Lars Dölken's research while affiliated with Universität Regensburg and other places
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Publications (206)
Human leucocyte antigen class I (HLA-I) molecules play a central role for both NK and T-cell responses that prevent serious human cytomegalovirus (HCMV) disease. To create opportunities for viral spread, several HCMV-encoded immunoevasins employ diverse strategies to target HLA-I. Among these, the glycoprotein US10 is so far insufficiently studied....
Respiratory viral infections (RVIs) are a major global contributor to morbidity and mortality. The susceptibility and outcome of RVIs are strongly age-dependent and show considerable inter-population differences, pointing to genetically and/or environmentally driven developmental variability. The factors determining the age-dependency and shaping t...
Introduction
During the COVID-19 pandemic, SARS-CoV-2 antigen rapid detection tests (RDTs) emerged as point-of-care diagnostics in addition to the RT-qPCR as the gold standard for SARS-CoV-2 diagnostics. Facing the course of the COVID-19 pandemic to an endemic characterised by several SARS-CoV-2 virus variants of concern (VOC) and an increasing pub...
Herpes simplex virus 1 (HSV-1) infection induces a genome-wide loss of host transcriptional activity and widespread disruption of host transcription termination. The latter leads to read-through transcription for thousands of nucleotides beyond poly(A) sites and is associated with induction of open chromatin downstream of genes. In this study, we s...
Human cytomegalovirus (HCMV) is a widespread pathogen that in immunocompromised hosts can cause life-threatening disease. Studying HCMV-exposed monocyte-derived dendritic cells by single-cell RNA sequencing, we observe that most cells are entered by the virus, whereas less than 30% of them initiate viral gene expression. Increased viral gene expres...
Nucleoside analogues like 4-thiouridine (4sU) are used to metabolically label newly synthesized RNA. Chemical conversion of 4sU before sequencing induces T-to-C mismatches in reads sequenced from labelled RNA, allowing to obtain total and labelled RNA expression profiles from a single sequencing library. Cytotoxicity due to extended periods of labe...
To better understand viral pathogenesis, host-virus interactions, and potential therapeutic interventions, the development of robust reverse genetics systems for SARS-CoV-2 is crucial. Here, we present a reverse genetics platform that enables the efficient manipulation, assembly, and rescue of recombinant SARS-CoV-2. The versatility of our reverse...
Allogeneic hematopoietic stem cell transplantation (alloSCT) is the only cure for many hematologic malignancies. However, alloSCT recipients are susceptible to opportunistic pathogens such as human cytomegalovirus (HCMV). Letermovir prophylaxis has revolutionized HCMV management, but the challenge of late HCMV reactivations has emerged. Immunologic...
Human cytomegalovirus (HCMV) reactivation poses a substantial risk to transplant patients. Effective risk stratification and vaccine development is hampered by a lack of HCMV-derived immunogenic peptides in patients with common HLA-A*03:01 and HLA-B*15:01 haplotypes. This study aimed to discover novel HCMV immunogenic peptides for these haplotypes...
Rapid diagnostic tests for SARS-CoV-2 antigen (RDTs) are an established point-of-care solution for diagnosis, screening and self-testing. On the other hand, the use of the reference standard in SARS-CoV-2 testing-the reverse transcription-quantitative polymerase chain reaction (RT-qPCR)-is limited by diagnostic capacities and infrastructural requir...
Regulation of viral RNA biogenesis is fundamental to productive SARS-CoV-2 infection. To characterize host RNA-binding proteins (RBPs) involved in this process, we biochemically identified proteins bound to genomic and subgenomic SARS-CoV-2 RNAs. We find that the host protein SND1 binds the 5′ end of negative-sense viral RNA and is required for SAR...
Cap0-mRNA is characterized by a 5′-5′triphosphate-linked N7-methylated guanosine(m7G). In higher eukaryotes, the methyltransferase CMTR1 additionally methylates the 2′O-position of the penultimate mRNA nucleotide(N1) ribose (cap1-mRNA). While the m7G cap is essential for mRNA export and translation initiation by the eIF4F complex, the N1-2′O-methyl...
