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Berlin Brandenburg

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  • 1
    In: Cell Research, 2013, Vol.23(12), p.1343
    Description: Since its discovery in 1989, researchers strive after a small animal model for Hepatitis C virus infection, so far with very limited success. A study recently published in Nature now for the first time reports the recapitulation of the complete life cycle of this virus in inbred mice with a functional adaptive immune system.
    Keywords: Virus Internalization ; Hepacivirus -- Physiology ; Hepatitis C -- Virology ; Membrane Proteins -- Metabolism;
    ISSN: 1001-0602
    E-ISSN: 17487838
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  • 2
    In: Nature, 2012, Vol.487(7408), p.486
    Description: Viruses must enter host cells to replicate, assemble and propagate. Because of the restricted size of their genomes, viruses have had to evolve efficient ways of exploiting host cell processes to promote their own life cycles and also to escape host immune defence mechanisms. Many viral open reading frames (viORFs) with immune-modulating functions essential for productive viral growth have been identified across a range of viral classes. However, there has been no comprehensive study to identify the host factors with which these viORFs interact for a global perspective of viral perturbation strategies. Here we show that different viral perturbation patterns of the host molecular defence network can be deduced from a mass-spectrometry-based host-factor survey in a defined human cellular system by using 70 innate immunemodulating viORFs from 30 viral species. The 579 host proteins targeted by the viORFs mapped to an unexpectedly large number of signalling pathways and cellular processes, suggesting yet unknown mechanisms of antiviral immunity. We further experimentally verified the targets heterogeneous nuclear ribonucleoprotein U, phosphatidylinositol-3-OH kinase, the WNK (with-no-lysine) kinase family and USP19 (ubiquitin-specific peptidase 19) as vulnerable nodes in the host cellular defence system. Evaluation of the impact of viral immune modulators on the host molecular network revealed perturbation strategies used by individual viruses and by viral classes. Our data are also valuable for the design of broad and specific antiviral therapies. [PUBLICATION ]
    Keywords: Endopeptidases–Metabolism ; Hek293 Cells–Metabolism ; Heterogeneous-Nuclear Ribonucleoprotein U–Immunology ; Host-Pathogen Interactions–Physiology ; Host-Pathogen Interactions–Immunology ; Humans–Genetics ; Immunity, Innate–Metabolism ; Mass Spectrometry–Metabolism ; Open Reading Frames–Genetics ; Phosphatidylinositol 3-Kinases–Immunology ; Protein-Serine-Threonine Kinases–Metabolism ; Reproducibility of Results–Immunology ; Signal Transduction–Metabolism ; Substrate Specificity–Metabolism ; Viral Proteins–Metabolism ; Viral Proteins–Metabolism ; Viral Proteins–Metabolism ; Viruses–Metabolism ; Viruses–Metabolism ; Proteins ; Viruses ; Infections ; Influenza ; Viral Infections ; Cell Cycle ; Mass Spectrometry ; Deoxyribonucleic Acid–DNA ; Genomes ; Heterogeneous-Nuclear Ribonucleoprotein U ; Viral Proteins ; Phosphatidylinositol 3-Kinases ; Protein-Serine-Threonine Kinases ; Endopeptidases ; Usp19 Protein, Human;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 3
    In: Nature, 2005, Vol.437(7062), p.1167
    Description: Antiviral immunity against a pathogen is mounted upon recognition by the host of virally associated structures. One of these viral 'signatures', double- stranded (ds) RNA, is a replication product of most viruses within infected cells and is sensed by Toll-like receptor 3 (TLR3) and the recently identified cytosolic RNA helicases RIG-I (retinoic acid inducible gene I, also known as Ddx58) and Mda5 (melanoma differentiation-associated gene 5, also known as Ifih1 or Helicard). Both helicases detect dsRNA, and through their protein-interacting CARD domains, relay an undefined signal resulting in the activation of the transcription factors interferon regulatory factor 3 (IRF3) and NF- Kappa B. Here we describe Cardif, a new CARD-containing adaptor protein that interacts with RIG-I and recruits IKK alpha , IKK beta and IKK[epsilon] kinases by means of its C-terminal region, leading to the activation of NF- Kappa B and IRF3. Overexpression of Cardif results in interferon- beta and NF- Kappa B promoter activation, and knockdown of Cardif by short interfering RNA inhibits RIG-I- dependent antiviral responses. Cardif is targeted and inactivated by NS3-4A, a serine protease from hepatitis C virus known to block interferon- beta production. Cardif thus functions as an adaptor, linking the cytoplasmic dsRNA receptor RIG-I to the initiation of antiviral programmes.
