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  • 1. Banse, Pia
    et al.
    Moeller, Rebecca
    Bruening, Janina
    Lasswitz, Lisa
    Kahl, Sina
    Khan, Abdul G
    Marcotrigiano, Joseph
    Pietschmann, Thomas
    Gerold, Gisa
    Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, 30625 Hannover, Germany.
    CD81 receptor regions outside the large extracellular loop determine hepatitis C virus entry into hepatoma cells2018Ingår i: Viruses, ISSN 1999-4915, E-ISSN 1999-4915, Vol. 10, nr 4, artikel-id 207Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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.

  • 2. Bruening, Janina
    et al.
    Lasswitz, Lisa
    Banse, Pia
    Kahl, Sina
    Marinach, Carine
    Vondran, Florian W.
    Kaderali, Lars
    Silvie, Olivier
    Pietschmann, Thomas
    Meissner, Felix
    Gerold, Gisa
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi. Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Insitute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany.
    Hepatitis C virus enters liver cells using the CD81 receptor complex proteins calpain-5 and CBLB2018Ingår i: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 14, nr 7, artikel-id e1007111Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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.

  • 3. Bruening, Janina
    et al.
    Weigel, Bettina
    Gerold, Gisa
    Institute for Experimental Virology, Centre for Experimental and Clinical Infection Research (TWINCORE), Hannover, Germany.
    The Role of Type III Interferons in Hepatitis C Virus Infection and Therapy2017Ingår i: Journal of Immunology Research, ISSN 2314-8861, E-ISSN 2314-7156, artikel-id 7232361Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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.

  • 4. de Diego, J L
    et al.
    Gerold, Gisa
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Zychlinsky, A
    Sensing, presenting, and regulating PAMPs.2007Ingår i: Ernst Schering Foundation symposium proceedings, nr 3, s. 83-95Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Recognition of microbial infection and initiation of immune responses are controlled by multiple mechanisms. Toll-like receptors (TLRs) are key components of the innate immune system that detect microbial infection. TLR activation helps to eliminate the invading pathogens, coordinate systemic defenses, and initiate adaptive immune responses. Despite progress elucidating the TLR signaling aspects and the physiological relevance of TLRs in microbial infections, the molecular basis of microbial recognition by TLRs is still not fully understood. In this article we focus on the availability of microbial ligands to regulate presentation to TLRs and assist in our understanding of TLR-mediated microbial recognition.

  • 5. Fedeli, Chiara
    et al.
    Torriani, Giulia
    Galan-Navarro, Clara
    Moraz, Marie-Laurence
    Moreno, Hector
    Gerold, Gisa
    TWINCORE, Center for Experimental and Clinical Infection Research, Institute for Experimental Virology, Hannover, Germany.
    Kunz, Stefan
    Axl can serve as entry factor for lassa virus depending on the functional glycosylation of dystroglycan2018Ingår i: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 92, nr 5, artikel-id e01613-17Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The highly pathogenic arenavirus Lassa virus (LASV) represents a serious public health problem in Africa. Although the principal LASV receptor, dystroglycan (DG), is ubiquitously expressed, virus binding critically depends on DG's posttranslational modification, which does not always correlate with tissue tropism. The broadly expressed phosphatidylserine receptor Axl was recently identified as an alternative LASV receptor candidate, but its role in LASV entry is unclear. Here, we investigate the exact role of Axl in LASV entry as a function of DG's posttranslational modification. We found that in the absence of functional DG, Axl can mediate LASV entry via apoptotic mimicry. Productive entry requires virus-induced receptor activation, involves macropinocytosis, and critically depends on LAMP-1. In endothelial cells that express low levels of glycosylated DG, both receptors can promote LASV entry. In sum, our study defines the roles of Axl in LASV entry and provides a rationale for targeting Axl in antiviral therapy.