Objectives:
COVID-19 vaccination is a key prevention strategy to reduce the spread and severity of SARS-CoV-2 infections. However, vaccine-related inability to work among healthcare workers (HCWs) could overstrain healthcare systems.
Study design:
The study presented was conducted as part of the prospective CoVacSer cohort study.
Methods:
This...
Herpes simplex virus 1 (HSV-1) infection and stress responses disrupt transcription termination by RNA Polymerase II (Pol II). In HSV-1 infection, but not upon salt or heat stress, this is accompanied by a dramatic increase in chromatin accessibility downstream of genes. Here, we show that the HSV-1 immediate-early protein ICP22 is both necessary a...
Background
In the context of the COVID-19 pandemic, a pronounced wave of Influenza A occurred in the 2022/23 winter season under generally relaxed post-pandemic non-pharmaceutical preventive measures.
Aim
This study aimed to investigate the Influenza A infection rate, factors influencing its occurrence and seasonal Influenza vaccine effectiveness...
Induction of type I interferon (IFN) gene expression is among the first lines of cellular defense a virus encounters during primary infection. We previously identified the tegument protein M35 of murine cytomegalovirus (MCMV) as an essential antagonist of this antiviral system, showing that M35 interferes with type I IFN induction downstream of pat...
Sleep modulates the immune response, and sleep loss can reduce vaccine immunogenicity; vice versa, immune responses impact sleep. We aimed to investigate the influence of mental health and sleep quality on the immunogenicity of COVID-19 vaccinations and, conversely, of COVID-19 vaccinations on sleep quality. The prospective CoVacSer study monitored...
The genomes of both human cytomegalovirus (HCMV) and murine cytomegalovirus (MCMV) were first sequenced over 20 years ago. Similar to HCMV, the MCMV genome had initially been proposed to harbor ≈170 open reading frames (ORFs). More recently, omics approaches revealed HCMV gene expression to be substantially more complex comprising several hundred v...
Introduction
Human cytomegalovirus (HCMV) causes significant morbidity and mortality in allogeneic stem cell transplant (alloSCT) recipients. Recently, antiviral letermovir prophylaxis during the first 100 days after alloSCT replaced PCR-guided preemptive therapy as the primary standard of care for HCMV reactivations. Here, we compared NK-cell and...
Herpes simplex virus 1 (HSV-1) infection exerts a profound shutoff of host gene expression at multiple levels. Recently, HSV-1 infection was reported to also impact promoter-proximal RNA polymerase II (Pol II) pausing, a key step in the eukaryotic transcription cycle, with decreased and increased Pol II pausing observed for activated and repressed...
Induction of type I interferon (IFN) gene expression is among the first lines of cellular defence a virus encounters during primary infection. We previously identified the tegument protein M35 of murine cytomegalovirus (MCMV) as an essential antagonist of this antiviral system. M35 localizes to the nucleus and interferes with type I IFN induction d...
Sleep modulates the immune response and sleep loss can reduce the immunogenicity of certain vaccinations. Vice versa immune responses impact sleep. We aimed to investigate the influence of mental health and sleep quality on the immunogenicity of COVID-19 vaccinations and, conversely, of COVID-19 vaccinations on sleep quality.
The prospective CoVacS...
To control human cytomegalovirus (HCMV) infection, NK cells and CD8+ T-cells are crucial. HLA class I (HLA-I) molecules play a central role for both NK and T-cell responses and are targets of multifaceted HCMV-encoded immunoevasins. A so far insufficiently studied HLA-I immunoevasin is the glycoprotein US10. It was shown that US10 targets HLA-G, bu...
Coadministration of seasonal quadrivalent influenza and COVID-19 booster vaccination is safe and does not increase vaccine-related side-effects, but may limit anti-SARS-CoV-2 antibody formation.
Magnetic nanoparticles (MNPs) have been adapted for many applications, e.g., bioassays for the detection of biomarkers such as antibodies, by controlled engineering of specific surface properties. Specific measurement of such binding states is of high interest but currently limited to highly sensitive techniques such as ELISA or flow cytometry, whi...
