Coronaviruses infect many different species including humans. The last two decades have seen three zoonotic coronaviruses, with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) causing a pandemic in 2020. Coronaviral non-structural proteins (nsps) form the replication-transcription complex (RTC). Nsp7 and nsp8 interact with and regulate...
Article
Full-text available
Trans-acting regulatory RNAs have the capacity to base pair with more mRNAs than generally detected under defined conditions, raising the possibility that sRNA target specificities vary depending on the specific metabolic or environmental conditions. In Sinorhizobium meliloti, the sRNA rnTrpL is derived from a tryptophan (Trp) transcription attenua...
Article
Full-text available
Significance We report an intersubunit interaction within the coronavirus replication–transcription complex that is critical for replication and evolutionarily conserved. We provide evidence that the nsp12-associated NiRAN domain has nucleoside monophosphate (NMP) transferase activity in trans and identified nsp9, an RNA-binding protein, as its tar...
Preprint
Full-text available
The increase in pandemics caused by RNA viruses of zoonotic origin highlights the urgent need for broad-spectrum antivirals against novel and re-emerging RNA viruses. Broad-spectrum antivirals could be deployed as first-line interventions during an outbreak while virus-specific drugs and vaccines are developed and rolled out. Viruses depend on the...
Article
Full-text available
The Front Cover presents an experimental weapon changing the outcome of a battle in the respiratory system. The picture shows severe acute respiratory syndrome corona virus (SARS‐CoV) particles and the virus′ own papain‐like protease (PLpro, PDB‐ID 3E9S) through the window of a cockpit. The essential protease is targeted and “bombarded” with the no...
Article
Full-text available
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of COVID-19, a severe respiratory disease with varying clinical presentations and outcomes, and responsible for a major pandemic that started in early 2020. With no vaccines or effective antiviral treatments available, the quest for novel therapeutic solutions remai...
Preprint
At least six small alternate-frame open reading frames (ORFs) overlapping well-characterized SARS-CoV-2 genes have been hypothesized to encode accessory proteins. Researchers have used different names for the same ORF or the same name for different ORFs, resulting in erroneous homological and functional inferences. We propose standard names for the...
Article
Despite the pandemic status of COVID-19, there is limited information about host risk factors and treatment beyond supportive care. Immunoglobulin G (IgG) could be a potential treatment target. Our aim was to determine the incidence of IgG deficiency and associated risk factors in a cohort of 62 critical ill COVID-19 patients admitted to two German...
Preprint
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a betacoronavirus in the subgenus Sarbecovirus causes a respiratory disease with varying symptoms referred to as coronavirus disease 2019 (COVID-19) and is responsible for a pandemic that started in early 2020. With no vaccines or effective antiviral treatments available, and infection a...
Article
Full-text available
CITATION: Walker P J, Cowley J A, Dong X, Huang J, Moody N, Ziebuhr J, ICTV Report Consortium. 2020. ICTV virus taxonomy profile: Roniviridae. J Gen Virol, doi: 10.1099/jgv.0.001514. ABSTRACT: The family Roniviridae includes the genus Okavirus for three species of viruses with enveloped, rod-shaped virions. The monopartite, positive-sense ssRNA ge...
Chapter
Man unterscheidet 7 humanpathogene Coronaviren, die entweder zum Genus Alphacoronavirus oder zum Genus Betacoronavirus gehören (Subfamilie Orthocoronavirinae, Familie Coronaviridae). Das vorläufig letzte, 7. humanpathogene Coronavirus, SARS-CoV-2 (Genus Betacoronavirus), wurde im Winter 2019/2020 entdeckt. Humane Coronaviren verursachen akute respi...
Technical Report
Full-text available
CITATION: Walker P J, Cowley J A, Dong X, Huang J, Moody N, Ziebuhr J, ICTV Report Consortium. 2020. ICTV virus taxonomy profile: Roniviridae. J Gen Virol, doi: 10.1099/jgv.0.001514. Original report: https://talk.ictvonline.org/ictv-reports/ictv_online_report/positive-sense-rna-viruses/w/roniviridae SUMMARY: The family Roniviridae includes a sing...
