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Search Results: 1 - 10 of 169030 matches for " Christiane E. Wobus "
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Glycosphingolipids as Receptors for Non-Enveloped Viruses
Stefan Taube,Mengxi Jiang,Christiane E. Wobus
Viruses , 2010, DOI: 10.3390/v2041011
Abstract: Glycosphingolipids are ubiquitous molecules composed of a lipid and a carbohydrate moiety. Their main functions are as antigen/toxin receptors, in cell adhesion/recognition processes, or initiation/modulation of signal transduction pathways. Microbes take advantage of the different carbohydrate structures displayed on a specific cell surface for attachment during infection. For some viruses, such as the polyomaviruses, binding to gangliosides determines the internalization pathway into cells. For others, the interaction between microbe and carbohydrate can be a critical determinant for host susceptibility. In this review, we summarize the role of glycosphingolipids as receptors for members of the non-enveloped calici-, rota-, polyoma- and parvovirus families.
VPg of murine norovirus binds translation initiation factors in infected cells
Katie F Daughenbaugh, Christiane E Wobus, Michele E Hardy
Virology Journal , 2006, DOI: 10.1186/1743-422x-3-33
Abstract: As shown previously for human norovirus VPg, MNV-1 VPg bound eIF3, eIF4GI, eIF4E, and S6 ribosomal protein in cell extracts by GST pull-down assay. Importantly, MNV-1 VPg co-precipitated eIF4GI and eIF4E from infected macrophages, providing evidence that VPg interacts with components of the translation machinery in norovirus infected cells.The interactions between MNV-1 VPg and eIFs completely mimic those reported for the human norovirus VPg, illustrating the utility of MNV-1 as a relevant molecular model to study mechanisms of human norovirus replication.Noroviruses constitute a genus in the family Caliciviridae and are the most frequent cause of foodborne viral gastroenteritis epidemics [1]. The norovirus genome is a 7.7 kb, positive-sense, single-stranded RNA that is polyadenylated at the 3' end. The genome codes for three open reading frames. ORF1 encodes the nonstructural proteins that are synthesized as a polyprotein precursor and processed by the 3C-like viral protease. ORF2 and ORF3 encode the capsid protein VP1 and minor structural protein VP2, respectively. Both VP1 and VP2 are synthesized from a subgenomic RNA that is 3' coterminal with the genomic RNA. Instead of a 7-methylguanosine (m7G) cap structure at the 5' end, genomic and subgenomic RNAs are covalently linked to a viral protein called VPg, for viral protein genome-linked. The linkage between VPg and the 5' nucleotide has been demonstrated experimentally only for the animal caliciviruses [2,3], but by analogy, it is assumed that VPg also is linked to norovirus genomes. The function(s) of VPg in the norovirus replication cycle are not known, but data that this small protein functions in translation initiation are accumulating. Studies of animal caliciviruses showed VPg is necessary for infectivity of native viral RNA [2], but an m7G cap can confer infectivity to in vitro synthesized feline calicivirus (FCV) genomic RNA transcripts [4]. Together, data from these studies conclude that the m7G cap func
Disruption of the Human Gut Microbiota following Norovirus Infection
Adam M. Nelson, Seth T. Walk, Stefan Taube, Mami Taniuchi, Eric R. Houpt, Christiane E. Wobus, Vincent B. Young
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0048224
Abstract: The gut microbiota, the collection of all bacterial members in the intestinal tract, plays a key role in health. Disruption of the indigenous microbiota by a variety of stressors, including antibiotic therapy and intestinal infections, is associated with multiple health problems. We sought to determine if infection with Norovirus disrupts the gut microbiota. Barcoded pyrosequencing of the 16S rRNA-encoding gene was used to characterize the stool microbiota in Norovirus-infected human patients (n = 38). While the microbiota in most infected patients (n = 31) resembled that seen in uninfected healthy controls, a minority of patients (n = 7) possessed a significantly altered microbiota characterized by reduced relative numbers of Bacteriodetes and a corresponding increase in Proteobacteria. In these patients, the increase in Proteobacteria was due to a single operational taxonomic unit (OTU) of Escherichia coli. We cultured E. coli from Norovirus-infected patients and characterized them using PCR-ribotyping and virulence factor analysis. Multiple ribotypes were encountered, but none possessed typical virulence factors commonly carried by enteropathogenic E. coli strains. Microbiota disruption and elevated Proteobacteria were not significantly correlated to patient age, gender, sampling time following illness onset, or overall gut inflammation. These results demonstrate that some patients have a disrupted microbiota following Norovirus infection, and therefore may be at elevated risk for long-term health complications.