Background
COVID-19 vaccination is a key prevention strategy to reduce the spread and severity of SARS-CoV-2 infections, especially among highly exposed healthcare workers (HCWs). However, vaccine-related inability to work among HCWs could overstrain healthcare systems.
Methods
This study examined sick leave and intake of pro re nata (PRN) medicati...
Human cytomegalovirus is responsible for morbidity and mortality in immune compromised patients and is the leading viral cause of congenital infection. Virus-encoded microRNAs (miRNAs) represent interesting targets for novel antiviral agents. While many cellular targets that augment productive infection have been identified in recent years, regulat...
The genomes of both human cytomegalovirus (HCMV) and murine cytomegalovirus (MCMV) were first sequenced over 20 years ago. Similar to HCMV, the MCMV genome had initially been proposed to harbor ≈170 open reading frames (ORFs). More recently, omics approaches revealed HCMV gene expression to be substantially more complex comprising several hundreds...
Background
Rapid antigen detection tests (RDT) are an easily accessible, feasible, inexpensive, and point of care method in SARS-CoV-2 diagnostics - established in adults as well as in children and adolescents. Despite this, large-scale data of clinical performance in the paediatric population especially regarding the influence of SARS-CoV-2 virus...
Against the background of the current COVID‐19 infection dynamics with its rapid spread of SARS‐CoV‐2 variants of concern (VOC), the immunity and the vaccine prevention of healthcare workers (HCWs) against SARS‐CoV‐2 continues to be of high importance. This observational cross‐section study assesses factors influencing the level of Anti‐SARS‐CoV‐2‐...
The evolutionarily conserved, structural HSV-1 tegument protein pUL36 is essential for both virus entry and assembly. While its N-terminal deubiquitinase (DUB) activity is dispensable for infection in cell culture, it is required for efficient virus spread in vivo, as it acts as a potent viral immune evasin. Interferon (IFN) induces the expression...
The herpes simplex virus 1 (HSV-1) virion host shut-off ( vhs ) protein cleaves both cellular and viral mRNAs by a translation-initiation-dependent mechanism, which should spare circular RNAs (circRNAs). Here, we show that vhs -mediated degradation of linear mRNAs leads to an enrichment of circRNAs relative to linear mRNAs during HSV-1 infection. T...
Single-cell RNA genomics technologies are revolutionizing biomedical science by profiling single cells with unprecedented resolution, providing fundamental insights into the role of different cellular states and intercellular heterogeneity in health and disease. The combination of single-cell RNA sequencing (scRNA-seq) with metabolic RNA labelling...
Herpes simplex virus 1 (HSV-1) infection exerts a profound shut-off of host gene expression at multiple levels. Recently, HSV-1 infection was reported to also impact promoter-proximal RNA Polymerase II (Pol II) pausing, a key step in the eukaryotic transcription cycle. Here, we reveal that HSV-1 infection induces complex alterations in promoter-pro...
Importance
Closure of day care centers (DCCs) to contain the COVID-19 pandemic has been associated with negative effects on children’s health and well-being.
Objective
To investigate the acceptance of self-sampling methods for continuous SARS-CoV-2 surveillance among asymptomatic children and childcare workers (CCWs) in DCCs.
Design, Setting, and...
Objectives
Antigen rapid diagnostic tests (RDT) for SARS-CoV-2 are quick, widely available, and inexpensive. Consequently, RDT have been established as an alternative and additional diagnostic strategy to quantitative reverse transcription polymerase chain reaction (RT-qPCR). However, reliable SARS-CoV-2 virus variant of concern (VOC) specific clin...
Background
A third dose of COVID-19 vaccination (‘COVID booster vaccination’) has become established as an important measure to strengthen the immune response against SARS-CoV-2. In contrast, seasonal influenza vaccination has been an important infection prevention measure for years, especially among highly exposed healthcare workers (HCWs). Coadmi...