  • 6.
    Gerold, Gisa
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Abu Ajaj, Khalid
    Bienert, Michael
    Laws, Hans-Jürgen
    Zychlinsky, Arturo
    de Diego, Juana L
    A Toll-like receptor 2-integrin beta3 complex senses bacterial lipopeptides via vitronectin.2008Ingår i: Nature Immunology, ISSN 1529-2908, E-ISSN 1529-2916, Vol. 9, nr 7, s. 761-8Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Toll-like receptor 2 (TLR2) initiates inflammation in response to bacterial lipopeptide (BLP). However, the molecular mechanisms enabling the detection of BLP by TLR2 are unknown. Here we investigated the interaction of BLP with human serum proteins and identified vitronectin as a BLP-recognition molecule. Vitronectin and its receptor, integrin beta(3), were required for BLP-induced TLR2-mediated activation of human monocytes. Furthermore, monocytes from patients with Glanzmann thrombasthenia, which lack integrin beta(3), were completely unresponsive to BLP. In addition, integrin beta(3) formed a complex with TLR2 and this complex dissociated after BLP stimulation. Notably, vitronectin and integrin beta(3) coordinated responses to other TLR2 agonists such as lipoteichoic acid and zymosan. Our findings show that vitronectin and integrin beta(3) contribute to the initiation of TLR2 responses.

  • 7.
    Gerold, Gisa
    et al.
    Insitute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, A joint Venture Between the Medical School Hannover and the Helmholtz Centre for Infection Research, 30652 Hannover, Germany.
    Bruening, Janina
    Pietschmann, Thomas
    Decoding protein networks during virus entry by quantitative proteomics2016Ingår i: Virus Research, ISSN 0168-1702, E-ISSN 1872-7492, Vol. 218, s. 25-39Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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.

  • 8.
    Gerold, Gisa
    et al.
    Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany.
    Bruening, Janina
    Weigel, Bettina
    Pietschmann, Thomas
    Protein Interactions during the Flavivirus and Hepacivirus Life Cycle2017Ingår i: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 16, nr 4, s. 75-91Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    interaction proteomics and why we believe these challenges should be met.

  • 9. Gerold, Gisa
    et al.
    Meissner, Felix
    Bruening, Janina
    Welsch, Kathrin
    Perin, Paula M
    Baumert, Thomas F
    Vondran, Florian W
    Kaderali, Lars
    Marcotrigiano, Joseph
    Khan, Abdul G
    Mann, Matthias
    Rice, Charles M
    Pietschmann, Thomas
    Quantitative Proteomics Identifies Serum Response Factor Binding Protein 1 as a Host Factor for Hepatitis C Virus Entry2015Ingår i: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 12, nr 5, s. 864-878, artikel-id S2211-1247(15)00689-0Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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.

  • 10.
    Gerold, Gisa
    et al.
    Center for Experimental and Clinical Infection Research Institute of Experimental Virology, TWINCORE Hannover Germany.
    Pietschmann, Thomas
    A circuit of paracrine signals between liver sinusoid endothelial cells and hepatocytes regulates hepatitis C virus replication2014Ingår i: Hepatology, ISSN 0270-9139, E-ISSN 1527-3350, Vol. 59, nr 2, s. 363-5Artikel i tidskrift (Refereegranskat)
  • 11.
    Gerold, Gisa
    et al.
    Institute of Experimental Virology Twincore – Center for Experimental and Clinical Infectious Disease Research Hannover, Germany.
    Pietschmann, Thomas
    Hepatitis C virus NS5B polymerase primes innate immune signaling2013Ingår i: Hepatology, ISSN 0270-9139, E-ISSN 1527-3350, Vol. 57, nr 3, s. 1275-1277Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Innate immunity controls pathogen replication and spread. Yet, certain pathogens, such as Hepatitis C Virus (HCV), escape immune elimination and establish persistent infections that promote chronic inflammation and related diseases. Whereas HCV regulatory proteins that attenuate antiviral responses are known, those that promote inflammation and liver injury remain to be identified. Here, we show that transient expression of HCV RNA-dependent RNA polymerase (RdRp), NS5B, in mouse liver and human hepatocytes results in production of small RNA species that activate innate immune signaling via TBK1-IRF3 and NF-kappa B and induce cytokine production, including type I interferons (IFN) and IL-6. NS5B-expression also results in liver damage.

