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Berlin Brandenburg

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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 21 March 2017, Vol.114(12), pp.E2430-E2439
    Description: Hepatitis C virus (HCV) displays a restricted host species tropism and only humans and chimpanzees are susceptible to infection. A robust immunocompetent animal model is still lacking, hampering mechanistic analysis of virus pathogenesis, immune control, and prophylactic vaccine development. The closest homolog of HCV is the equine nonprimate hepacivirus (NPHV), which shares similar features with HCV and thus represents an animal model to study hepacivirus infections in their natural hosts. We aimed to dissect equine immune responses after experimental NPHV infection and conducted challenge experiments to investigate immune protection against secondary NPHV infections. Horses were i.v. injected with NPHV containing plasma. Flow cytometric analysis was used to monitor immune cell frequencies and activation status. All infected horses became viremic after 1 or 2 wk and viremia could be detected in two horses for several weeks followed by a delayed seroconversion and viral clearance. Histopathological examinations of liver biopsies revealed mild, periportally accentuated infiltrations of lymphocytes, macrophages, and plasma cells with some horses displaying subclinical signs of hepatitis. Following viral challenge, an activation of equine immune responses was observed. Importantly, after a primary NPHV infection, horses were protected against rechallenge with the homologous as well as a distinct isolate with only minute amounts of circulating virus being detectable.
    Keywords: Hepatitis C Virus ; Immune Protection ; Infection ; Nonprimate Hepacivirus ; Rechallenge ; Hepacivirus -- Physiology ; Hepatitis C -- Veterinary ; Horse Diseases -- Immunology
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    Language: English
    In: Journal of Immunology Research, 2017
    Description: The human interferon (IFN) response is a key innate immune mechanism to fight virus infection. IFNs are host-encoded secreted proteins, which induce IFN-stimulated genes (ISGs) with antiviral properties. Among the three classes of IFNs, type III IFNs, also called IFN lambdas (IFNLs), are an essential component of the innate immune response to hepatitis C virus (HCV). In particular, human polymorphisms in IFNL gene loci correlate with hepatitis C disease progression and with treatment response. To date, the underlying mechanisms remain mostly elusive; however it seems clear that viral infection of the liver induces IFNL responses. As IFNL receptors show a more restricted tissue expression than receptors for other classes of IFNs, IFNL treatment has reduced side effects compared to the classical type I IFN treatment. In HCV therapy, however, IFNL will likely not play an important role as highly effective direct acting antivirals (DAA) exist. Here, we will review our current knowledge on IFNL gene expression, protein properties, signaling, ISG induction, and its implications on HCV infection and treatment. Finally, we will discuss the lessons learnt from the HCV and IFNL field for virus infections beyond hepatitis C.
    Keywords: Medical And Health Sciences ; Basic Medicine ; Immunology In The Medical Area ; Medicin Och Hälsovetenskap ; Medicinska Och Farmaceutiska Grundvetenskaper ; Immunologi Inom Det Medicinska Området
    ISSN: 2314-8861
    E-ISSN: 23147156
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  • 3
    In: Toxins, 2016, Vol.9(1)
    Description: Lethal Toxin from Clostridium sordellii (TcsL), which is casually involved in the toxic shock syndrome and in gas gangrene, enters its target cells by receptor-mediated endocytosis. Inside the cell, TcsL mono-O-glucosylates and thereby inactivates Rac/Cdc42 and Ras subtype GTPases, resulting in actin reorganization and an activation of p38 MAP kinase. While a role of p38 MAP kinase in TcsL-induced cell death is well established, data on a role of p38 MAP kinase in TcsL-induced actin reorganization are not available. In this study, TcsL-induced Rac/Cdc42 glucosylation and actin reorganization are differentially analyzed in p38 alpha −/− MSCV empty vector MEFs and the corresponding cell line with reconstituted p38 alpha expression (p38 alpha −/− MSCV p38 alpha MEFs). Genetic deletion of p38 alpha results in reduced susceptibility of cells to TcsL-induced Rac/Cdc42 glucosylation and actin reorganization. Furthermore, SB203580, a pyridinyl imidazole inhibitor of p38 alpha/beta MAP kinase, also protects cells from TcsL-induced effects in both p38 −/− MSCV empty vector MEFs and in p38 alpha −/− MSCV p38 alpha MEFs, suggesting that inhibition of p38 beta contributes to the protective effect of SB203580. In contrast, the effects of the related C. difficile Toxin B are responsive neither to SB203580 treatment nor to p38 alpha deletion. In conclusion, the protective effects of SB203580 and of p38 alpha deletion are likely not based on inhibition of the toxins’ glucosyltransferase activity rather than on inhibited endocytic uptake of specifically TcsL into target cells.