Activation of intronic polyadenylation signals results in premature cleavage and polyadenylation (PCPA). The majority of mammalian miRNAs are also located within intronic regions of protein-coding genes and are transcriptionally co-expressed with their host genes. Here we show that U1-dependent PCPA by telescripting dysregulates miRNA biogenesis. W...
In the last decade Magnetic nanoparticles (MNPs) have gained an enormous interest in specialized areas such as medicine, cancer theranostics, biosensing, catalysis, agriculture, and the environmental protection. By controlled engineering of specific surface properties, named functionalization, MNPs are gaining special features for desired applicati...
Herpesviruses have mastered host cell modulation and immune evasion to augment productive infection, life-long latency and reactivation1,2. A long appreciated, yet undefined relationship exists between the lytic–latent switch and viral non-coding RNAs3,4. Here we identify viral microRNA (miRNA)-mediated inhibition of host miRNA processing as a cell...
Background
Against the background of the current COVID-19 infection dynamics with the rapid spread of SARS-CoV-2 variants of concern (VOC), above all the Omicron VOC, the immunity of healthcare workers (HCWs) against SARS-CoV-2 continues to be of high importance. Vaccination plays a central role in reducing the severity and potentially the spread o...
Viruses play a key role in explaining the pathogenesis of various autoimmune disorders, whose underlying principle is defined by the activation of autoreactive T-cells. In many cases, T-cells escape self-tolerance due to the failure in encountering certain MHC-I self-peptide complexes at substantial levels, whose peptides remain invisible from the...
Respiratory viruses were detected by multiplex-polymerase chain reaction from oropharyngeal swabs in 114/168 (67.9%) children with acute respiratory infection presenting to 5 pediatric practices in Germany between November 2020 and April 2021. In contrast to rhino- (48.8%), adeno- (14.3%) and endemic coronaviruses (14.9%), SARS-CoV-2 and influenza...
For decades, human cytomegalovirus (HCMV) was thought to express ≈200 viral proteins during lytic infection. In recent years, systems biology approaches uncovered hundreds of additional viral gene products and suggested thousands of viral sites of transcription initiation. Despite all available data, the molecular mechanisms of HCMV gene regulation...
Importance
Closure of day care centers has been implemented globally to contain the COVID-19 pandemic but has negative effects on children’s health and psychosocial well-being.
Objective
To investigate the feasibility of surveillance among children and childcare workers and to model the efficacy of surveillance on viral spread prevention.
Design,...
The herpes simplex virus 1 (HSV-1) virion host shut-off (vhs) protein cleaves both cellular and viral mRNAs but not circular RNAs (circRNAs) without an internal ribosome entry site. Here, we show that vhs activity leads to an accumulation of circRNAs relative to linear mRNAs during HSV-1 infection. Strikingly, we found that circular splicing of the...
Background:
Research of SARS-CoV-2 has so far largely focused on symptomatic cases. The STAAB-COVID study therefore examined the seroprevalence of COVID-19 in the general population and the psychosocial effects of the pandemic.
Methods:
From June-October 2020, a sub-study was conducted within the "Characteristics and Course of Heart Failure Stag...
During lytic infection, herpes simplex virus (HSV) 1 induces a rapid shutoff of host RNA synthesis while redirecting transcriptional machinery to viral genes. In addition to being a major human pathogen, there is burgeoning clinical interest in HSV as a vector in gene delivery and oncolytic therapies, necessitating research into transcriptional con...
Fluorogenic aptamers are an alternative to established methodology for real-time imaging of RNA transport and dynamics. We developed Broccoli-aptamer concatemers ranging from 4 to 128 substrate-binding site repeats and characterized their behavior fused to an mCherry-coding mRNA in transient transfection, stable expression, and in recombinant cytom...
For the control of immunity in COVID-19 survivors and vaccinated subjects there is an urgent need for reliable and rapid serological assays.
Based on samples from 63 COVID-19 survivors up to seven months after symptom onset, and on 50 serum samples taken before the beginning of the pandemic, we compared the performance of three commercial immunoass...