  • 12.
    Gerold, Gisa
    et al.
    TWINCORE – Institute of Experimental Virology, Centre for Experimental and Clinical Infection Research, Hannover , Germany.
    Pietschmann, Thomas
    The HCV life cycle: in vitro tissue culture systems and therapeutic targets2014Ingår i: Digestive Diseases, ISSN 0257-2753, E-ISSN 1421-9875, Vol. 32, nr 5, s. 525-537Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hepatitis C virus (HCV) is a highly variable plus-strand RNA virus of the family Flaviviridae. Viral strains are grouped into six epidemiologically relevant genotypes that differ from each other by more than 30% at the nucleotide level. The variability of HCV allows immune evasion and facilitates persistence. It is also a substantial challenge for the development of specific antiviral therapies effective across all HCV genotypes and for prevention of drug resistance. Novel HCV cell culture models were instrumental for identification and profiling of therapeutic strategies. Concurrently, these models revealed numerous host factors critical for HCV propagation, some of which have emerged as targets for antiviral therapy. It is generally assumed that the use of host factors is conserved among HCV isolates and genotypes. Additionally, the barrier to viral resistance is thought to be high when interfering with host factors. Therefore, current drug development includes both targeting of viral factors but also of host factors essential for virus replication. In fact, some of these host-targeting agents, for instance inhibitors of cyclophilin A, have advanced to late stage clinical trials. Here, we highlight currently available cell culture systems for HCV, review the most prominent host-targeting strategies against hepatitis C and critically discuss opportunities and risks associated with host-targeting antiviral strategies.

  • 13.
    Gerold, Gisa
    et al.
    Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York, USA.
    Rice, Charles M
    Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York, USA.
    Locking out hepatitis C2011Ingår i: Nature Medicine, ISSN 1078-8956, E-ISSN 1546-170X, Vol. 17, nr 5, s. 542-4Artikel i tidskrift (Refereegranskat)
  • 14.
    Gerold, Gisa
    et al.
    Center for the Study of Hepatitis C Laboratory of Virology and Infectious Diseases Rockefeller University, New York, NY.
    Rice, Charles M
    Ploss, Alexander
    Teaching new tricks to an old foe: murinizing hepatitis C virus2010Ingår i: Hepatology, ISSN 0270-9139, E-ISSN 1527-3350, Vol. 52, nr 6, s. 2233-2236Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hepatitis C virus (HCV) naturally infects only humans and chimpanzees. The determinants responsible for this narrow species tropism are not well defined. Virus cell entry involves human scavenger receptor class B type I (SR‐BI), CD81, claudin‐1 and occludin. Among these, at least CD81 and occludin are utilized in a highly species‐specific fashion, thus contributing to the narrow host range of HCV. We adapted HCV to mouse CD81 and identified three envelope glycoprotein mutations which together enhance infection of cells with mouse or other rodent receptors approximately 100‐fold. These mutations enhanced interaction with human CD81 and increased exposure of the binding site for CD81 on the surface of virus particles. These changes were accompanied by augmented susceptibility of adapted HCV to neutralization by E2‐specific antibodies indicative of major conformational changes of virus‐resident E1/E2‐complexes. Neutralization with CD81, SR‐BI‐ and claudin‐1‐specific antibodies and knock down of occludin expression by siRNAs indicate that the adapted virus remains dependent on these host factors but apparently utilizes CD81, SR‐BI and occludin with increased efficiency. Importantly, adapted E1/E2 complexes mediate HCV cell entry into mouse cells in the absence of human entry factors. These results further our knowledge of HCV receptor interactions and indicate that three glycoprotein mutations are sufficient to overcome the species‐specific restriction of HCV cell entry into mouse cells. Moreover, these findings should contribute to the development of an immunocompetent small animal model fully permissive to HCV.

