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Stephen A. Stohlman - One of the best experts on this subject based on the ideXlab platform.
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GENETIC CONTROL OF RESISTANCE OF Mouse Hepatitis Virus, STRAIN JHM, INDUCED ENCEPHALOMYELITIS
Animal Virus Genetics, 2013Co-Authors: Stephen A. Stohlman, Jeffrey A. FrelingerAbstract:ABSTRACT Inbred Mouse strains were crossed with the resistant SJL strain to detect strains carrying one of the two genes responsible for resistance to Mouse Hepatitis Virus. Forty percent of the (SJL × BALB/c) F1's were resistant. Backcrosses of F1 on both the susceptible (BALB/c) and resistant (SJL) parent revealed the expected survival rates consistent with BALB/c genotype containing the Rhv-1 resistant, Rhv-2 susceptible genotype.
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Expression of the Mouse Hepatitis Virus receptor by central nervous system microglia
Journal of Virology, 2004Co-Authors: Chandran Ramakrishna, Cornelia C. Bergmann, Kathryn V. Holmes, Stephen A. StohlmanAbstract:Detection of the Mouse Hepatitis Virus receptor within the central nervous system (CNS) has been elusive. Receptor expression on microglia was reduced during acute infection and restored following immune-mediated Virus control. Receptor down regulation was independent of neutrophils, NK cells, gamma interferon, or perforin. Infection of mice devoid of distinct inflammatory cells revealed CD4 + T cells as the major cell type influencing receptor expression by microglia. In addition to demonstrating receptor expression on CNS resident cells, these data suggest that transient receptor down regulation on microglia aids in establishing persistence in the CNS by assisting Virus infection of other glial cell types.
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Contributions of Fas-Fas Ligand Interactions to the Pathogenesis of Mouse Hepatitis Virus in the Central Nervous System
Journal of Virology, 2000Co-Authors: Beatriz Parra, Stephen A. Stohlman, Cornelia C. Bergmann, Mark T. Lin, Roscoe Atkinson, David R. HintonAbstract:The pathogenesis of the neurotropic strain of Mouse Hepatitis Virus in Fas-deficient mice suggested that Fas-mediated cytotoxicity may be required during viral clearance after the loss of perforin-mediated cytotoxicity. The absence of both Fas- and perforin-mediated cytolysis resulted in an uncontrolled infection, suggesting a redundancy of cytolytic pathways to control Virus replication.
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Mouse Hepatitis Virus Nucleocapsid Protein as a Translational Effector of Viral mRNAs
Advances in Experimental Medicine and Biology, 1998Co-Authors: Stanley M. Tahara, Stephen A. Stohlman, Gary W. Nelson, Therese A. Dietlin, David J. MannoAbstract:The Mouse Hepatitis Virus (MHV) nucleocapsid protein stimulated translation of a chimeric reporter mRNA containing an intact MHV 5’-untranslated region and the chloramphenicol acetyltransferase (CAT) coding region. The nucleocapsid protein binds specifically the tandemly repeated -UCYAA- of the MHV leader. This RNA sequence is the same as the intergenic motif found in the genome RNA.
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Specificity of the H-2 L(d)-restricted cytotoxic T-lymphocyte response to the Mouse Hepatitis Virus nucleocapsid protein.
Journal of Virology, 1996Co-Authors: Cornelia C. Bergmann, Stephen A. StohlmanAbstract:Cytotoxic T lymphocytes provide protection against persistent infection of the central nervous system by the JHM strain of Mouse Hepatitis Virus. In BALB/c (H-2d) mice, the dominant response is directed against an Ld-restricted peptide in the nucleocapsid protein (APTAGAFFF). Characterization of the fine specificity of this response revealed that the predicted anchor residues at positions 2 and 9 were the most critical for class I binding. Amino acids at positions 7 and 8 were identified as T-cell receptor contact residues. Virus-induced cytotoxic T lymphocytes to other Ld motif-containing nucleocapsid peptides were not detected, despite the identification of two epitopes with reduced Ld affinity. These data suggest that mutations within four residues of the dominant epitope could contribute to the persistence of the JHM strain of Mouse Hepatitis Virus.
Boyd Yount - One of the best experts on this subject based on the ideXlab platform.
