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Article ; Online: Gene Expression Profiling of Different Huh7 Variants Reveals Novel Hepatitis C Virus Host Factors.

Dächert, Christopher / Gladilin, Evgeny / Binder, Marco

2019 Volume 12, Issue 1

Abstract: Chronic Hepatitis C virus (HCV) infection still constitutes a major global health problem with almost half a million deaths per year. To date, the human hepatoma cell line Huh7 and its derivatives is the only cell line that robustly replicates HCV. ... ...

Abstract	Chronic Hepatitis C virus (HCV) infection still constitutes a major global health problem with almost half a million deaths per year. To date, the human hepatoma cell line Huh7 and its derivatives is the only cell line that robustly replicates HCV. However, even different subclones and passages of this single cell line exhibit tremendous differences in HCV replication efficiency. By comparative gene expression profiling using a multi-pronged correlation analysis across eight different Huh7 variants, we identified 34 candidate host factors possibly affecting HCV permissiveness. For seven of the candidates, we could show by knock-down studies their implication in HCV replication. Notably, for at least four of them, we furthermore found that overexpression boosted HCV replication in lowly permissive Huh7 cells, most prominently for the histone-binding transcriptional repressor THAP7 and the nuclear receptor NR0B2. For NR0B2, our results suggest a finely balanced expression optimum reached in highly permissive Huh7 cells, with even higher levels leading to a nearly complete breakdown of HCV replication, likely due to a dysregulation of bile acid and cholesterol metabolism. Our unbiased expression-profiling approach, hence, led to the identification of four host cellular genes that contribute to HCV permissiveness in Huh7 cells. These findings add to an improved understanding of the molecular underpinnings of the strict host cell tropism of HCV.
MeSH term(s)	Carcinoma, Hepatocellular/virology ; Cell Line, Tumor ; Gene Expression Profiling ; Hepacivirus/genetics ; Hepacivirus/physiology ; Host Microbial Interactions/genetics ; Humans ; Liver Neoplasms/virology ; Viral Tropism ; Virus Replication/genetics
Language	English
Publishing date	2019-12-28
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v12010036
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Gene Expression Profiling of Different Huh7 Variants Reveals Novel Hepatitis C Virus Host Factors

Dächert, Christopher / Gladilin, Evgeny / Binder, Marco

Viruses. 2019 Dec. 28, v. 12, no. 1

2019

Abstract	Chronic Hepatitis C virus (HCV) infection still constitutes a major global health problem with almost half a million deaths per year. To date, the human hepatoma cell line Huh7 and its derivatives is the only cell line that robustly replicates HCV. However, even different subclones and passages of this single cell line exhibit tremendous differences in HCV replication efficiency. By comparative gene expression profiling using a multi-pronged correlation analysis across eight different Huh7 variants, we identified 34 candidate host factors possibly affecting HCV permissiveness. For seven of the candidates, we could show by knock-down studies their implication in HCV replication. Notably, for at least four of them, we furthermore found that overexpression boosted HCV replication in lowly permissive Huh7 cells, most prominently for the histone-binding transcriptional repressor THAP7 and the nuclear receptor NR0B2. For NR0B2, our results suggest a finely balanced expression optimum reached in highly permissive Huh7 cells, with even higher levels leading to a nearly complete breakdown of HCV replication, likely due to a dysregulation of bile acid and cholesterol metabolism. Our unbiased expression-profiling approach, hence, led to the identification of four host cellular genes that contribute to HCV permissiveness in Huh7 cells. These findings add to an improved understanding of the molecular underpinnings of the strict host cell tropism of HCV.
Keywords	Hepatitis C virus ; bile acids ; cholesterol metabolism ; chronic hepatitis C ; gene expression regulation ; genes ; hepatoma ; human cell lines ; human diseases ; neoplasm cells ; repressor proteins
Language	English
Dates of publication	2019-1228
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2516098-9
ISSN	1999-4915
ISSN	1999-4915
DOI	10.3390/v12010036
Database	NAL-Catalogue (AGRICOLA)

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

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

PLoS computational biology

2022 Volume 18, Issue 10, Page(s) e1010623

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.
MeSH term(s)	Interferon Type I/metabolism ; Signal Transduction ; Interferon-alpha/pharmacology ; Antiviral Agents/pharmacology ; STAT1 Transcription Factor/metabolism
Chemical Substances	Interferon Type I ; Interferon-alpha ; Antiviral Agents ; STAT1 Transcription Factor
Language	English
Publishing date	2022-10-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	2193340-6
ISSN	1553-7358 ; 1553-734X
ISSN (online)	1553-7358
ISSN	1553-734X
DOI	10.1371/journal.pcbi.1010623
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Article ; Online: Mpox-specific immune responses elicited by vaccination or infection in people living with HIV.

