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Article ; Online: SARS-CoV-2 in humans

Marco Binder / Emanuel Wyler

Berliner und Münchener Tierärztliche Wochenschrift (2021)

2021

Abstract: The novel coronavirus SARS-CoV-2 became pandemic at the beginning of 2020, and caused about 80 million cases and more than 1.8 million deaths by the end of the year. As its relatives MERS- and SARS-CoV, but in contrast to the four human coronaviruses ... ...

Abstract	The novel coronavirus SARS-CoV-2 became pandemic at the beginning of 2020, and caused about 80 million cases and more than 1.8 million deaths by the end of the year. As its relatives MERS- and SARS-CoV, but in contrast to the four human coronaviruses circulating worldwide, SARS-CoV-2 in a sizeable fraction of cases leads to a severe and potentially life-threatening disease, called COVID-19. Since in addition this virus is very contagious, particularly prior to onset or in absence of symptoms, and pre-existing immunity appears to be largely absent or at least of very little relevance, it is spreading rapidly in the population. A hallmark of COVID-19 is an at least partially detrimental immune response that not only can lead to serious lung damage, but may also damage organs outside the respiratory tract such as the heart and kidneys. This review summarizes current knowledge about the virus and the disease it causes, and outlines open questions in the different research fields.
Keywords	sars-cov-2 ; covid-19 ; molecular biology ; transmission ; epidemiol-ogy ; pathogenesis ; immunity ; Veterinary medicine ; SF600-1100
Language	German
Publishing date	2021-04-01T00:00:00Z
Publisher	Schlütersche Fachmedien GmbH
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Comparative Analysis of Six IRF Family Members in Alveolar Epithelial Cell-Intrinsic Antiviral Responses

Sandra Wüst / Paulina Schad / Sandy Burkart / Marco Binder

Cells, Vol 10, Iss 2600, p

2021 Volume 2600

Abstract: Host cell-intrinsic antiviral responses are largely mediated by pattern-recognition receptor (PRR) signaling and the interferon (IFN) system. The IFN regulatory factor (IRF) family of transcription factors takes up a central role in transcriptional ... ...

Abstract	Host cell-intrinsic antiviral responses are largely mediated by pattern-recognition receptor (PRR) signaling and the interferon (IFN) system. The IFN regulatory factor (IRF) family of transcription factors takes up a central role in transcriptional regulation of antiviral innate immunity. IRF3 and IRF7 are known to be key players downstream of PRRs mediating the induction of type I and III IFNs. IFN signaling then requires IRF9 for the expression of the full array of interferon stimulated genes (ISGs) ultimately defining the antiviral state of the cell. Other members of the IRF family clearly play a role in mediating or modulating IFN responses, such as IRF1, IRF2 or IRF5, however their relative contribution to mounting a functional antiviral response is much less understood. In this study, we systematically and comparatively assessed the impact of six members of the IRF family on antiviral signaling in alveolar epithelial cells. We generated functional knockouts of IRF1, -2, -3, -5, -7, and -9 in A549 cells, and measured their impact on the expression of IFNs and further cytokines, ISGs and other IRFs, as well as on viral replication. Our results confirmed the vital importance of IRF3 and IRF9 in establishing an antiviral state, whereas IRF1, 5 and 7 were largely dispensable. The previously described inhibitory activity of IRF2 could not be observed in our experimental system.
Keywords	innate immunity ; antiviral response ; interferon ; cytokines ; RIG-I-like receptors ; RLR signaling ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2021-09-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Stochastic dynamics of Type-I interferon responses.

Benjamin D Maier / Luis U Aguilera / Sven Sahle / Pascal Mutz / Priyata Kalra / Christopher Dächert / Ralf Bartenschlager / Marco Binder / Ursula Kummer

PLoS Computational Biology, Vol 18, Iss 10, p e

2022 Volume 1010623

Abstract: Interferon (IFN) activates the transcription of several hundred of IFN stimulated genes (ISGs) that constitute a highly effective antiviral defense program. Cell-to-cell variability in the induction of ISGs is well documented, but its source and effects ... ...

Abstract	Interferon (IFN) activates the transcription of several hundred of IFN stimulated genes (ISGs) that constitute a highly effective antiviral defense program. Cell-to-cell variability in the induction of ISGs is well documented, but its source and effects are not completely understood. The molecular mechanisms behind this heterogeneity have been related to randomness in molecular events taking place during the JAK-STAT signaling pathway. Here, we study the sources of variability in the induction of the IFN-alpha response by using MxA and IFIT1 activation as read-out. To this end, we integrate time-resolved flow cytometry data and stochastic modeling of the JAK-STAT signaling pathway. The complexity of the IFN response was matched by fitting probability distributions to time-course flow cytometry snapshots. Both, experimental data and simulations confirmed that the MxA and IFIT1 induction circuits generate graded responses rather than all-or-none responses. Subsequently, we quantify the size of the intrinsic variability at different steps in the pathway. We found that stochastic effects are transiently strong during the ligand-receptor activation steps and the formation of the ISGF3 complex, but negligible for the final induction of the studied ISGs. We conclude that the JAK-STAT signaling pathway is a robust biological circuit that efficiently transmits information under stochastic environments.
Keywords	Biology (General) ; QH301-705.5
Subject code	612
Language	English
Publishing date	2022-10-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Mathematical modeling of plus-strand RNA virus replication to identify broad-spectrum antiviral treatment strategies.