Antiviral Activity of a Small Molecule Deubiquitinase Inhibitor Occurs via Induction of the Unfolded Protein Response
Jeffrey W. Perry,Mohammad Ahmed,Kyeong-Ok Chang,Nicholas J. Donato,Hollis D. Showalter,Christiane E. Wobus
PLOS Pathogens , 2012, DOI: 10.1371/journal.ppat.1002783
Abstract: Ubiquitin (Ub) is a vital regulatory component in various cellular processes, including cellular responses to viral infection. As obligate intracellular pathogens, viruses have the capacity to manipulate the ubiquitin (Ub) cycle to their advantage by encoding Ub-modifying proteins including deubiquitinases (DUBs). However, how cellular DUBs modulate specific viral infections, such as norovirus, is poorly understood. To examine the role of DUBs during norovirus infection, we used WP1130, a small molecule inhibitor of a subset of cellular DUBs. Replication of murine norovirus in murine macrophages and the human norovirus Norwalk virus in a replicon system were significantly inhibited by WP1130. Chemical proteomics identified the cellular DUB USP14 as a target of WP1130 in murine macrophages, and pharmacologic inhibition or siRNA-mediated knockdown of USP14 inhibited murine norovirus infection. USP14 is a proteasome-associated DUB that also binds to inositol-requiring enzyme 1 (IRE1), a critical mediator of the unfolded protein response (UPR). WP1130 treatment of murine macrophages did not alter proteasome activity but activated the X-box binding protein-1 (XBP-1) through an IRE1-dependent mechanism. In addition, WP1130 treatment or induction of the UPR also reduced infection of other RNA viruses including encephalomyocarditis virus, Sindbis virus, and La Crosse virus but not vesicular stomatitis virus. Pharmacologic inhibition of the IRE1 endonuclease activity partially rescued the antiviral effect of WP1130. Taken together, our studies support a model whereby induction of the UPR through cellular DUB inhibition blocks specific viral infections, and suggest that cellular DUBs and the UPR represent novel targets for future development of broad spectrum antiviral therapies.
Chemical Derivatives of a Small Molecule Deubiquitinase Inhibitor Have Antiviral Activity against Several RNA Viruses
Marta J. Gonzalez-Hernandez, Anupama Pal, Kofi E. Gyan, Marie-Eve Charbonneau, Hollis D. Showalter, Nicholas J. Donato, Mary O'Riordan, Christiane E. Wobus
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0094491
Abstract: Most antiviral treatment options target the invading pathogen and unavoidably encounter loss of efficacy as the pathogen mutates to overcome replication restrictions. A good strategy for circumventing drug resistance, or for pathogens without treatment options, is to target host cell proteins that are utilized by viruses during infection. The small molecule WP1130 is a selective deubiquitinase inhibitor shown previously to successfully reduce replication of noroviruses and some other RNA viruses. In this study, we screened a library of 31 small molecule derivatives of WP1130 to identify compounds that retained the broad-spectrum antiviral activity of the parent compound in vitro but exhibited improved drug-like properties, particularly increased aqueous solubility. Seventeen compounds significantly reduced murine norovirus infection in murine macrophage RAW 264.7 cells, with four causing decreases in viral titers that were similar or slightly better than WP1130 (1.9 to 2.6 log scale). Antiviral activity was observed following pre-treatment and up to 1 hour postinfection in RAW 264.7 cells as well as in primary bone marrow-derived macrophages. Treatment of the human norovirus replicon system cell line with the same four compounds also decreased levels of Norwalk virus RNA. No significant cytotoxicity was observed at the working concentration of 5 μM for all compounds tested. In addition, the WP1130 derivatives maintained their broad-spectrum antiviral activity against other RNA viruses, Sindbis virus, LaCrosse virus, encephalomyocarditis virus, and Tulane virus. Thus, altering structural characteristics of WP1130 can maintain effective broad-spectrum antiviral activity while increasing aqueous solubility.
Replication of Norovirus in Cell Culture Reveals a Tropism for Dendritic Cells and Macrophages
Christiane E. Wobus,Stephanie M. Karst,Larissa B. Thackray,Kyeong-Ok Chang,Stanislav V. Sosnovtsev,Ga?l Belliot,Anne Krug,Jason M. Mackenzie,Kim Y. Green,Herbert W. Virgin IV
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.0020432
Abstract: Noroviruses are understudied because these important enteric pathogens have not been cultured to date. We found that the norovirus murine norovirus 1 (MNV-1) infects macrophage-like cells in vivo and replicates in cultured primary dendritic cells and macrophages. MNV-1 growth was inhibited by the interferon-αβ receptor and STAT-1, and was associated with extensive rearrangements of intracellular membranes. An amino acid substitution in the capsid protein of serially passaged MNV-1 was associated with virulence attenuation in vivo. This is the first report of replication of a norovirus in cell culture. The capacity of MNV-1 to replicate in a STAT-1-regulated fashion and the unexpected tropism of a norovirus for cells of the hematopoietic lineage provide important insights into norovirus biology.