Grüner, Eva / Grossegesse, Marica / Stern, Daniel / Ober, Veronica / Eser, Tabea M / Reiling, Gabriele / Stirner, Renate / Ibarra, Gerardo / Postel, Nils / Conca, Raffaele / Dächert, Christopher / Grifoni, Alba / Sette, Alessandro / Bogner, Johannes / Seybold, Ulrich / Roider, Julia

The Journal of infectious diseases

2024

Abstract: In the recent mpox outbreak, people living with HIV (PLWH) were at high risk both for contracting infection and for suffering a more severe disease course. We studied cellular and humoral immune responses elicited by mpox infection (n = 5; n = 3 PLWH) or ...

Abstract	In the recent mpox outbreak, people living with HIV (PLWH) were at high risk both for contracting infection and for suffering a more severe disease course. We studied cellular and humoral immune responses elicited by mpox infection (n = 5; n = 3 PLWH) or smallpox vaccination (n = 17; all PLWH) in a cohort of men who have sex with men. All PLWH were successfully treated, with stable CD4 counts and undetectable HIV viral loads. 11/17 vaccinated individuals had received childhood smallpox vaccination. In this group of individuals, both two-dose MVA-vaccination and natural infection evoked mpox-specific immune responses mediated by B cells as well as CD4 and CD8 T cells. This study improves our understanding of smallpox vaccination mediated cross-reactivity to other orthopox viruses, and the long-lasting durability of childhood smallpox vaccination mediated immune responses including in PLWH.
Language	English
Publishing date	2024-03-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	3019-3
ISSN	1537-6613 ; 0022-1899
ISSN (online)	1537-6613
ISSN	0022-1899
DOI	10.1093/infdis/jiae138
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Book ; Online ; Thesis: Mathematical modeling of host cell determinants and pharmacological intervention in hepatitis c virus replication

Dächert, Christopher Armin [Verfasser] / Binder, Marco [Akademischer Betreuer]

2020

Author's details	Christopher Armin Dächert ; Betreuer: Marco Binder
Keywords	Naturwissenschaften ; Science
Subject code	sg500
Language	English
Publisher	Universitätsbibliothek Heidelberg
Publishing place	Heidelberg
Document type	Book ; Online ; Thesis
Database	Digital theses on the web

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Article ; Online: Omicron subvariants illustrate reduced respiratory tissue penetration, cell damage and inflammatory responses in human airway epithelia.

Zaderer, Viktoria / Abd El Halim, Hussam / Wyremblewsky, Anna-Lena / Lupoli, Gaia / Dächert, Christopher / Muenchhoff, Maximilian / Graf, Alexander / Blum, Helmut / Lass-Flörl, Cornelia / Keppler, Oliver T / Huber, Lukas A / Posch, Wilfried / Wilflingseder, Doris

Frontiers in immunology

2023 Volume 14, Page(s) 1258268

Abstract: Introduction: To explore whether the reported lower pathogenicity in infected individuals of variant of concern (VoC) Omicron and its current subvariants compared to VoC Delta may be related to fundamental differences in the initial virus-tissue ... ...