Carolin Zitzmann / Christopher Dächert / Bianca Schmid / Hilde van der Schaar / Martijn van Hemert / Alan S Perelson / Frank J M van Kuppeveld / Ralf Bartenschlager / Marco Binder / Lars Kaderali

PLoS Computational Biology, Vol 19, Iss 4, p e

2023 Volume 1010423

Abstract: Plus-strand RNA viruses are the largest group of viruses. Many are human pathogens that inflict a socio-economic burden. Interestingly, plus-strand RNA viruses share remarkable similarities in their replication. A hallmark of plus-strand RNA viruses is ... ...

Abstract	Plus-strand RNA viruses are the largest group of viruses. Many are human pathogens that inflict a socio-economic burden. Interestingly, plus-strand RNA viruses share remarkable similarities in their replication. A hallmark of plus-strand RNA viruses is the remodeling of intracellular membranes to establish replication organelles (so-called "replication factories"), which provide a protected environment for the replicase complex, consisting of the viral genome and proteins necessary for viral RNA synthesis. In the current study, we investigate pan-viral similarities and virus-specific differences in the life cycle of this highly relevant group of viruses. We first measured the kinetics of viral RNA, viral protein, and infectious virus particle production of hepatitis C virus (HCV), dengue virus (DENV), and coxsackievirus B3 (CVB3) in the immuno-compromised Huh7 cell line and thus without perturbations by an intrinsic immune response. Based on these measurements, we developed a detailed mathematical model of the replication of HCV, DENV, and CVB3 and showed that only small virus-specific changes in the model were necessary to describe the in vitro dynamics of the different viruses. Our model correctly predicted virus-specific mechanisms such as host cell translation shut off and different kinetics of replication organelles. Further, our model suggests that the ability to suppress or shut down host cell mRNA translation may be a key factor for in vitro replication efficiency, which may determine acute self-limited or chronic infection. We further analyzed potential broad-spectrum antiviral treatment options in silico and found that targeting viral RNA translation, such as polyprotein cleavage and viral RNA synthesis, may be the most promising drug targets for all plus-strand RNA viruses. Moreover, we found that targeting only the formation of replicase complexes did not stop the in vitro viral replication early in infection, while inhibiting intracellular trafficking processes may even lead to amplified viral ...
Keywords	Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2023-04-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: NUDT2 initiates viral RNA degradation by removal of 5′-phosphates

Beatrice T. Laudenbach / Karsten Krey / Quirin Emslander / Line Lykke Andersen / Alexander Reim / Pietro Scaturro / Sarah Mundigl / Christopher Dächert / Katrin Manske / Markus Moser / Janos Ludwig / Dirk Wohlleber / Andrea Kröger / Marco Binder / Andreas Pichlmair

Nature Communications, Vol 12, Iss 1, Pp 1-

2021 Volume 13

Abstract: RNA of some viruses is protected from degradation by a 5′ triphosphate group. Here the authors identify nudix hydrolase 2 (NUDT2) as novel antiviral defense protein that dephosphorylates viral RNA and thereby enables its degradation. ...

Abstract	RNA of some viruses is protected from degradation by a 5′ triphosphate group. Here the authors identify nudix hydrolase 2 (NUDT2) as novel antiviral defense protein that dephosphorylates viral RNA and thereby enables its degradation.
Keywords	Science ; Q
Language	English
Publishing date	2021-11-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Host factor prioritization for pan-viral genetic perturbation screens using random intercept models and network propagation.

Simon Dirmeier / Christopher Dächert / Martijn van Hemert / Ali Tas / Natacha S Ogando / Frank van Kuppeveld / Ralf Bartenschlager / Lars Kaderali / Marco Binder / Niko Beerenwinkel

PLoS Computational Biology, Vol 16, Iss 2, p e

2020 Volume 1007587

Abstract: Genetic perturbation screens using RNA interference (RNAi) have been conducted successfully to identify host factors that are essential for the life cycle of bacteria or viruses. So far, most published studies identified host factors primarily for single ...