  • 15.
    Gerold, Gisa
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Zychlinsky, Arturo
    de Diego, Juana L
    What is the role of Toll-like receptors in bacterial infections?2007Ingår i: Seminars in Immunology, ISSN 1044-5323, E-ISSN 1096-3618, Vol. 19, nr 1, s. 41-7Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Innate immunity relies on signalling by Toll-like receptors (TLRs) to alert the immune system of the presence of invading bacteria. TLR activation leads to the release of cytokines that allow for effective innate and adaptive immune responses. However, the contribution of different TLRs depends on the site of the infection and the pathogen. This review will describe the involvement of TLRs in the development of three different bacterial infections as well as our current understanding of the role of TLRs during microbial pathogenesis.

  • 16. Herrador, Antonio
    et al.
    Fedeli, Chiara
    Radulovic, Emilia
    Campbell, Kevin P.
    Moreno, Hector
    Gerold, Gisa
    Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. TWINCORE - Center for Experimental and Clinical Infection Research, Institute for Experimental Virology, Hannover, Germany.
    Kunz, Stefan
    Dynamic Dystroglycan Complexes Mediate Cell Entry of Lassa Virus2019Ingår i: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 10, nr 2, artikel-id e02869-18Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Recognition of functional receptors by viruses is a key determinant for their host range, tissue tropism, and disease potential. The highly pathogenic Lassa virus (LASV) currently represents one of the most important emerging pathogens. The major cellular receptor for LASV in human cells is the ubiquitously expressed and evolutionary highly conserved extracellular matrix receptor dystroglycan (DG). In the host, DG interacts with many cellular proteins in a tissue-specific manner. The resulting distinct supramolecular complexes likely represent the functional units for viral entry, and preexisting protein-protein interactions may critically influence DG's function in productive viral entry. Using an unbiased shotgun proteomic approach, we define the largely unknown molecular composition of DG complexes present in highly susceptible epithelial cells that represent important targets for LASV during viral transmission. We further show that the specific composition of cellular DG complexes can affect DG's function in receptor-mediated endocytosis of the virus. Under steady-state conditions, epithelial DG complexes underwent rapid turnover via an endocytic pathway that shared some characteristics with DG-mediated LASV entry. However, compared to steady-state uptake of DG, LASV entry via DG occurred faster and critically depended on additional signaling by receptor tyrosine kinases and the downstream effector p21-activating kinase. In sum, we show that the specific molecular composition of DG complexes in susceptible cells is a determinant for productive virus entry and that the pathogen can manipulate the existing DG-linked endocytic pathway. This highlights another level of complexity of virus-receptor interaction and provides possible cellular targets for therapeutic antiviral intervention.

    Importance: Recognition of cellular receptors allows emerging viruses to break species barriers and is an important determinant for their disease potential. Many virus receptors have complex tissue-specific interactomes, and preexisting protein-protein interactions may influence their function. Combining shotgun proteomics with a biochemical approach, we characterize the molecular composition of the functional receptor complexes used by the highly pathogenic Lassa virus (LASV) to invade susceptible human cells. We show that the specific composition of the receptor complexes affects productive entry of the virus, providing proof-of-concept. In uninfected cells, these functional receptor complexes undergo dynamic turnover involving an endocytic pathway that shares some characteristics with viral entry. However, steady-state receptor uptake and virus endocytosis critically differ in kinetics and underlying signaling, indicating that the pathogen can manipulate the receptor complex according to its needs. Our study highlights a remarkable complexity of LASV-receptor interaction and identifies possible targets for therapeutic antiviral intervention.