Abstract	Introduction: To explore whether the reported lower pathogenicity in infected individuals of variant of concern (VoC) Omicron and its current subvariants compared to VoC Delta may be related to fundamental differences in the initial virus-tissue interaction, we assessed their ability to penetrate, replicate and cause damage in a human 3D respiratory model. Methods: For this, we used TEER measurements, real-time PCR, LDH, cytokine and complex confocal imaging analyses. Results and discussion: We observed that Delta readily penetrated deep into the respiratory epithelium and this was associated with major tissue destruction, high LDH activity, high viral loads and pronounced innate immune activation as observed by intrinsic C3 activation and IL-6 release at infection sites. In contrast, Omicron subvariants BA.5, BQ.1.1 and BF7 remained superficially in the mucosal layer resulting merely in outward-directed destruction of cells, maintenance of epithelial integrity, minimal LDH activity and low basolateral release of virus at infection sites, as well as significantly smaller areas of complement activation and lower IL-6 secretion. Interestingly, also within Omicron subvariants differences were observed with newer Omicron subvariants BQ.1.1 and BF.7 illustrating significantly reduced viral loads, IL-6 release and LDH activity compared to BA.5. Our data indicate that earliest interaction events after SARS-CoV-2 transmission may have a role in shaping disease severity.
MeSH term(s)	Humans ; Interleukin-6 ; Respiratory Insufficiency ; Epithelium ; Respiratory Mucosa ; Complement Activation
Chemical Substances	Interleukin-6
Language	English
Publishing date	2023-10-17
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1258268
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Article ; Online: Mathematical modeling of plus-strand RNA virus replication to identify broad-spectrum antiviral treatment strategies.

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

PLoS computational biology

2023 Volume 19, Issue 4, Page(s) e1010423

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 growth.
MeSH term(s)	Humans ; Antiviral Agents/pharmacology ; RNA Viruses ; Virus Replication/physiology ; RNA, Viral/genetics ; Models, Theoretical ; Hepatitis C
Chemical Substances	Antiviral Agents ; RNA, Viral
Language	English
Publishing date	2023-04-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2193340-6
ISSN	1553-7358 ; 1553-734X
ISSN (online)	1553-7358
ISSN	1553-734X
DOI	10.1371/journal.pcbi.1010423
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Salivary antibodies induced by BA.4/BA.5-convalescence or bivalent booster Immunoglobulin vaccination protect against novel SARS-COV-2 variants of concern.

Diem, Gabriel / Dichtl, Stefanie / Zaderer, Viktoria / Lass-Flörl, Cornelia / Reindl, Markus / Lupoli, Gaia / Dächert, Christopher / Muenchhoff, Maximilian / Graf, Alexander / Blum, Helmut / Keppler, Oliver T / Wilflingseder, Doris / Posch, Wilfried

Microbiology spectrum

2023 , Page(s) e0179323

Abstract: Currently, SARS-CoV-2 Omicron BA.5 subvariants BF.7 and BQ.1.1 are rapidly emerging worldwide. To evaluate the SARS-CoV-2-neutralizing capacity of sera and saliva from triple vaccinated individuals, either boosted with an adapted bivalent COVID-19 ... ...

Abstract	Currently, SARS-CoV-2 Omicron BA.5 subvariants BF.7 and BQ.1.1 are rapidly emerging worldwide. To evaluate the SARS-CoV-2-neutralizing capacity of sera and saliva from triple vaccinated individuals, either boosted with an adapted bivalent COVID-19 vaccine or recovered from BA.4/BA.5 infection, we analyzed the sensitivity of replication-competent SARS-CoV-2 Omicron subvariants BA.4/5, BQ.1.1 and BF.7 to neutralization. Analysis of SARS-CoV-2-specific IgGs and IgAs showed increased serum IgG titers in the vaccinated group, while the serum and salivary IgA levels were comparable. Similar and efficient serum neutralization against the ancestral strain of SARS-CoV-2 and Omicron BA.4/BA.5 was detected in both cohorts, but critically reduced for BQ.1.1 and BF.7. In contrast, salivary neutralization against BA.4/BA.5 was increased in the convalescent compared to the vaccinated group, while salivary neutralizing capacity against BQ.1.1 and BF.7 was comparable in these groups. Further, personalized protective effects studied in a human 3D respiratory model revealed the importance of salivary protection against different Omicron subvariants. IMPORTANCE In BA.4/BA.5-convalescent versus vaccinated groups, salivary neutralization capacity increased against SARS-CoV-2 Omicron BA.4/BA.5. In contrast, it neutralized novel Omicron subvariants BQ.1.1 and BF.7 similarly. Salivary protection against various Omicron subvariants was even more evident when tested in a personalized approach using highly differentiated respiratory human 3D models.
Language	English
Publishing date	2023-08-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	2807133-5
ISSN	2165-0497 ; 2165-0497
ISSN (online)	2165-0497
ISSN	2165-0497
DOI	10.1128/spectrum.01793-23
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Article ; Online: Antiviral drugs block replication of highly immune-evasive Omicron subvariants ex vivo, but fail to reduce tissue inflammation.