Abstract	Genetic perturbation screens using RNA interference (RNAi) have been conducted successfully to identify host factors that are essential for the life cycle of bacteria or viruses. So far, most published studies identified host factors primarily for single pathogens. Furthermore, often only a small subset of genes, e.g., genes encoding kinases, have been targeted. Identification of host factors on a pan-pathogen level, i.e., genes that are crucial for the replication of a diverse group of pathogens has received relatively little attention, despite the fact that such common host factors would be highly relevant, for instance, for devising broad-spectrum anti-pathogenic drugs. Here, we present a novel two-stage procedure for the identification of host factors involved in the replication of different viruses using a combination of random effects models and Markov random walks on a functional interaction network. We first infer candidate genes by jointly analyzing multiple perturbations screens while at the same time adjusting for high variance inherent in these screens. Subsequently the inferred estimates are spread across a network of functional interactions thereby allowing for the analysis of missing genes in the biological studies, smoothing the effect sizes of previously found host factors, and considering a priori pathway information defined over edges of the network. We applied the procedure to RNAi screening data of four different positive-sense single-stranded RNA viruses, Hepatitis C virus, Chikungunya virus, Dengue virus and Severe acute respiratory syndrome coronavirus, and detected novel host factors, including UBC, PLCG1, and DYRK1B, which are predicted to significantly impact the replication cycles of these viruses. We validated the detected host factors experimentally using pharmacological inhibition and an additional siRNA screen and found that some of the predicted host factors indeed influence the replication of these pathogens.
Keywords	Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2020-02-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: SARS-CoV-2 infection induces a pro-inflammatory cytokine response through cGAS-STING and NF-κB

Communications Biology, Vol 5, Iss 1, Pp 1-

2022 Volume 15

Abstract: Neufeldt et al. evaluate transcriptional and cytokine secretion profiles of cells and patient sera following SARS-CoV-2 infection and detect distinct upregulation of inflammatory cytokines. They also demonstrate that this upregulation is mediated by cGAS- ...

Abstract	Neufeldt et al. evaluate transcriptional and cytokine secretion profiles of cells and patient sera following SARS-CoV-2 infection and detect distinct upregulation of inflammatory cytokines. They also demonstrate that this upregulation is mediated by cGAS-STING and NF-κB signalling, which could provide a potential avenue for the development of future therapies against SARS-CoV-2.
Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Activation of Type I and III Interferon Response by Mitochondrial and Peroxisomal MAVS and Inhibition by Hepatitis C Virus.

Silke Bender / Antje Reuter / Florian Eberle / Evelyne Einhorn / Marco Binder / Ralf Bartenschlager

PLoS Pathogens, Vol 11, Iss 11, p e

2015 Volume 1005264

Abstract: Sensing viruses by pattern recognition receptors (PRR) triggers the innate immune system of the host cell and activates immune signaling cascades such as the RIG-I/IRF3 pathway. Mitochondrial antiviral-signaling protein (MAVS, also known as IPS-1, Cardif, ...

Abstract	Sensing viruses by pattern recognition receptors (PRR) triggers the innate immune system of the host cell and activates immune signaling cascades such as the RIG-I/IRF3 pathway. Mitochondrial antiviral-signaling protein (MAVS, also known as IPS-1, Cardif, and VISA) is the crucial adaptor protein of this pathway localized on mitochondria, peroxisomes and mitochondria-associated membranes of the endoplasmic reticulum. Activation of MAVS leads to the production of type I and type III interferons (IFN) as well as IFN stimulated genes (ISGs). To refine the role of MAVS subcellular localization for the induction of type I and III IFN responses in hepatocytes and its counteraction by the hepatitis C virus (HCV), we generated various functional and genetic knock-out cell systems that were reconstituted to express mitochondrial (mito) or peroxisomal (pex) MAVS, exclusively. Upon infection with diverse RNA viruses we found that cells exclusively expressing pexMAVS mounted sustained expression of type I and III IFNs to levels comparable to cells exclusively expressing mitoMAVS. To determine whether viral counteraction of MAVS is affected by its subcellular localization we employed infection of cells with HCV, a major causative agent of chronic liver disease with a high propensity to establish persistence. This virus efficiently cleaves MAVS via a viral protease residing in its nonstructural protein 3 (NS3) and this strategy is thought to contribute to the high persistence of this virus. We found that both mito- and pexMAVS were efficiently cleaved by NS3 and this cleavage was required to suppress activation of the IFN response. Taken together, our findings indicate comparable activation of the IFN response by pex- and mitoMAVS in hepatocytes and efficient counteraction of both MAVS species by the HCV NS3 protease.
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2015-11-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Cohort profile

Allan Hildesheim / Tim Waterboer / Julia Butt / Mitchell H Gail / Alejandro Calderón / Rolando Herrero / Carolina Porras / Bernal Cortes / Viviana Loría / Amada Aparicio / Gloriana Barrientos / Daniela Retana / Kaiyuan Sun / Rebeca Ocampo / D. Rebecca Prevots / Michael Zúñiga / Roy Wong-McClure / Melvin Morera / Marco Binder /

Arturo Abdelnour / Ruth M Pfeiffer / Cristina Barboza Solís / Romain Fantin / Juan Carlos Vanegas / Rachel Mercado / Carlos Ávila

BMJ Open, Vol 13, Iss

evaluation of immune response and household transmission of SARS-CoV-2 in Costa Rica: the RESPIRA study

2023 Volume 12

Abstract: Purpose The RESPIRA cohort aims to describe the nature, magnitude, time course and efficacy of the immune response to SARS-CoV-2 infection and vaccination, population prevalence, and household transmission of COVID-19.Participants From November 2020, we ... ...