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subgenomic negative strand rna function during Mouse Hepatitis Virus infection
Journal of Virology, 2000Co-Authors: Ralph S. Baric, Boyd YountAbstract:Mouse Hepatitis Virus (MHV)-infected cells contain full-length and subgenomic-length positive- and negative-strand RNAs. The origin and function of the subgenomic negative-strand RNAs is controversial. In this report we demonstrate that the synthesis and molar ratios of subgenomic negative strands are similar in alternative host cells, suggesting that these RNAs function as important mediators of positive-strand synthesis. Using kinetic labeling experiments, we show that the full-length and subgenomic-length replicative form RNAs rapidly accumulate and then saturate with label, suggesting that the subgenomic-length negative strands are the principal mediators of positive-strand synthesis. Using cycloheximide, which preferentially inhibits negative-strand and to a lesser extent positive-strand synthesis, we demonstrate that cycloheximide treatment equally inhibits full-length and subgenomic-length negative-strand synthesis. Importantly, following treatment, previously transcribed negative strands remain in transcriptionally active complexes even in the absence of new negative-strand synthesis. These findings indicate that the subgenomic-length negative strands are the principal templates of positive-strand synthesis during MHV infection.
Kathryn V. Holmes - One of the best experts on this subject based on the ideXlab platform.
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Genetic resistance to Mouse Hepatitis Virus correlates with absence of Virus-binding activity on target tissues.
Journal of Virology, 2020Co-Authors: John F. Boyle, D G Weismiller, Kathryn V. HolmesAbstract:The molecular mechanism of genetic resistance of inbred Mouse strains to Mouse Hepatitis Virus, a murine coronaVirus, was studied by comparing Virus binding to plasma membranes of intestinal epithelium or liver from susceptible BALB/c and resistant SJL/J mice with a new solid-phase assay for Virus-binding activity. Virus bound to isolated membranes from susceptible mice, but not to membranes from resistant mice. F1 progeny of SJL/J X BALB/c mice had an intermediate level of Virus-binding activity on their enterocyte and hepatocyte membranes. This correlated well with previous studies showing that susceptibility to Mouse Hepatitis Virus strain A59 is controlled by a single autosomal dominant gene (M. S. Smith, R. E. Click, and P. G. W. Plagemann, J. Immunol. 133:428-432). Because Virus binding was not prevented by treating membranes with sodium dodecyl sulfate, the Virus-binding molecule could be identified by a Virus overlay protein blot assay. Virus bound to a single broad band of Mr 100,000 to 110,000 in membranes from hepatocytes or enterocytes of susceptible BALB/c and semisusceptible C3H mice, but no Virus-binding band was detected in comparable preparations of resistant SJL/J Mouse membranes. Therefore, SJL/J mice may be resistant to Mouse Hepatitis Virus A59 infection because they lack a specific Virus receptor which is present on the plasma membranes of target cells from genetically susceptible BALB/c and semisusceptible C3H mice.
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Role of Virus receptor-bearing endothelial cells of the blood-brain barrier in preventing the spread of Mouse Hepatitis Virus-A59 into the central nervous system
Journal of NeuroVirology, 2020Co-Authors: Catherine Godfraind, Kathryn V. Holmes, Nathalie Havaux, Jean-paul CoutelierAbstract:BALB/c mice develop a neurologic demyelinating disease after inoculation of Mouse Hepatitis Virus (MHV), strain A59, by the intracranial, but not by the intraperitoneal route. To determine the mechanisms that prevent Virus spreading through the blood-brain barrier, we analyzed expression of MHVR, a glycoprotein that serves as receptor for Mouse Hepatitis Virus on endothelial cells of cerebral blood vessels. Our results indicated that MHVR was strongly expressed on the endoluminal pole of these cells. In addition, a direct Virus binding assay showed that Mouse Hepatitis Virus was able to bind endothelial cells via this receptor. Despite this expression of a functional viral receptor, in normal mice infected with Mouse Hepatitis Virus by the contra-peritoneal route, no in vivo viral replication could be detected in endothelial cells from the brain, contrasting with the equivalent cells from the liver. However, shortly after i.v. administration of sodium dodecylsulfate detergent to the mice, Virus infection of some cerebral endothelial cells was detected in a few mice. As a consequence of detergent treatment, Virus infection was able to cross the blood-brain barrier. These results suggest that the protective role of the blood-brain barrier against spreading of Mouse Hepatitis Virus A59 into the central nervous system is determined by a specific restriction of viral entry into the endothelial cells of cerebral origin.