Dichtl, Stefanie / Diem, Gabriel / Jäger, Michael / Zaderer, Viktoria / Lupoli, Gaia / Dächert, Christopher / Muenchhoff, Maximilian / Graf, Alexander / Blum, Helmut / Keppler, Oliver T / Lass-Flörl, Cornelia / Weiss, Günter / Wilflingseder, Doris / Posch, Wilfried

Antiviral research

2023 Volume 213, Page(s) 105581

Abstract: The identification of the SARS-CoV-2 Omicron variants BA.4/BA.5, BF.7 and BQ.1.1 immediately raised concerns regarding the efficacy of currently used monoclonal antibody therapies. Here we examined the activity of monoclonal antibody therapies and ... ...

Abstract	The identification of the SARS-CoV-2 Omicron variants BA.4/BA.5, BF.7 and BQ.1.1 immediately raised concerns regarding the efficacy of currently used monoclonal antibody therapies. Here we examined the activity of monoclonal antibody therapies and antiviral drugs against clinical specimens for SARS-CoV-2 Omicron BA.4/BA.5, BF.7 and BQ.1.1 employing an immunofluorescence neutralization assay. Further we explored treatment of BA.4/BA.5 infections with efficient antiviral drugs and monoclonal antibodies in a 3D model of primary human bronchial epithelial cells. We found that the antiviral drugs Molnupiravir, Nirmatrelvir and Remdesivir efficiently inhibit BA.4/BA.5, BF.7 and BQ.1.1 replication. In contrast, only the monoclonal antibody Cilgavimab exerted an inhibitory effect, while Tixagevimab, Regdanvimab and Sotrovimab lost their efficacy against BA.4/BA.5. We found that only the prophylactic treatment with Cilgavimab impacted on tissue inflammation by reducing intracellular complement component 3 (C3) activation following BA.4/BA.5 infection in primary human airway epithelial grown in air-liquid-interphase, which was not the case when using antiviral drugs or Cilgavimab after establishment of infection. Of note, all tested monoclonal antibodies had no neutralizing activity during infection by BF.7 and BQ.1.1 variants. Our results suggest that despite a marked reduction of viral replication, potent antiviral drugs fail to reduce tissue levels of inflammatory compounds such as C3, which can still result in tissue destruction.
MeSH term(s)	Humans ; COVID-19 ; SARS-CoV-2 ; Antibodies, Monoclonal ; Antibodies, Neutralizing/pharmacology ; Antiviral Agents/pharmacology ; Antibodies, Viral
Chemical Substances	Antibodies, Monoclonal ; Antibodies, Neutralizing ; Antiviral Agents ; Antibodies, Viral
Language	English
Publishing date	2023-03-23
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	306628-9
ISSN	1872-9096 ; 0166-3542
ISSN (online)	1872-9096
ISSN	0166-3542
DOI	10.1016/j.antiviral.2023.105581
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Article: Mathematical modeling of plus-strand RNA virus replication to identify broad-spectrum antiviral treatment strategies.

bioRxiv : the preprint server for biology

2022

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 show that only small virus-specific changes in the model were necessary to describe the Author summary: Plus-strand RNA viruses comprise a large group of related and medically relevant viruses. The current global pandemic of COVID-19 caused by the SARS-coronavirus-2 as well as the constant spread of diseases such as dengue and chikungunya fever show the necessity of a comprehensive and precise analysis of plus-strand RNA virus infections. Plus-strand RNA viruses share similarities in their life cycle. To understand their within-host replication strategies, we developed a mathematical model that studies pan-viral similarities and virus-specific differences of three plus-strand RNA viruses, namely hepatitis C, dengue, and coxsackievirus. By fitting our model to
Language	English
Publishing date	2022-07-25
Publishing country	United States
Document type	Preprint
DOI	10.1101/2022.07.25.501353
Database	MEDical Literature Analysis and Retrieval System OnLINE

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