Preprint
Full-text available
Coronaviruses infect many different species including humans. The last two decades have seen three zoonotic coronaviruses with SARS-CoV-2 causing a pandemic in 2020. Coronaviral non-structural proteins (nsp) built up the replication-transcription complex (RTC). Nsp7 and nsp8 interact with and regulate the RNA-dependent RNA-polymerase and other enzy...
Article
Full-text available
Inhibition of coronavirus (CoV)-encoded papain-like cysteine proteases (PLpro) represents an attractive strategy to treat infections by these important human pathogens. Herein we report on structure-activity relationships (SAR) of the non-covalent active-site directed inhibitor (R)-5-amino-2-methyl-N-(1-(naphthalen-1-yl)ethyl)benzamide (2b), which...
Preprint
Coronaviruses (CoVs) are important human pathogens for which no specific treatment is available. Here, we provide evidence that pharmacological reprogramming of ER stress pathways can be exploited to suppress CoV replication. We found that the ER stress inducer thapsigargin efficiently inhibits coronavirus (HCoV-229E, MERS-CoV, SARS-CoV-2) replicat...
Preprint
Full-text available
The sudden global emergence of SARS-CoV-2 urgently requires an in-depth understanding of molecular functions of viral proteins and their interactions with the host proteome. Several omics studies have extended our knowledge of COVID-19 pathophysiology, including some focused on proteomic aspects. To understand how SARS-CoV-2 and related coronavirus...
Article
Full-text available
The present outbreak of a coronavirus-associated acute respiratory disease called coronavirus disease 19 (COVID-19) is the third documented spillover of an animal coronavirus to humans in only two decades that has resulted in a major epidemic. The Coronaviridae Study Group (CSG) of the International Committee on Taxonomy of Viruses, which is respon...
Preprint
Full-text available
The present outbreak of lower respiratory tract infections, including respiratory distress syndrome, is the third spillover, in only two decades, of an animal coronavirus to humans resulting in a major epidemic. Here, the Coronavirus Study Group (CSG) of the International Committee on Taxonomy of Viruses, which is responsible for developing the off...
Article
Full-text available
Sequence analyses of RNA virus genomes remain challenging owing to the exceptional genetic plasticity of these viruses. Because of high mutation and recombination rates, genome replication by viral RNA-dependent RNA polymerases leads to populations of closely related viruses, so-called "quasispecies." Standard (short-read) sequencing technologies a...
Article
Full-text available
Cavally virus (CavV)is a mosquito-borne plus-strand RNA virus in the family Mesoniviridae (order Nidovirales). We present X-ray structures for the CavV 3C-like protease (3CL pro ), as a free enzyme and in complex with a peptide aldehyde inhibitor mimicking the P4-to-P1 residues of a natural substrate. The 3CL pro structure (refined to 1.94 Å)shows...
Article
Full-text available
Ribosome-mediated transcription attenuation is a basic posttranscriptional regulation mechanism in bacteria. Liberated attenuator RNAs arising in this process are generally considered nonfunctional. In Sinorhizobium meliloti, the tryptophan (Trp) biosynthesis genes are organized into three operons, trpE(G), ppiD-trpDC-moaC-moeA, and trpFBA-accD-fol...
Preprint
Full-text available
Ribosome-mediated transcription attenuation in bacteria is an important regulatory mechanism that is controlled by the translation of a short upstream ORF (uORF). Efficient uORF translation causes transcription termination downstream of the uORF. The resulting leader peptide and small attenuator RNA are generally considered nonfunctional. Here, we...
Article
Previously, coronavirus nsp8 proteins were suggested to have template-dependent RNA polymerase activities resembling those of RNA primases or even canonical RNA-dependent RNA polymerases, while more recent studies have suggested an essential cofactor function of nsp8 (plus nsp7) for nsp12-mediated RNA-dependent RNA polymerase activity. In an effort...
Preprint
Full-text available
Sequence analyses of RNA virus genomes remain challenging due to the exceptional genetic plasticity of these viruses. Because of high mutation and recombination rates, genome replication by viral RNA-dependent RNA polymerases leads to populations of closely related viruses, so-called 'quasispecies'. Standard (short-read) sequencing technologies are...
Article
Full-text available
Feline infectious peritonitis (FIP), one of the most important lethal infections of cats, is caused by feline infectious peritonitis virus (FIPV), the high-virulence biotype of feline coronaviruses (FCoVs). FIPVs are suggested to emerge from feline enteric coronaviruses (FECVs) by acquiring mutations in specific genes in the course of persistent in...