    Keywords: Article ; Endocytosis ; Ras ; Toxin B ; Mono-O-Glucosylation ; P21-Activated Kinase ; Actin
    E-ISSN: 2072-6651
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  • 4
    Language: English
    In: Virus Research, 15 June 2016, Vol.218, pp.25-39
    Description: Virus entry into host cells relies on interactions between viral and host structures including lipids, carbohydrates and proteins. Particularly, protein–protein interactions between viral surface proteins and host proteins as well as secondary host protein–protein interactions play a pivotal role in coordinating virus binding and uptake. These interactions are dynamic and frequently involve multiprotein complexes. In the past decade mass spectrometry based proteomics methods have reached sensitivities and high throughput compatibilities of genomics methods and now allow the reliable quantitation of proteins in complex samples from limited material. As proteomics provides essential information on the biologically active entity namely the protein, including its posttranslational modifications and its interactions with other proteins, it is an indispensable method in the virologist's toolbox. Here we review protein interactions during virus entry and compare classical biochemical methods to study entry with novel technically advanced quantitative proteomics techniques. We highlight the value of quantitative proteomics in mapping functional virus entry networks, discuss the benefits and limitations and illustrate how the methodology will help resolve unsettled questions in virus entry research in the future.
    Keywords: Virus Entry ; Protein–Protein Interactions ; Quantitative Proteomics ; Protein Interaction Networks ; Biology
    ISSN: 0168-1702
    E-ISSN: 1872-7492
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  • 5
    Language: English
    In: Molecular & Cellular Proteomics, 2017, Vol.16(4), pp.75-91
    Description: interaction proteomics and why we believe these challenges should be met.
    Keywords: Natural Sciences ; Biological Sciences ; Biochemistry And Molecular Biology ; Naturvetenskap ; Biologiska Vetenskaper ; Biokemi Och Molekylärbiologi
    ISSN: 1535-9476
    E-ISSN: 15359484
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  • 6
    Language: English
    In: PLoS Pathogens, 2018, Vol. 14(7)
    Description: Hepatitis C virus (HCV) and the malaria parasite Plasmodium use the membrane protein CD81 to invade human liver cells. Here we mapped 33 host protein interactions of CD81 in primary human liver and hepatoma cells using high-resolution quantitative proteomics. In the CD81 protein network, we identified five proteins which are HCV entry factors or facilitators including epidermal growth factor receptor (EGFR). Notably, we discovered calpain-5 (CAPN5) and the ubiquitin ligase Casitas B-lineage lymphoma proto-oncogene B (CBLB) to form a complex with CD81 and support HCV entry. CAPN5 and CBLB were required for a post-binding and pre-replication step in the HCV life cycle. Knockout of CAPN5 and CBLB reduced susceptibility to all tested HCV genotypes, but not to other enveloped viruses such as vesicular stomatitis virus and human coronavirus. Furthermore, Plasmodium sporozoites relied on a distinct set of CD81 interaction partners for liver cell entry. Our findings reveal a comprehensive CD81 network in human liver cells and show that HCV and Plasmodium highjack selective CD81 interactions, including CAPN5 and CBLB for HCV, to invade cells.
    Keywords: Medical And Health Sciences ; Basic Medicine ; Microbiology In The Medical Area ; Medicin Och Hälsovetenskap ; Medicinska Och Farmaceutiska Grundvetenskaper ; Mikrobiologi Inom Det Medicinska Området
    ISSN: 1553-7366
    E-ISSN: 15537374
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  • 7
    Language: English
    In: Viruses, 2018, Vol. 10(4)
    Description: Hepatitis C virus (HCV) enters human hepatocytes using four essential entry factors, one of which is human CD81 (hCD81). The tetraspanin hCD81 contains a large extracellular loop (LEL), which interacts with the E2 glycoprotein of HCV. The role of the non-LEL regions of hCD81 (intracellular tails, four transmembrane domains, small extracellular loop and intracellular loop) is poorly understood. Here, we studied the contribution of these domains to HCV susceptibility of hepatoma cells by generating chimeras of related tetraspanins with the hCD81 LEL. Our results show that non-LEL regions in addition to the LEL determine susceptibility of cells to HCV. While closely related tetraspanins (X. tropicalis CD81 and D. rerio CD81) functionally complement hCD81 non-LEL regions, distantly related tetraspanins (C. elegans TSP9 amd D. melanogaster TSP96F) do not and tetraspanins with intermediate homology (hCD9) show an intermediate phenotype. Tetraspanin homology and susceptibility to HCV correlate positively. For some chimeras, infectivity correlates with surface expression. In contrast, the hCD9 chimera is fully surface expressed, binds HCV E2 glycoprotein but is impaired in HCV receptor function. We demonstrate that a cholesterol-coordinating glutamate residue in CD81, which hCD9 lacks, promotes HCV infection. This work highlights the hCD81 non-LEL regions as additional HCV susceptibility-determining factors.