    Keywords: Immune Response & Immune Mechanisms ; Virus ; RNA/DNA Role in Infection & Immune Response ; Cardif Protein ; Ddx58 Protein ; Rig-I Protein;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 4
    Language: English
    In: FEBS Letters, 21 May 2013, Vol.587(10), pp.1571-1578
    Description: JAK/STAT signalling is essential for anti-viral immunity, making IFN-α an obvious anti-viral therapeutic. However, many HCV+ patients fail treatment, indicating that the virus blocks successful IFN-α signalling. We found that STAT1 and STAT3 proteins, key components of the IFN-α signalling pathway were reduced in immune cells and hepatocytes from HCV infected patients, and upon HCV expression in Huh7 hepatocytes. However, STAT1 and STAT3 mRNA levels were normal. Mechanistic analysis revealed that in the presence of HCV, STAT3 protein was preferentially ubiquitinated, and degradation was blocked by the proteasomal inhibitor MG132. These findings show that HCV inhibits IFN-α responses in a broad spectrum of cells via proteasomal degradation of JAK/STAT pathway components.
    Keywords: Hepatitis C Virus ; Interferon ; Jak/Stat ; Ubiquitination ; Proteasome ; Biology ; Chemistry ; Anatomy & Physiology
    ISSN: 0014-5793
    E-ISSN: 1873-3468
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  • 5
    In: The Journal of Virology, 2010, Vol. 84(11), p.5775
    Description: Hepatitis C virus (HCV) is an important human pathogen affecting 170 million chronically infected individuals. In search for cellular proteins involved in HCV replication, we have developed a purification strategy for viral replication complexes and identified annexin A2 (ANXA2) as an associated host factor. ANXA2 colocalized with viral nonstructural proteins in cells harboring genotype 1 or 2 replicons as well as in infected cells. In contrast, we found no obvious colocalization of ANXA2 with replication sites of other positive-strand RNA viruses. The silencing of ANXA2 expression showed no effect on viral RNA replication but resulted in a significant reduction of extra- and intracellular virus titers. Therefore, it seems likely that ANXA2 plays a role in HCV assembly rather than in genome replication or virion release. Colocalization studies with individually expressed HCV nonstructural proteins indicated that NS5A specifically recruits ANXA2, probably by an indirect mechanism. By the deletion of individual NS5A subdomains, we identified domain III (DIII) as being responsible for ANXA2 recruitment. These data identify ANXA2 as a novel host factor contributing, with NS5A, to the formation of infectious HCV particles.