SARS-CoV-2 infection can cause fatal inflammatory lung pathology, including thrombosis and increased pulmonary vascular permeability leading to edema and hemorrhage. In addition to the lung, cytokine storm-induced inflammatory cascade also affects other organs. SARS-CoV-2 infection-related vascular inflammation is characterized by endotheliopathy i...
Background:
Antigen rapid diagnostic tests (RDT) for SARS-CoV-2 are fast, broadly available, and inexpensive. Despite this, reliable clinical performance data from large field studies is sparse.
Methods:
In a prospective performance evaluation study, RDT from three manufacturers (NADAL®, Panbio™, MEDsan®, conducted on different samples) were com...
Transcriptional activity of RNA polymerase II (Pol II) is orchestrated by post-translational modifications of the C-terminal domain (CTD) of the largest Pol II subunit, RPB1. Herpes Simplex Virus type 1 (HSV-1) usurps the cellular transcriptional machinery during lytic infection to efficiently express viral mRNA and shut down host gene expression....
After more than one year of the COVID-19 pandemic, antiviral treatment options against SARS-CoV-2 are still severely limited. High hopes that had initially been placed on antiviral drugs like remdesivir have so far not been fulfilled. While individual case reports provide striking evidence for the clinical efficacy of remdesivir in the right clinic...
Interferon-stimulated gene products (ISGs) play a crucial role in early infection control. The ISG zinc finger CCCH-type antiviral protein 1 (ZAP/ZC3HAV1) antagonizes several RNA viruses by binding to CG-rich RNA sequences, whereas its effect on DNA viruses is less well understood. Here, we decipher the role of ZAP in the context of human cytomegal...
Viral infections during pregnancy are a considerable cause of adverse outcomes and birth defects, and the underlying mechanisms are poorly understood. Among those, cytomegalovirus (CMV) infection stands out as the most common intrauterine infection in humans, putatively causing early pregnancy loss. We employed murine CMV as a model to study the co...
Many recent studies highlight the fundamental importance of viruses. Besides their important role as human and animal pathogens, their beneficial, commensal or harmful functions are poorly understood. By developing and applying tailored bioinformatical tools in important virological models, the Marie Skłodowska-Curie Initiative International Traini...
Background
Antigen rapid diagnostic tests (RDT) for SARS-CoV-2 are fast, broadly available, and inexpensive. Despite this, reliable clinical performance data is sparse.
Methods
In a prospective performance evaluation study, RDT from three manufacturers (NADAL, Panbio, MEDsan) were compared to quantitative reverse transcription polymerase chain reac...
Many experimental approaches have been developed to identify transcription start sites (TSS) from genomic scale data. However, experiment specific biases lead to large numbers of false positive calls. Here, we present our integrative approach iTiSS, which is an accurate and generic TSS caller for any TSS profiling experiment in eukaryotes, and subs...
Eukaryotic gene expression is extensively regulated by cellular stress and pathogen infections. We have previously shown that herpes simplex virus 1 (HSV-1) and several cellular stresses cause widespread disruption of transcription termination (DoTT) of RNA polymerase II (RNAPII) in host genes and that the viral immediate early factor ICP27 plays a...
Characterizing the interactions that SARS-CoV-2 viral RNAs make with host cell proteins during infection can improve our understanding of viral RNA functions and the host innate immune response. Using RNA antisense purification and mass spectrometry, we identified up to 104 human proteins that directly and specifically bind to SARS-CoV-2 RNAs in in...
For the control of immunity in COVID-19 survivors and vaccinated subjects there is an urgent need for reliable and rapid serological assays.
Based on samples from 63 COVID-19 survivors up to seven months after symptom onset, and on 50 serum samples taken before the beginning of the pandemic, we compared the performance of three commercial immunoass...
The conserved, structural HSV-1 tegument protein pUL36 is essential for both virus entry and assembly. While its N-terminal de-ubiquitinase (DUB) activity is dispensable for infection in cell culture, it is required for efficient virus spread in vivo by acting as a potent viral immune evasin. Here, we show that the pUL36 DUB activity was required t...