  • 17. Kapoor, Amit
    et al.
    Simmonds, Peter
    Gerold, Gisa
    Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065.
    Qaisar, Natasha
    Jain, Komal
    Henriquez, Jose A
    Firth, Cadhla
    Hirschberg, David L
    Rice, Charles M
    Shields, Shelly
    Lipkin, W Ian
    Characterization of a canine homolog of hepatitis C virus2011Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, nr 28, s. 11608-11613Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    An estimated 3% of the world's population is chronically infected with hepatitis C virus (HCV). Although HCV was discovered more than 20 y ago, its origin remains obscure largely because no closely related animal virus homolog has been identified; furthermore, efforts to understand HCV pathogenesis have been hampered by the absence of animal models other than chimpanzees for human disease. Here we report the identification in domestic dogs of a nonprimate hepacivirus. Comparative phylogenetic analysis of the canine hepacivirus (CHV) confirmed it to be the most genetically similar animal virus homolog of HCV. Bayesian Markov chains Monte Carlo and associated time to most recent common ancestor analyses suggest a mean recent divergence time of CHV and HCV clades within the past 500-1,000 y, well after the domestication of canines. The discovery of CHV may provide new insights into the origin and evolution of HCV and a tractable model system with which to probe the pathogenesis, prevention, and treatment of diseases caused by hepacivirus infection.

  • 18. Lasswitz, Lisa
    et al.
    Chandra, Naresh
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Arnberg, Niklas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Gerold, Gisa
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi. Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany.
    Glycomics and Proteomics Approaches to Investigate Early Adenovirus-Host Cell Interactions2018Ingår i: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 430, nr 13, s. 1863-1882Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Adenoviruses as most viruses rely on glycan and protein interactions to attach to and enter susceptible host cells. The Adenoviridae family comprises more than 80 human types and they differ in their attachment factor and receptor usage, which likely contributes to the diverse tropism of the different types. In the past years, methods to systematically identify glycan and protein interactions have advanced. In particular sensitivity, speed and coverage of mass spectrometric analyses allow for high-throughput identification of glycans and peptides separated by liquid chromatography. Also, developments in glycan microarray technologies have led to targeted, high-throughput screening and identification of glycan-based receptors. The mapping of cell surface interactions of the diverse adenovirus types has implications for cell, tissue, and species tropism as well as drug development. Here we review known adenovirus interactions with glycan- and protein-based receptors, as well as glycomics and proteomics strategies to identify yet elusive virus receptors and attachment factors. We finally discuss challenges, bottlenecks, and future research directions in the field of non-enveloped virus entry into host cells.

  • 19. Loll, Bernhard
    et al.
    Gerold, Gisa
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Slowik, Daria
    Voelter, Wolfgang
    Jung, Christiane
    Saenger, Wolfram
    Irrgang, Klaus-Dieter
    Thermostability and Ca2+ binding properties of wild type and heterologously expressed PsbO protein from cyanobacterial photosystem II.2005Ingår i: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 44, nr 12, s. 4691-8Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Oxygenic photosynthesis takes place in the thylakoid membrane of cyanobacteria, algae, and higher plants. Initially light is absorbed by an oligomeric pigment-protein complex designated as photosystem II (PSII), which catalyzes light-induced water cleavage under release of molecular oxygen for the biosphere on our planet. The membrane-extrinsic manganese stabilizing protein (PsbO) is associated on the lumenal side of the thylakoids close to the redox-active (Mn)(4)Ca cluster at the catalytically active site of PSII. Recombinant PsbO from the thermophilic cyanobacterium Thermosynechococcus elongatus was expressed in Escherichia coli and spectroscopically characterized. The secondary structure of recombinant PsbO (recPsbO) was analyzed in the absence and presence of Ca(2+) using Fourier transform infrared spectroscopy (FTIR) and circular dichroism spectropolarimetry (CD). No significant structural changes could be observed when the PSII subunit was titrated with Ca(2+) in vitro. These findings are compared with data for spinach PsbO. Our results are discussed in the light of the recent 3D-structural analysis of the oxygen-evolving PSII and structural/thermodynamic differences between the two homologous proteins from thermophilic cyanobacteria and plants.