    Keywords: Cd81 ; Hcv ; Chimeras ; Cholesterol-Binding Residue ; Hepatitis C Virus ; Receptor ; Susceptibility-Determining Domains ; Tetraspanin ; Transmembrane Domain Four ; Medical And Health Sciences ; Clinical Medicine ; Infectious Medicine ; Medicin Och Hälsovetenskap ; Klinisk Medicin ; Infektionsmedicin
    ISSN: 1999-4915
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  • 8
    Language: English
    In: Journal of Hepatology, September 2017, Vol.67(3), pp.480-489
    Description: Hepatitis C virus (HCV) evades humoral immunity and establishes chronic infections. Virus particles circulate in complex with lipoproteins facilitating antibody escape. Apolipoprotein E (ApoE) is essential for intracellular HCV assembly and for HCV cell entry. We aimed to explore if ApoE released from non-infected cells interacts with and modulates secreted HCV particles. ApoE secreted from non-infected cells was incubated with HCV from primary human hepatocytes or Huh-7.5 cells. Co-immunoprecipitation, viral infectivity and neutralization experiments were conducted. Physiological levels of secreted ApoE (10–60 µg/ml) enhanced the infectivity of HCV up to 8-fold across all genotypes, which indirectly decreased virus neutralization by antibodies targeting E1 or E2 up to 10-fold. Infection enhancement was observed for particles produced in primary human hepatocytes and Huh-7.5 cells. Selective depletion of ApoE ablated infection enhancement. Addition of HA-tagged ApoE to HCV particles permitted co-precipitation of HCV virions. Serum ApoE levels ranged between 10–60 µg/ml, which is ca 100-fold higher than in Huh-7.5 conditioned cell culture fluids. Serum-derived HCV particles carried much higher amounts of ApoE than cell culture-derived HCV particles. Serum ApoE levels correlated with efficiency of co-precipitation of HCV upon exogenous addition of HA-ApoE. ApoE-dependent infection enhancement was independent of the hypervariable region 1 and SR-B1, but was dependent on heparan sulfate proteoglycans (HSPGs). Physiological quantities of secreted ApoE stimulate HCV infection and increase antibody escape, by incorporating into virus particles and enhancing particle interactions with cellular HSPGs. Thus, secreted particles undergo ApoE-dependent maturation to enhance infectivity and to facilitate evasion from neutralizing antibodies. This study shows that HCV particle infectivity is remodeled by secreted ApoE after particle release from cells. Fluctuation of the availability of ApoE likely influences HCV infectivity, antibody escape and transmission.
    Keywords: Hepatitis C Virus ; Apolipoprotein E ; Assembly ; Antibody Escape ; Neutralizing Antibody ; Entry ; Medicine
    ISSN: 0168-8278
    E-ISSN: 1600-0641
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  • 9
    Language: English
    In: Cell Reports, 04 August 2015, Vol.12(5), pp.864-878
    Description: Hepatitis C virus (HCV) enters human hepatocytes through a multistep mechanism involving, among other host proteins, the virus receptor CD81. How CD81 governs HCV entry is poorly characterized, and CD81 protein interactions after virus binding remain elusive. We have developed a quantitative proteomics protocol to identify HCV-triggered CD81 interactions and found 26 dynamic binding partners. At least six of these proteins promote HCV infection, as indicated by RNAi. We further characterized serum response factor binding protein 1 (SRFBP1), which is recruited to CD81 during HCV uptake and supports HCV infection in hepatoma cells and primary human hepatocytes. SRFBP1 facilitates host cell penetration by all seven HCV genotypes, but not of vesicular stomatitis virus and human coronavirus. Thus, SRFBP1 is an HCV-specific, pan-genotypic host entry factor. These results demonstrate the use of quantitative proteomics to elucidate pathogen entry and underscore the importance of host protein-protein interactions during HCV invasion. Hepatitis C virus (HCV) enters human hepatocytes through a multistep mechanism. Gerold et al. apply quantitative proteomics to define the protein network responsible for HCV entry and identify SRFBP1 as a partner for the virus receptor CD81.
    Keywords: Biology
    ISSN: 2211-1247
    E-ISSN: 2211-1247
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  • 10
    Language: English
    In: Antiviral Research, March 2019, Vol.163, pp.34-49
    Description: Hepatitis E virus (HEV) is the causative agent of hepatitis E in humans and is the leading cause of enterically-transmitted viral hepatitis worldwide. Increasing numbers of HEV infections, together with no available specific anti-HEV treatment, contributes to the pathogen's major health burden. A robust cell culture system is required for virologic studies and the development of new antiviral drugs. Unfortunately, like other hepatitis viruses, HEV is difficult to propagate in conventional cell lines. Many different cell culture systems have been tested using various HEV strains, but viral replication usually progresses very slowly, and infection with low virion counts results in non-productive HEV replication. However, recent progress involving generation of cDNA clones and passaging primary patient isolates in distinct cell lines has improved HEV propagation. This review describes various approaches to cultivate HEV in cellular and animal models and how these systems are used to study HEV infections and evaluate anti-HEV drug candidates.
    Keywords: Hepatitis E Virus ; Ribavirin ; Cell Culture ; Therapy ; Viral Genomes ; Cdna Clones ; Animal Models ; Medicine ; Biology
    ISSN: 0166-3542
    E-ISSN: 1872-9096
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