Abstract	Purpose The RESPIRA cohort aims to describe the nature, magnitude, time course and efficacy of the immune response to SARS-CoV-2 infection and vaccination, population prevalence, and household transmission of COVID-19.Participants From November 2020, we selected age-stratified random samples of COVID-19 cases from Costa Rica confirmed by PCR. For each case, two population-based controls, matched on age, sex and census tract were recruited, supplemented with hospitalised cases and household contacts. Participants were interviewed and blood and saliva collected for antibodies and PCR tests. Participants will be followed for 2 years to assess antibody response and infection incidence.Findings to date Recruitment included 3860 individuals: 1150 COVID-19 cases, 1999 population controls and 719 household contacts from 304 index cases. The age and regional distribution of cases was as planned, including four age strata, 30% rural and 70% urban. The control cohort had similar sex, age and regional distribution as the cases according to the study design. Among the 1999 controls recruited, 6.8% reported at enrolment having had COVID-19 and an additional 12.5% had antibodies against SARS-CoV-2. Compliance with visits and specimens has been close to 70% during the first 18 months of follow-up. During the study, national vaccination was implemented and nearly 90% of our cohort participants were vaccinated during follow-up.Future plans RESPIRA will enable multiple analyses, including population prevalence of infection, clinical, behavioural, immunological and genetic risk factors for SARS-CoV-2 acquisition and severity, and determinants of household transmission. We are conducting retrospective and prospective assessment of antibody levels, their determinants and their protective efficacy after infection and vaccination, the impact of long-COVID and a series of ancillary studies. Follow-up continues with bimonthly saliva collection for PCR testing and biannual blood collection for immune response analyses. Follow-up will be ...
Keywords	Medicine ; R
Language	English
Publishing date	2023-12-01T00:00:00Z
Publisher	BMJ Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Disentangling molecular mechanisms regulating sensitization of interferon alpha signal transduction

Frédérique Kok / Marcus Rosenblatt / Melissa Teusel / Tamar Nizharadze / Vladimir Gonçalves Magalhães / Christopher Dächert / Tim Maiwald / Artyom Vlasov / Marvin Wäsch / Silvana Tyufekchieva / Katrin Hoffmann / Georg Damm / Daniel Seehofer / Tobias Boettler / Marco Binder / Jens Timmer / Marcel Schilling / Ursula Klingmüller

Molecular Systems Biology, Vol 16, Iss 7, Pp n/a-n/a (2020)

2020

Abstract: Abstract Tightly interlinked feedback regulators control the dynamics of intracellular responses elicited by the activation of signal transduction pathways. Interferon alpha (IFNα) orchestrates antiviral responses in hepatocytes, yet mechanisms that ... ...

Abstract	Abstract Tightly interlinked feedback regulators control the dynamics of intracellular responses elicited by the activation of signal transduction pathways. Interferon alpha (IFNα) orchestrates antiviral responses in hepatocytes, yet mechanisms that define pathway sensitization in response to prestimulation with different IFNα doses remained unresolved. We establish, based on quantitative measurements obtained for the hepatoma cell line Huh7.5, an ordinary differential equation model for IFNα signal transduction that comprises the feedback regulators STAT1, STAT2, IRF9, USP18, SOCS1, SOCS3, and IRF2. The model‐based analysis shows that, mediated by the signaling proteins STAT2 and IRF9, prestimulation with a low IFNα dose hypersensitizes the pathway. In contrast, prestimulation with a high dose of IFNα leads to a dose‐dependent desensitization, mediated by the negative regulators USP18 and SOCS1 that act at the receptor. The analysis of basal protein abundance in primary human hepatocytes reveals high heterogeneity in patient‐specific amounts of STAT1, STAT2, IRF9, and USP18. The mathematical modeling approach shows that the basal amount of USP18 determines patient‐specific pathway desensitization, while the abundance of STAT2 predicts the patient‐specific IFNα signal response.
Keywords	dynamic pathway modeling ; feedback control ; interferon ; personalized treatment ; signal transduction ; Biology (General) ; QH301-705.5 ; Medicine (General) ; R5-920
Subject code	616
Language	English
Publishing date	2020-07-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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