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Expression of the Mouse Hepatitis Virus receptor by central nervous system microglia
Journal of Virology, 2004Co-Authors: Chandran Ramakrishna, Cornelia C. Bergmann, Kathryn V. Holmes, Stephen A. StohlmanAbstract:Detection of the Mouse Hepatitis Virus receptor within the central nervous system (CNS) has been elusive. Receptor expression on microglia was reduced during acute infection and restored following immune-mediated Virus control. Receptor down regulation was independent of neutrophils, NK cells, gamma interferon, or perforin. Infection of mice devoid of distinct inflammatory cells revealed CD4 + T cells as the major cell type influencing receptor expression by microglia. In addition to demonstrating receptor expression on CNS resident cells, these data suggest that transient receptor down regulation on microglia aids in establishing persistence in the CNS by assisting Virus infection of other glial cell types.
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Purified, Soluble Recombinant Mouse Hepatitis Virus Receptor, Bgp1b, and Bgp2 Murine CoronaVirus Receptors Differ in Mouse Hepatitis Virus Binding and Neutralizing Activities
Journal of Virology, 1998Co-Authors: Bruce D. Zelus, David R. Wessner, Richard K. Williams, M. N. Pensiero, Fenna T. Phibbs, Mark Desouza, Gabriela S. Dveksler, Kathryn V. HolmesAbstract:Mouse Hepatitis Virus receptor (MHVR) is a murine biliary glycoprotein (Bgp1a). Purified, soluble MHVR expressed from a recombinant vaccinia Virus neutralized the infectivity of the A59 strain of Mouse Hepatitis Virus (MHV-A59) in a concentration-dependent manner. Several anchored murine Bgps in addition to MHVR can also function as MHV-A59 receptors when expressed at high levels in nonmurine cells. To investigate the interactions of these alternative MHVR glycoproteins with MHV, we expressed and purified to apparent homogeneity the extracellular domains of several murine Bgps as soluble, six-histidine-tagged glycoproteins, using a baculoVirus expression system. These include MHVR isoforms containing four or two extracellular domains and the corresponding Bgp1b glycoproteins from MHV-resistant SJL/J mice, as well as Bgp2 and truncation mutants of MHVR and Bgp1b comprised of the first two immunoglobulin-like domains. The soluble four-domain MHVR glycoprotein (sMHVR[1-4]) had fourfold more MHV-A59 neutralizing activity than the corresponding soluble Bgp1b (sBgp1b) glycoprotein and at least 1,000-fold more neutralizing activity than sBgp2. Although Virus binds to the N-terminal domain (domain 1), soluble truncation mutants of MHVR and Bgp1b containing only domains 1 and 2 bound Virus poorly and had 10- and 300-fold less MHV-A59 neutralizing activity than the corresponding four-domain glycoproteins. In contrast, the soluble MHVR glycoprotein containing domains 1 and 4 (sMHVR[1,4]) had as much neutralizing activity as the four-domain glycoprotein, sMHVR[1-4]. Thus, the Virus neutralizing activity of MHVR domain 1 appears to be enhanced by domain 4. The sBgp1b[1-4] glycoprotein had 500-fold less neutralizing activity for MHV-JHM than for MHV-A59. Thus, MHV strains with differences in S-glycoprotein sequence, tissue tropism, and virulence can differ in the ability to utilize the various murine Bgps as receptors.
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Role of Mouse Hepatitis Virus-A59 receptor Bgp1a expression in Virus-induced pathogenesis.
Advances in Experimental Medicine and Biology, 1998Co-Authors: Catherine Godfraind, Kathryn V. Holmes, Jean-paul CoutelierAbstract:Expression of Bgp1a, a glycoprotein that serves as receptor for Mouse Hepatitis Virus-A59 has been analyzed in various Mouse tissues and correlated with the pathogenicity that this Virus induces in the corresponding organs. Expression of Bgp1a was observed in many cells of epithelial origin, including hepatocytes and endothelial cells. It was also shown on macrophages and B lymphocytes. Bgp1a localization may easily explain infection and lysis of some cell types like hepatocytes. In contrast, other cell types that express the viral receptor are not infected after in vivo inoculation with Mouse Hepatitis Virus-A59, which may be due to inaccessibility of the receptor to the Virus during Mouse infection, or to resistance to this Virus in some cell types. This may account for the ability of the blood-brain barrier to prevent Mouse Hepatitis Virus-A59 spreading into the central nervous system. In other organs, the Virus may induce pathogenesis indirectly, resulting in the destruction of cells that do not express Bgp1a, like thymic lymphocytes, or else impair cell functions such as cytokine and immunoglobulin production by macrophages and B lymphocytes, respectively.
Ralph S. Baric - One of the best experts on this subject based on the ideXlab platform.
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Spike gene determinants of Mouse Hepatitis Virus host range expansion.