    Keywords: Virus Replication ; Annexin A2 -- Physiology ; Hepacivirus -- Ultrastructure ; Viral Nonstructural Proteins -- Physiology ; Virion -- Growth & Development;
    ISSN: 0022-538X
    ISSN: 0022538X
    E-ISSN: 10985514
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  • 6
    Language: English
    In: BMC Bioinformatics, Dec 20, 2011, Vol.12, p.485
    Description: Background High-content, high-throughput RNA interference (RNAi) offers unprecedented possibilities to elucidate gene function and involvement in biological processes. Microscopy based screening allows phenotypic observations at the level of individual cells. It was recently shown that a cell's population context significantly influences results. However, standard analysis methods for cellular screens do not currently take individual cell data into account unless this is important for the phenotype of interest, i.e. when studying cell morphology. Results We present a method that normalizes and statistically scores microscopy based RNAi screens, exploiting individual cell information of hundreds of cells per knockdown. Each cell's individual population context is employed in normalization. We present results on two infection screens for hepatitis C and dengue virus, both showing considerable effects on observed phenotypes due to population context. In addition, we show on a non-virus screen that these effects can be found also in RNAi data in the absence of any virus. Using our approach to normalize against these effects we achieve improved performance in comparison to an analysis without this normalization and hit scoring strategy. Furthermore, our approach results in the identification of considerably more significantly enriched pathways in hepatitis C virus replication than using a standard analysis approach. Conclusions Using a cell-based analysis and normalization for population context, we achieve improved sensitivity and specificity not only on a individual protein level, but especially also on a pathway level. This leads to the identification of new host dependency factors of the hepatitis C and dengue viruses and higher reproducibility of results.
    Keywords: Genes -- Identification And Classification ; Genetic Testing -- Methods ; Genetic Testing -- Research ; Rna Interference -- Physiological Aspects ; Rna Interference -- Usage
    ISSN: 1471-2105
    Source: Cengage Learning, Inc.
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  • 7
    Language: English
    In: BMC Bioinformatics, Dec 20, 2011, Vol.12, p.485
    Description: Background High-content, high-throughput RNA interference (RNAi) offers unprecedented possibilities to elucidate gene function and involvement in biological processes. Microscopy based screening allows phenotypic observations at the level of individual cells. It was recently shown that a cell's population context significantly influences results. However, standard analysis methods for cellular screens do not currently take individual cell data into account unless this is important for the phenotype of interest, i.e. when studying cell morphology. Results We present a method that normalizes and statistically scores microscopy based RNAi screens, exploiting individual cell information of hundreds of cells per knockdown. Each cell's individual population context is employed in normalization. We present results on two infection screens for hepatitis C and dengue virus, both showing considerable effects on observed phenotypes due to population context. In addition, we show on a non-virus screen that these effects can be found also in RNAi data in the absence of any virus. Using our approach to normalize against these effects we achieve improved performance in comparison to an analysis without this normalization and hit scoring strategy. Furthermore, our approach results in the identification of considerably more significantly enriched pathways in hepatitis C virus replication than using a standard analysis approach. Conclusions Using a cell-based analysis and normalization for population context, we achieve improved sensitivity and specificity not only on a individual protein level, but especially also on a pathway level. This leads to the identification of new host dependency factors of the hepatitis C and dengue viruses and higher reproducibility of results.
    Keywords: Genes -- Identification And Classification ; Genetic Testing -- Methods ; Genetic Testing -- Research ; Rna Interference -- Physiological Aspects ; Rna Interference -- Usage
    ISSN: 1471-2105
    Source: Cengage Learning, Inc.
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  • 8
    Language: English
    In: 2015, Vol.11(11), p.e1005264
    Description: 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. ; Mammalian cells developed several defense mechanisms against viral infection. One major strategy involves pattern recognition receptors (PRRs) recognizing non-self motifs in viral RNA and triggering the production of type I and III interferon (IFN) that induce an antiviral state. One central signaling molecule in this cascade is MAVS (Mitochondrial Antiviral Signaling protein), residing on mitochondria, mitochondria-associated membranes of the endoplasmic reticulum, and peroxisomes. Here we characterized the role of mitochondrial and peroxisomal MAVS for the activation of the IFN response and their counteraction by the hepatitis C virus (HCV), a major causative agent of chronic liver disease with a high propensity to establish persistence. By using various functional and genetic knock-out cell systems reconstituted to express exclusively mitochondrial or peroxisomal MAVS, we observed comparable activation of type I and III IFN response by either MAVS species. In addition, we found that the HCV protease residing in nonstructural protein 3 (NS3) efficiently cleaves MAVS independent from its subcellular localization. This cleavage is required for suppression of the IFN response and might contribute to HCV persistence. Our results indicate a largely localization-independent activation of the IFN response by MAVS in hepatocytes and its efficient counteraction by the HCV NS3 protease.