Article
White bream virus (WBV), a poorly characterized plus-strand RNA virus infecting freshwater fish of the Cyprinidae family, is the prototype species of the genus Bafinivirus in the subfamily Torovirinae (family Coronaviridae, order Nidovirales). In common with other nidoviruses featuring >20 kilobase genomes, bafiniviruses have been predicted to enco...
Article
Full-text available
Viral respiratory infections are among the most common causes of disease in humans, particularly in young children, and remain a major public health problem worldwide. For many geographic regions, there is limited epidemiological information on the main causative agents of these diseases. In this article, we investigated, in a prospective study, th...
Article
Full-text available
Recently, a novel antiviral compound (K22) that inhibits replication of a broad range of animal and human coronaviruses was reported to interfere with viral RNA synthesis by impairing double-membrane vesicle (DMV) formation (Lundin et al., 2014). Here we assessed potential antiviral activities of K22 against a range of viruses representing two (sub...
Article
Structure predictions suggest a partial conservation of RNA structure elements in coronavirus terminal genome regions. Here, we determined the structures of stem-loops (SL) 1 and 2 of two alphacoronaviruses, human coronavirus (HCoV) 229E and NL63, by RNA structure probing and studied the functional relevance of these putative cis-acting elements. H...
Article
Coronaviruses (CoV) and picornaviruses are plus-strand RNA viruses that use 5' cap-dependent and cap-independent strategies, respectively, for viral mRNA translation initiation. Here, we analyzed the effects of the plant compound silvestrol, a specific inhibitor of the DEAD-box RNA helicase eIF4A, on viral translation using a dual luciferase assay...
Article
Full-text available
Coronavirus replication is associated with intracellular membrane rearrangements in infected cells, resulting in the formation of double-membrane vesicles (DMVs) and other membranous structures that are referred to as replicative organelles (ROs). The latter provide a structural scaffold for viral replication/transcription complexes (RTCs) and help...
Article
Full-text available
Feline coronaviruses encode five accessory proteins with largely elusive functions. Here, one of these proteins, called 7b (206 residues), was investigated using a reverse genetic approach established for feline infectious peritonitis virus (FIPV) strain 79-1146. Recombinant FIPVs (rFPIVs) expressing mutant and/or FLAG-tagged forms of 7b were gener...
Article
Full-text available
Coronavirus replication takes place in the host cell cytoplasm and triggers inflammatory gene expression by poorly characterized mechanisms. To obtain more insight into the signals and molecular events that coordinate global host responses in the nucleus of coronavirus-infected cells, first, transcriptome dynamics was studied in human coronavirus 2...
Data
Related to Fig 2. HCoV-229E-induced genes in HuH7 cells. (A) Time course experiments were performed and the mRNA expression of the indicated genes was analyzed by RT-qPCR. Data show means +/- s.e.m. from three (uninfected, HCoV-229E) or two (HCoV-229Einactive) independent experiments. (B) Depicted are all individual ratio values for the right heatm...
Data
Related to Figs 2 and 3. Gene expression, RNA pol II recruitment and histone modifications in HuH7 cells infected with HCoV-229E or treated with IL-1. (A) HuH7 cells were infected for 24 h or treated with IL-1 for 1 h and the mRNA expression of the indicated genes was determined by RT-qPCR. Data show means +/- s.e.m. from two (CHAC1, HERPUD1), thre...
Data
Related to Figs 7 and 8. ChIP-seq profiles across a gene-rich non-regulated genomic region and GO annotation of enhancer-associated genes. (A) Shown is an example for all ChIP-seq data obtained for HuH7 cells in this study showing non-regulated enhancers (blue bars), regions of constitutive P(S5)-pol II recruitment (gray bars), NF-κB binding (red b...
Data
Contains data belonging to Fig 1C. (XLSX)
Data
Related to Figs 4 and 5. Regulation of IKK complex subunits and of IκBα at the mRNA level. (A) HuH7 cells were infected for 24 h with HCoV-229E or heat-inactivated virus or were treated with IL-1 for 1 h. Then, the levels of mRNAs encoding IKKα (IKBKA/CHUK), IKKβ (IKBKB), NEMO (IKBKG) or IκBα (NFKBIA) were determined. Data show means +/- s.e.m. fro...