Advances in Experimental Medicine and Biology, 2006Co-Authors: Willie C. Mcroy, Ralph S. BaricAbstract:increased attention in the wake of HIV, hantaViruses, avian influenza Virus, and the SARS-CoV. We are using Mouse Hepatitis Virus (MHV) as a model to explore potential mechanisms that mediate coronaVirus cross-species transmission. These previously published models include a persistent infection system 2 and a mixed infection system. Both systems resulted in MHV variants with extended host range. Our current efforts involve characterizing the genetic determinants of the expanded host range phenotype and receptor usage of these variants as compared with the parental Viruses.
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subgenomic negative strand rna function during Mouse Hepatitis Virus infection
Journal of Virology, 2000Co-Authors: Ralph S. Baric, Boyd YountAbstract:Mouse Hepatitis Virus (MHV)-infected cells contain full-length and subgenomic-length positive- and negative-strand RNAs. The origin and function of the subgenomic negative-strand RNAs is controversial. In this report we demonstrate that the synthesis and molar ratios of subgenomic negative strands are similar in alternative host cells, suggesting that these RNAs function as important mediators of positive-strand synthesis. Using kinetic labeling experiments, we show that the full-length and subgenomic-length replicative form RNAs rapidly accumulate and then saturate with label, suggesting that the subgenomic-length negative strands are the principal mediators of positive-strand synthesis. Using cycloheximide, which preferentially inhibits negative-strand and to a lesser extent positive-strand synthesis, we demonstrate that cycloheximide treatment equally inhibits full-length and subgenomic-length negative-strand synthesis. Importantly, following treatment, previously transcribed negative strands remain in transcriptionally active complexes even in the absence of new negative-strand synthesis. These findings indicate that the subgenomic-length negative strands are the principal templates of positive-strand synthesis during MHV infection.
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Evolution and persistence mechanisms of Mouse Hepatitis Virus
Advances in Experimental Medicine and Biology, 1995Co-Authors: Wan Chen, Ralph S. BaricAbstract:We established and characterized persistently-infected DBT cells with Mouse Hepatitis Virus to study the molecular mechanisms of MHV persistence and evolution in vitro. Following infection, viral mRNA and RF RNA were coordinately reduced by about 70% as compared to acute infection suggesting that the reduction in mRNA synthesis was due to reduced levels of transcriptionally active full length and subgenomic length negativestranded RNAs. Although the rates of mRNA synthesis were also reduced, the relative percent molar ratio of the mRNAs and RF RNAs were similar to those detected during acute infection. In contrast to the finding during BCV persistence, analysis of the MHV leader RNA indicated that the leader RNA and leader/body junction sequences were extremely stable. These data suggested that polymorphism and mutations resulting in intraleader ORFs was not required for MHV persistence. Conversely MHV persistence was significantly associated with a A to G mutation at nt 77 in the 5′ end untranslated region (UTR) of the genomic RNA.
Zihe Rao - One of the best experts on this subject based on the ideXlab platform.
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structural basis for coronaVirus mediated membrane fusion crystal structure of Mouse Hepatitis Virus spike protein fusion core
Journal of Biological Chemistry, 2004Co-Authors: Yiwei Liu, Zhiyong Lou, Lan Qin, Zhihong Bai, Hai Pang, Po Tien, George F Gao, Zihe RaoAbstract:Abstract The surface transmembrane glycoprotein is responsible for mediating virion attachment to cell and subsequent Virus-cell membrane fusion. However, the molecular mechanisms for the viral entry of coronaViruses remain poorly understood. The crystal structure of the fusion core of Mouse Hepatitis Virus S protein, which represents the first fusion core structure of any coronaVirus, reveals a central hydrophobic coiled coil trimer surrounded by three helices in an oblique, antiparallel manner. This structure shares significant similarity with both the low pH-induced conformation of influenza hemagglutinin and fusion core of HIV gp41, indicating that the structure represents a fusion-active state formed after several conformational changes. Our results also indicate that the mechanisms for the viral fusion of coronaViruses are similar to those of influenza Virus and HIV. The coiled coil structure has unique features, which are different from other viral fusion cores. Highly conserved heptad repeat 1 (HR1) and HR2 regions in coronaVirus spike proteins indicate a similar three-dimensional structure among these fusion cores and common mechanisms for the viral fusion. We have proposed the binding regions of HR1 and HR2 of other coronaViruses and a structure model of their fusion core based on our Mouse Hepatitis Virus fusion core structure and sequence alignment. Drug discovery strategies aimed at inhibiting viral entry by blocking hairpin formation may be applied to the inhibition of a number of emerging infectious diseases, including severe acute respiratory syndrome.