The HSV-1 virion host shutoff ( vhs ) protein efficiently cleaves both host and viral mRNAs in a translation-dependent manner. In this study, we model and quantify changes in vhs activity, as well as virus-induced global loss of host transcriptional activity, during productive HSV-1 infection. In general, HSV-1-induced alterations in total RNA leve...
Fluorogenic aptamers are an alternative to established methodology for real-time imaging of RNA transport and dynamics. We developed Broccoli-aptamer concatemers ranging from 4 to 128 substrate-binding site repeats and characterized their behavior fused to an mCherry-coding mRNA in transient transfection, stable expression, and in recombinant cytom...
Eukaryotic gene expression is extensively regulated by cellular stress and pathogen infections. We have previously shown that herpes simplex virus 1 (HSV-1) and several cellular stresses cause widespread disruption of transcription termination (DoTT) of RNA polymerase II (RNAPII) in host genes and that the viral immediate early factor ICP27 plays a...
Background
The viral load and tissue distribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain important questions. The current study investigated SARS-CoV-2 viral load, biodistribution and anti-SARS-CoV-2 antibody formation in patients suffering from severe corona virus disease 2019 (COVID-19) induced acute respiratory di...
Interferon-stimulated gene products (ISGs) play a crucial role in early infection control. The ISG zinc finger CCCH-type antiviral protein 1 (ZAP/ZC3HAV1) antagonises several RNA viruses by binding to CG-rich RNA sequences, whereas its effect on DNA viruses is largely unknown. Here, we decipher the role of ZAP in the context of human cytomegaloviru...
Dendritic cells (DC) play a key role in the adaptive immune response due to their ability to present antigens and stimulate naïve T cells. Many bacteria and viruses can efficiently target DC, resulting in impairment of their immunostimulatory function or elimination. Hence, the DC compartment requires replenishment following infection to ensure con...
The success of cancer immunotherapy relies on the ability of cytotoxic T cells to specifically recognize and eliminate tumor cells based on peptides presented by HLA-I. Although the peptide epitopes that elicit the corresponding immune response often remain unidentified, it is generally assumed that neoantigens, due to tumor-specific mutations, are...
Herpes simplex virus 1 (HSV-1) installs a profound host shut-off during lytic infection. The virion host shut-off ( vhs ) protein plays a key role in this process by efficiently cleaving both host and viral mRNAs in a translation-initiation-dependent manner. Furthermore, the onset of viral DNA replication is accompanied by a rapid decline in transc...
The predicted 80 open reading frames (ORFs) of herpes simplex virus 1 (HSV-1) have been intensively studied for decades. Here, we unravel the complete viral transcriptome and translatome during lytic infection with base-pair resolution by computational integration of multi-omics data. We identify a total of 201 transcripts and 284 ORFs including al...
Infection by viruses, including herpes simplex virus-1 (HSV-1), and cellular stresses cause widespread disruption of transcription termination (DoTT) of RNA polymerase II (RNAPII) in host genes. However, the underlying mechanisms remain unclear. Here, we demonstrate that the HSV-1 immediate early protein ICP27 induces DoTT by directly binding to th...
The activity of neutral sphingomyelinase-2 (NSM2) to catalyze the conversion of sphingomyelin (SM) to ceramide and phosphocholine at the cytosolic leaflet of plasma membrane (PM) is important in T cell receptor (TCR) signaling. We recently identified PKCζ as a major NSM2 downstream effector which regulates microtubular polarization. It remained, ho...
Single-cell RNA sequencing (scRNA-seq) has highlighted the important role of intercellular heterogeneity in phenotype variability in both health and disease¹. However, current scRNA-seq approaches provide only a snapshot of gene expression and convey little information on the true temporal dynamics and stochastic nature of transcription. A further...
CMVs efficiently target MHC I molecules to avoid recognition by cytotoxic T cells. However, the lack of MHC I on the cell surface renders the infected cell susceptible to NK cell killing upon missing self recognition. To counter this, mouse CMV (MCMV) rescues some MHC I molecules to engage inhibitory Ly49 receptors. Here we identify a new viral pro...
Background:
The prevalence of, and risk factors for, herpes simplex virus type-1 (HSV-1) infection and reactivation in older individuals are poorly understood.