  • 20. Lump, Edina
    et al.
    Castellano, Laura M
    Meier, Christoph
    Seeliger, Janine
    Erwin, Nelli
    Sperlich, Benjamin
    Stürzel, Christina M
    Usmani, Shariq
    Hammond, Rebecca M
    von Einem, Jens
    Gerold, Gisa
    Kreppel, Florian
    Bravo-Rodriguez, Kenny
    Pietschmann, Thomas
    Holmes, Veronica M
    Palesch, David
    Zirafi, Onofrio
    Weissman, Drew
    Sowislok, Andrea
    Wettig, Burkhard
    Heid, Christian
    Kirchhoff, Frank
    Weil, Tanja
    Klärner, Frank-Gerrit
    Schrader, Thomas
    Bitan, Gal
    Sanchez-Garcia, Elsa
    Winter, Roland
    Shorter, James
    Münch, Jan
    A molecular tweezer antagonizes seminal amyloids and HIV infection2015Ingår i: eLIFE, E-ISSN 2050-084X, Vol. 4, artikel-id e05397Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Semen is the main vector for HIV transmission and contains amyloid fibrils that enhance viral infection. Available microbicides that target viral components have proven largely ineffective in preventing sexual virus transmission. In this study, we establish that CLR01, a 'molecular tweezer' specific for lysine and arginine residues, inhibits the formation of infectivity-enhancing seminal amyloids and remodels preformed fibrils. Moreover, CLR01 abrogates semen-mediated enhancement of viral infection by preventing the formation of virion-amyloid complexes and by directly disrupting the membrane integrity of HIV and other enveloped viruses. We establish that CLR01 acts by binding to the target lysine and arginine residues rather than by a non-specific, colloidal mechanism. CLR01 counteracts both host factors that may be important for HIV transmission and the pathogen itself. These combined anti-amyloid and antiviral activities make CLR01 a promising topical microbicide for blocking infection by HIV and other sexually transmitted viruses.

  • 21. Scull, Margaret A
    et al.
    Shi, Chao
    de Jong, Ype P
    Gerold, Gisa
    Ries, Moritz
    von Schaewen, Markus
    Donovan, Bridget M
    Labitt, Rachael N
    Horwitz, Joshua A
    Gaska, Jenna M
    Hrebikova, Gabriela
    Xiao, Jing W
    Flatley, Brenna
    Fung, Canny
    Chiriboga, Luis
    Walker, Christopher M
    Evans, David T
    Rice, Charles M
    Ploss, Alexander
    Hepatitis C virus infects rhesus macaque hepatocytes and simianized mice.2015Ingår i: Hepatology, ISSN 0270-9139, E-ISSN 1527-3350, Vol. 62, nr 1, s. 57-67Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    UNLABELLED: At least 170 million people are chronically infected with hepatitis C virus (HCV). Owing to the narrow host range of HCV and restricted use of chimpanzees, there is currently no suitable animal model for HCV pathogenesis studies or the development of a HCV vaccine. To identify cellular determinants of interspecies transmission and establish a novel immunocompetent model system, we examined the ability of HCV to infect hepatocytes from a small nonhuman primate, the rhesus macaque (Macaca mulatta). We show that the rhesus orthologs of critical HCV entry factors support viral glycoprotein-dependent virion uptake. Primary hepatocytes from rhesus macaques are also permissive for HCV-RNA replication and particle production, which is enhanced when antiviral signaling is suppressed. We demonstrate that this may be owing to the diminished capacity of HCV to antagonize mitochondrial antiviral-signaling protein-dependent innate cellular defenses. To test the ability of HCV to establish persistent replication in vivo, we engrafted primary rhesus macaque hepatocytes into immunocompromised xenorecipients. Inoculation of resulting simian liver chimeric mice with either HCV genotype 1a or 2a resulted in HCV serum viremia for up to 10 weeks.

    CONCLUSION: Together, these data indicate that rhesus macaques may be a viable model for HCV and implicate host immunity as a potential species-specific barrier to HCV infection. We conclude that suppression of host immunity or further viral adaptation may allow robust HCV infection in rhesus macaques and creation of a new animal model for studies of HCV pathogenesis, lentivirus coinfection, and vaccine development.