    Keywords: Research Article
    ISSN: 1553-7366
    E-ISSN: 1553-7374
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  • 9
    Language: English
    In: BMC Bioinformatics, 01 December 2011, Vol.12(1), p.485
    Description: Abstract Background High-content, high-throughput RNA interference (RNAi) offers unprecedented possibilities to elucidate gene function and involvement in biological processes. Microscopy based screening allows phenotypic observations at the level of individual cells. It was recently shown that a cell's population context significantly influences results. However, standard analysis methods for cellular screens do not currently take individual cell data into account unless this is important for the phenotype of interest, i.e. when studying cell morphology. Results We present a method that normalizes and statistically scores microscopy based RNAi screens, exploiting individual cell information of hundreds of cells per knockdown. Each cell's individual population context is employed in normalization. We present results on two infection screens for hepatitis C and dengue virus, both showing considerable effects on observed phenotypes due to population context. In addition, we show on a non-virus screen that these effects can be found also in RNAi data in the absence of any virus. Using our approach to normalize against these effects we achieve improved performance in comparison to an analysis without this normalization and hit scoring strategy. Furthermore, our approach results in the identification of considerably more significantly enriched pathways in hepatitis C virus replication than using a standard analysis approach. Conclusions Using a cell-based analysis and normalization for population context, we achieve improved sensitivity and specificity not only on a individual protein level, but especially also on a pathway level. This leads to the identification of new host dependency factors of the hepatitis C and dengue viruses and higher reproducibility of results.
    Keywords: Biology
    ISSN: 1471-2105
    E-ISSN: 1471-2105
    Source: Directory of Open Access Journals (DOAJ)
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  • 10
    Language: English
    In: Gastroenterology, May 2018, Vol.154(6), pp.1791-1804.e22
    Description: Hepatitis C virus (HCV) infection is sensitive to interferon (IFN)-based therapy, whereas hepatitis B virus (HBV) infection is not. It is unclear whether HBV escapes detection by the IFN-mediated immune response or actively suppresses it. Moreover, little is known on how HBV and HCV influence each other in coinfected cells. We investigated interactions between HBV and the IFN-mediated immune response using HepaRG cells and primary human hepatocytes (PHHs). We analyzed the effects of HBV on HCV replication, and vice versa, at the single-cell level. PHHs were isolated from liver resection tissues from HBV-, HCV-, and human immunodeficiency virus–negative patients. Differentiated HepaRG cells overexpressing the HBV receptor sodium taurocholate cotransporting polypeptide (dHepaRGNTCP) and PHHs were infected with HBV. Huh7.5 cells were transfected with circular HBV DNA genomes resembling viral covalently closed circular DNA (cccDNA), and subsequently infected with HCV; this served as a model of HBV and HCV coinfection. Cells were incubated with IFN inducers, or IFNs, and antiviral response and viral replication were analyzed by immune fluorescence, reverse-transcription quantitative polymerase chain reaction, enzyme-linked immunosorbent assays, and flow cytometry. HBV infection of dHepaRGNTCP cells and PHHs neither activated nor inhibited signaling via pattern recognition receptors. Incubation of dHepaRGNTCP cells and PHHs with IFN had little effect on HBV replication or levels of cccDNA. HBV infection of these cells did not inhibit JAK-STAT signaling or up-regulation of IFN-stimulated genes. In coinfected cells, HBV did not prevent IFN-induced suppression of HCV replication. In dHepaRGNTCP cells and PHHs, HBV evades the induction of IFN and IFN-induced antiviral effects. HBV infection does not rescue HCV from the IFN-mediated response.
    Keywords: Coinfection ; Interferon-Stimulated Gene ; Prr ; Rig-I ; Medicine
    ISSN: 0016-5085
    E-ISSN: 1528-0012
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