Methods:
This is a prospective population-based study among community-dwelling individuals aged 40-79 years, followed from 1993, formed as a random subsample of the UK-based EPIC-Norfolk...
DNA damage response (DDR) involves dramatic transcriptional alterations, the mechanisms of which remain ill defined. Here, we show that following genotoxic stress, the RNA-binding motif protein 7 (RBM7) stimulates RNA polymerase II (Pol II) transcription and promotes cell viability by activating the positive transcription elongation factor b (P-TEF...
Since the genome of herpes simplex virus 1 (HSV-1) was first sequenced more than 30 years ago, its predicted 80 genes have been intensively studied. Here, we unravel the complete viral transcriptome and translatome during lytic infection with base-pair resolution by computational integration of multi-omics data. We identified a total of 201 viral t...
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 pisc...
Current single-cell RNA sequencing approaches gives a snapshot of a cellular phenotype but convey no information on the temporal dynamics of transcription. Moreover, the stochastic nature of transcription at molecular level is not recovered. Here, we present single-cell SLAM-seq (scSLAM-seq), which integrates metabolic RNA labeling, biochemical nuc...
Cellular DNA damage response (DDR) involves dramatic transcriptional alterations, the mechanisms of which remain ill-defined. Given the centrality of RNA polymerase II (Pol II) promoter-proximal pause release in transcriptional control, we evaluated its importance in DDR. Here we show that following genotoxic stress, the RNA-binding motif protein 7...
Global quantification of total RNA is used to investigate steady state levels of gene expression. However, being able to differentiate pre-existing RNA (that has been synthesized prior to a defined point in time) and newly transcribed RNA can provide invaluable information e.g. to estimate RNA half-lives or identify fast and complex regulatory proc...
Ribosome profiling has been used to predict thousands of short open reading frames (sORFs) in eukaryotic cells, but it suffers from substantial levels of noise. PRICE (https://github.com/erhard-lab/price) is a computational method that models experimental noise to enable researchers to accurately resolve overlapping sORFs and noncanonical translati...
Supplementary tables.
Table A provides read-through values obtained from 4sU-seq data for HSV-1 infection, salt and heat stress. Table B provides read-through values for total, cytoplasmic, nucleoplasmic and chromatin-associated RNA at 8h p.i. HSV-1 infection. Table C lists genes for which read-through transcripts at 8h p.i. HSV-1 infection appear...
Supplementary methods.
Protocol for the separation of subcellular RNA fractions used in this study.
(PDF)
Supplementary figures.
Contains Supplementary Figures A-R and legends.
(PDF)
Lytic herpes simplex virus 1 (HSV-1) infection triggers disruption of transcription termination (DoTT) of most cellular genes, resulting in extensive intergenic transcription. Similarly, cellular stress responses lead to gene-specific transcription downstream of genes (DoG). In this study, we performed a detailed comparison of DoTT/DoG transcriptio...
Ribosome profiling has predicted thousands of short open reading frames (sORFs) in eukaryotic cells, but still suffers from substantial levels of noise. PRICE (https://github.com/erhard-lab/price) is a computational method modeling the experimental noise to accurately resolve overlapping sORFs and non-canonical translation initiation. We experiment...
p>The combination of metabolic RNA labeling with biochemical nucleoside conversion now adds a broadly applicable temporal dimension to RNA sequencing.</p
Citations
... In a previous study, we demonstrated that stimulation of DC with birch pollen extract resulted in a pro-inflammatory gene signature controlled by the transcription factor NF-κB, which was responsible for enhanced human cytomegalovirus (HCMV) replication in the cells (Fneish et al., 2022). In line with that, we also showed that in DC activation of stimulator of interferon signaling (STING) enhances HCMV infection presumably via NF-κB activation (Costa et al., 2024). ...