  • 22. Vieyres, Gabrielle
    et al.
    Welsch, Kathrin
    Gerold, Gisa
    Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
    Gentzsch, Juliane
    Kahl, Sina
    Vondran, Florian W R
    Kaderali, Lars
    Pietschmann, Thomas
    ABHD5/CGI-58, the Chanarin-Dorfman Syndrome Protein, Mobilises Lipid Stores for Hepatitis C Virus Production2016Ingår i: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 12, nr 4, artikel-id e1005568Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hepatitis C virus (HCV) particles closely mimic human very-low-density lipoproteins (VLDL) to evade humoral immunity and to facilitate cell entry. However, the principles that govern HCV association with VLDL components are poorly defined. Using an siRNA screen, we identified ABHD5 (α/β hydrolase domain containing protein 5, also known as CGI-58) as a new host factor promoting both virus assembly and release. ABHD5 associated with lipid droplets and triggered their hydrolysis. Importantly, ABHD5 Chanarin-Dorfman syndrome mutants responsible for a rare lipid storage disorder in humans were mislocalised, and unable to consume lipid droplets or support HCV production. Additional ABHD5 mutagenesis revealed a novel tribasic motif that does not influence subcellular localization but determines both ABHD5 lipolytic and proviral properties. These results indicate that HCV taps into the lipid droplet triglyceride reservoir usurping ABHD5 lipase cofactor function. They also suggest that the resulting lipid flux, normally devoted to VLDL synthesis, also participates in the assembly and release of the HCV lipo-viro-particle. Altogether, our study provides the first association between the Chanarin-Dorfman syndrome protein and an infectious disease and sheds light on the hepatic manifestations of this rare genetic disorder as well as on HCV morphogenesis.

  • 23. Vogt, Alexander
    et al.
    Scull, Margaret A
    Friling, Tamar
    Horwitz, Joshua A
    Donovan, Bridget M
    Dorner, Marcus
    Gerold, Gisa
    Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065, USA.
    Labitt, Rachael N
    Rice, Charles M
    Ploss, Alexander
    Recapitulation of the hepatitis C virus life-cycle in engineered murine cell lines2013Ingår i: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 444, nr 1-2, s. 1-11Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hepatitis C virus (HCV) remains a major medical problem. In-depth study of HCV pathogenesis and immune responses is hampered by the lack of suitable small animal models. The narrow host range of HCV remains incompletely understood. We demonstrate that the entire HCV life-cycle can be recapitulated in mouse cells. We show that antiviral signaling interferes with HCV RNA replication in mouse cells. We were able to infect mouse cells expressing human CD81 and occludin (OCLN)-the minimal set of entry factor factors required for HCV uptake into mouse cells. Infected mouse cells sustain HCV RNA replication in the presence of miR122 and release infectious particles when mouse apoE is supplied. Our data demonstrate that the barriers of HCV interspecies transmission can be overcome by engineering a suitable cellular environment and provide a blue-print towards constructing a small animal model for HCV infection.

  • 24. von Schaewen, Markus
    et al.
    Dorner, Marcus
    Hueging, Kathrin
    Foquet, Lander
    Gerges, Sherif
    Hrebikova, Gabriela
    Heller, Brigitte
    Bitzegeio, Julia
    Doerrbecker, Juliane
    Horwitz, Joshua A
    Gerold, Gisa
    Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany.
    Suerbaum, Sebastian
    Rice, Charles M
    Meuleman, Philip
    Pietschmann, Thomas
    Ploss, Alexander
    Expanding the Host Range of Hepatitis C Virus through Viral Adaptation2016Ingår i: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 7, nr 6, artikel-id e01915-16Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hepatitis C virus (HCV) species tropism is incompletely understood. We have previously shown that at the level of entry, human CD81 and occludin (OCLN) comprise the minimal set of human factors needed for viral uptake into murine cells. As an alternative approach to genetic humanization, species barriers can be overcome by adapting HCV to use the murine orthologues of these entry factors. We previously generated a murine tropic HCV (mtHCV or Jc1/mCD81) strain harboring three mutations within the viral envelope proteins that allowed productive entry into mouse cell lines. In this study, we aimed to characterize the ability of mtHCV to enter and infect mouse hepatocytes in vivo and in vitro Using a highly sensitive, Cre-activatable reporter, we demonstrate that mtHCV can enter mouse hepatocytes in vivo in the absence of any human cofactors. Viral entry still relied on expression of mouse CD81 and SCARB1 and was more efficient when mouse CD81 and OCLN were overexpressed. HCV entry could be significantly reduced in the presence of anti-HCV E2 specific antibodies, suggesting that uptake of mtHCV is dependent on viral glycoproteins. Despite mtHCV's ability to enter murine hepatocytes in vivo, we did not observe persistent infection, even in animals with severely blunted type I and III interferon signaling and impaired adaptive immune responses. Altogether, these results establish proof of concept that the barriers limiting HCV species tropism can be overcome by viral adaptation. However, additional viral adaptations will likely be needed to increase the robustness of a murine model system for hepatitis C.