Replication of Norovirus in Cell Culture Reveals a Tropism for Dendritic Cells and Macrophages
Christiane E Wobus,Stephanie M Karst,Larissa B Thackray,Kyeong-Ok Chang,Stanislav V Sosnovtsev,Ga?l Belliot,Anne Krug,Jason M Mackenzie,Kim Y Green,Herbert W. Virgin IV
PLOS Biology , 2004, DOI: 10.1371/journal.pbio.0020432
Abstract: Noroviruses are understudied because these important enteric pathogens have not been cultured to date. We found that the norovirus murine norovirus 1 (MNV-1) infects macrophage-like cells in vivo and replicates in cultured primary dendritic cells and macrophages. MNV-1 growth was inhibited by the interferon-αβ receptor and STAT-1, and was associated with extensive rearrangements of intracellular membranes. An amino acid substitution in the capsid protein of serially passaged MNV-1 was associated with virulence attenuation in vivo. This is the first report of replication of a norovirus in cell culture. The capacity of MNV-1 to replicate in a STAT-1-regulated fashion and the unexpected tropism of a norovirus for cells of the hematopoietic lineage provide important insights into norovirus biology.
Overexpression of CD97 in Intestinal Epithelial Cells of Transgenic Mice Attenuates Colitis by Strengthening Adherens Junctions
Susann Becker,Elke Wandel,Manja Wobus,Rick Schneider,Salah Amasheh,Doreen Sittig,Christiane Kerner,Ronald Naumann,Joerg Hamann,Gabriela Aust
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0008507
Abstract: The adhesion G-protein-coupled receptor CD97 is present in normal colonic enterocytes but overexpressed in colorectal carcinoma. To investigate the function of CD97 in colorectal carcinogenesis, transgenic Tg(villin-CD97) mice overexpressing CD97 in enterocytes were generated and subjected to azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colitis-associated tumorigenesis. Unexpectedly, we found a CD97 cDNA copy number-dependent reduction of DSS-induced colitis in Tg compared to wild-type (WT) mice that was confirmed by applying a simple DSS protocol. Ultrastructural analysis revealed that overexpression of CD97 strengthened lateral cell-cell contacts between enterocytes, which, in contrast, were weakened in CD97 knockout (Ko) mice. Transepithelial resistance was not altered in Tg and Ko mice, indicating that tight junctions were not affected. In Tg murine and normal human colonic enterocytes as well as in colorectal cell lines CD97 was localized preferentially in E-cadherin-based adherens junctions. CD97 overexpression upregulated membrane-bound but not cytoplasmic or nuclear β-catenin and reduced phospho-β-catenin, labeled for degradation. This was associated with inactivation of glycogen synthase kinase-3β (GSK-3β) and activation of Akt. In summary, CD97 increases the structural integrity of enterocytic adherens junctions by increasing and stabilizing junctional β-catenin, thereby regulating intestinal epithelial strength and attenuating experimental colitis.
A comparison of macroscopic models describing the collective response of sedimenting rod-like particles in shear flows
Christiane Helzel,Athanasios E. Tzavaras
Physics , 2015,
Abstract: We consider a kinetic model, which describes the sedimentation of rod-like particles in dilute suspensions under the influence of gravity. This model has recently been derived by Helzel and Tzavaras in \cite{HT2015}. Here we restrict our considerations to shear flow and consider a simplified situation, where the particle orientation is restricted to the plane spanned by the direction of shear and the direction of gravity. For this simplified kinetic model we carry out a linear stability analysis and we derive two different macroscopic models which describe the formation of clusters of higher particle density. One of these macroscopic models is based on a diffusive scaling, the other one is based on a so-called quasi-dynamic approximation. Numerical computations, which compare the predictions of the macroscopic models with the kinetic model, complete our presentation.
A kinetic model for the sedimentation of rod-like particles
Christiane Helzel,Athanasios E. Tzavaras
Physics , 2015,
Abstract: We consider a coupled system consisting of a kinetic equation coupled to a macroscopic Stokes (or Navier-Stokes) equation and describing the motion of a suspension of rigid rods in gravity. A reciprocal coupling leads to the formation of clusters: The buoyancy force creates a macroscopic velocity gradient that causes the microscopic particles to align so that their sedimentation reinforces the formation of clusters of higher particle density. We provide a quantitative analysis of cluster formation. We derive a nonlinear moment closure model, which consists of evolution equations for the density and second order moments and that uses the structure of spherical harmonics to suggest a closure strategy. For a rectilinear flow we employ the moment closure together with a quasi-dynamic approximation to derive an effective equation, The effective equation is an advection-diffusion equation with nonisotropic diffusion coupled to a Poisson equation, and belongs to the class of the so-called flux-limited Keller-Segel models. For shear flows, we provide an argument for the validity of the effective equation and perform numerical comparisons that indicate good agreement between the original system and the effective theory. Finally, a linear stability analysis on the moment system shows that linear theory predicts a wavelength selection mechanism for the cluster width, provided that the Reynolds number is larger than zero.
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