... Prior studies have provided substantial evidence of the presence of both CD4 + and CD8 + T-cell epitopes within UL36/ORFL101C. 42,43,106 Dhanwani and colleagues identified a total of five UL36/ORFL101C-derived T-cell epitopes for which either CD8 + or CD4 + T-cell responses could be detected in 5.2% to 15.8% of the tested donors. 42 Moreover, UL36/ORFL101C-derived T-cell epitopes have been described by Lübke et al., which were found to elicit T-cell responses in 35.7% to 40% of healthy donors. ...
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... [14] The following correlations have already been proven in the evidence to date as decisive factors influencing test performance: the presence of typical COVID-19 symptoms and high viral load correlate positively with high sensitivity values of RDTs. [13,[15][16][17][18][19][20][21] However, since the establishment of RDTs in COVID-19 diagnostics, many circumstances in the test environment have changed which requires the re-evaluation of RDT performance under this current conditions. [22] With the course of the pandemic, the infestation of society and the availability of COVID-19 vaccines, there is now a basic immunised test collective. ...
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... There is little shown in the literature regarding direct Nsp9-host protein interactions, and this topic warrants further investigation. 72 Together, our findings point to a novel mechanism by which Nsp9 antagonizes IFN signaling through targeting multiple components of the innate antiviral host response ( Figure 6A). Pieced together with the known interactions of Orf3a and Orf6 with STAT1, Figure 6 illustrates how these viral proteins target the host's antiviral response to undergo viral evasion. ...
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... Furthermore, individuals with two or more co-morbidities exhibited decreased negative perceptions of COVID-19 compared to those with one or no comorbidities. Given that AI/AN exhibit lower life expectancy than most other ethnic groups, partly due to an increased likelihood of obesity and diabetes, addressing misconceptions and promoting positive attitudes towards COVID-19 vaccination becomes imperative [33,59,60]. According to the Great Lakes Inter-Tribal Epidemiology Center 2021 report of AI/AN in Michigan, Minnesota, and Wisconsin, AI/AN individuals reported having higher prevalence of hypertension at 35.7% and diabetes at 16% compared to their White counterparts in this three-state area [61]. ...
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... [3] The acute phase of the pandemic has now passed, and COVID-19 is in transition as a seasonal pathogen of acute respiratory diseases and is now a new player alongside Influenza and RSV. [4][5][6][7][8] In the acute phase of the COVID-19 pandemic in particular, an important pandemic management strategy, alongside the development of therapies and vaccines and the establishment of public measures such as contact restrictions, was the timely, rapid and reliable diagnosis of SARS-CoV-2 as the central key to breaking chains of infection. [9][10][11][12] As a well-established, very precise method, reverse transcription polymerase chain reaction (RT-qPCR) has been the gold standard for diagnostics since the beginning of the pandemic. ...
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... We confirmed that insertion of the point mutations R66E and D522R disturb the dimerization interface, resulting in a mutant protein that is monomeric in solution and human cells. Opposed to our findings with the M35 tegument protein of murine CMV, which also presented as a dimer but whose expression was severely impaired when the dimer is disrupted (Schwanke et al., 2023), the UL82 dimerization mutant was expressed to levels as high as UL82-WT, which will allow continuing functional characterization. ...
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... The detailled study protocol of the CoVacSer study has been described previously. (22) The Influenza A season 2022/23 in Germany (predominantly H3N2) lasted from 24 October 2022 to 8 January 2023 with its peak occurring in the 50 th calendar week of 2022. Subsequently, there was no second Influenza A wave during the 2022/23 winter season. ...
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... In mCMV-WT infection, m152 is expressed quite early in the Early (E) phase of the viral replication cycle (24,39). Antigens expressed even earlier, that is, in the Immediate-Early (IE) phase, may profit from a head start advantage of presentation before immune evasion can operate. ...
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... Over the past decade, signi cant progresses have been made in understanding the immune control system during CMV exposure following allo-HSCT (22)(23)(24)(25). Earlier studies suggested that the reconstitution of CD4 + T cells precedes and subsequently orchestrates CD8 + T cell reconstitution to provide enhanced protection against CMV disease (26,27). CMV-speci c CD4 + T cells have been reported to be indispensable for maintaining CMV-speci c CD8 + T cell levels that ensure long-term viral control (27,28). ...