    IMPORTANCE: At least 150 million individuals are chronically infected with HCV and are at risk of developing serious liver disease. Despite the advent of effective antiviral therapy, the frequency of chronic carriers has only marginally decreased. A major roadblock in developing a vaccine that would prevent transmission is the scarcity of animal models that are susceptible to HCV infection. It is poorly understood why HCV infects only humans and chimpanzees. To develop an animal model for hepatitis C, previous efforts focused on modifying the host environment of mice, for example, to render them more susceptible to HCV infection. Here, we attempted a complementary approach in which a laboratory-derived HCV variant was tested for its ability to infect mice. We demonstrate that this engineered HCV strain can enter mouse liver cells but does not replicate efficiently. Thus, additional adaptations are likely needed to construct a robust animal model for HCV.

  • 25. Zapatero-Belinchon, Francisco J.
    et al.
    Dietzel, Erik
    Dolnik, Olga
    Doehner, Katinka
    Costa, Rui
    Hertel, Barbara
    Veselkova, Barbora
    Kirui, Jared
    Klintworth, Anneke
    Manns, Michael P.
    Poehlmann, Stefan
    Pietschmann, Thomas
    Krey, Thomas
    Ciesek, Sandra
    Gerold, Gisa
    Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Avdelningen för virologi. TWINCORE, Center for Experimental and Clinical Infection Research, Institute for Experimental Virology, Hannover, Germany.
    Sodeik, Beate
    Becker, Stephan
    von Hahn, Thomas
    Characterization of the Filovirus-Resistant Cell Line SH-SY5Y Reveals Redundant Role of Cell Surface Entry Factors2019Ingår i: Viruses, ISSN 1999-4915, E-ISSN 1999-4915, Vol. 11, nr 3, artikel-id 275Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Filoviruses infect a wide range of cell types with the exception of lymphocytes. The intracellular proteins cathepsin B and L, two-pore channel 1 and 2, and bona fide receptor Niemann-Pick Disease C1 (NPC1) are essential for the endosomal phase of cell entry. However, earlier steps of filoviral infection remain poorly characterized. Numerous plasma membrane proteins have been implicated in attachment but it is still unclear which ones are sufficient for productive entry. To define a minimal set of host factors required for filoviral glycoprotein-driven cell entry, we screened twelve cell lines and identified the nonlymphocytic cell line SH-SY5Y to be specifically resistant to filovirus infection. Heterokaryons of SH-SY5Y cells fused to susceptible cells were susceptible to filoviruses, indicating that SH-SY5Y cells do not express a restriction factor but lack an enabling factor critical for filovirus entry. However, all tested cell lines expressed functional intracellular factors. Global gene expression profiling of known cell surface entry factors and protein expression levels of analyzed attachment factors did not reveal any correlation between susceptibility and expression of a specific host factor. Using binding assays with recombinant filovirus glycoprotein, we identified cell attachment as the step impaired in filovirus entry in SH-SY5Y cells. Individual overexpression of attachment factors T-cell immunoglobulin and mucin domain 1 (TIM-1), Axl, Mer, or dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) rendered SH-SY5Y cells susceptible to filovirus glycoprotein-driven transduction. Our study reveals that a lack of attachment factors limits filovirus entry and provides direct experimental support for a model of filoviral cell attachment where host factor usage at the cell surface is highly promiscuous.

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