Data
Related to Fig 8. The IKKβ inhibitor PHA-408 suppresses histone modifications and p65 recruitment at HCoV-229E- or IL-1-regulated enhancers. Chromatin prepared from HuH7 cells treated exactly as described in the legend of Fig 5E was used to determine by ChIP experiments the histone modifications, p65 recruitment and histone densities at the virus-s...
Data
Related to Fig 1. HCoV-229E virus replication in A549 cells. (A) Expression of HCoV-229E genomic RNAs (RNA1 encoding nsp8 and RNA2 encoding spike) in cells infected with replicating HCoV-229E or inactivated versions of HCoV-229E for different length of time. Shown are the means +/- s.e.m. of a technical replicate from a representative experiment. (...
Data
Related to Fig 1. KEGG pathway analysis of genes differentially expressed in HCoV-229E-infected A549 cells. (A) Overrepresentation analysis (ORA, blue colors) of differentially expressed genes (upper panels) and gene set enrichment analyses (GSEA, green, red and yellow colors) using the entire set of expressed genes (lower panels) were used to iden...
Data
Related to Fig 5. Subcellular distributions of host cell proteins in HCoV-229E-infected or IL-1-treated HuH7 or HeLa cells. (A) Immunoblots from experiments using HuH7 cells were performed as described in the legend of Fig 5A. Membranes were probed with an additional antibody recognizing p65 NF-κB or with antibodies against the c-REL NF-κB subunit....
Data
Related to Figs 7 and 8. Total peak numbers and overlaps of regulated genomic regions from ChIP-seq experiments assessing histone modifications and recruitment of P(S5)-pol II in HuH7 cells. Shown are the total numbers of peaks for histone modifications and P(S5)-polymerase II recruitment. Numbers for peaks regulated by HCoV-229E or IL-1 were deriv...
Data
Contains data belonging to Fig 1A. (XLSX)
Data
Contains data belonging to Fig 2C. (XLSX)
Data
Contains statistics for Fig 7B and 7D and Fig 8C. (XLSX)
Article
Full-text available
Coronaviruses are of veterinary and medical importance and include highly pathogenic zoonotic viruses, such as SARS-CoV and MERS-CoV. They are known to efficiently evade early innate immune responses, manifesting in almost negligible expression of type-I interferons (IFN-I). This evasion strategy suggests an evolutionary conserved viral function th...
Data
Assessment of OAS1a, OAS2, OAS3 and RNase L mRNA baseline expression. Baseline expression levels of OAS1a, OAS2, OAS3, RNase L mRNA in C57BL/6, Mda5-/-, MAVS-/-, RNase L-/-, PKR-/-, IRF3/5/7-/-, IFNAR-/-, and RNase L-/-/PKR-/-macrophages was assessed by qRT-PCR. Levels of mRNA expression relative to GAPDH are shown as log10(2ΔCT), where ΔCT = (CT r...
Data
EndoU-deficient MHV induces elevated expression of IFN-β and assessment of OAS1a-3 and RNase L mRNA expression levels in L929 cells. (a) Replication kinetics of MHV-A59 and MHVH277A following infection (MOI = 1) of L929 cells, which were left untreated (left panel) or were pre-treated for 16h with 12.5 U of IFN-I (right panel). Data represent four...
Data
The sensitivity of MHVH277A towards IFN-I is in the range observed for the highly sensitive 2’O-methyltransferase mutant. Comparative analysis of the sensitivity of MHV-A59, MHVH277A and MHVD130A (lacking the 2’-O methyltransferase activity) to IFN-I pre-treatment. L929 cells were pre-treated with various dosages of type-I IFN for four hours. There...
Data
EndoU deficient mutant triggers rRNA breakdown in MAVS-/- and IRF3/5/7-/- macrophages. (a) Degradation of rRNA in MHV-A59 and MHVH277A infected (MOI = 1) MAVS-/- and IRF3/5/7-/- bone marrow-derived macrophages. Total RNA was isolated at indicated time points and degradation of ribosomal RNA was assessed with a Fragment Analyzer. One representative...
Data
Primers and probes used in qRT-PCR. (PDF)
Data
(A) Preparation of genomic and subgenomic RNA standards. (B) Primers and probes used in the multiplex qRT-PCR reaction. (PDF)