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Pseudovirion particles bearing native HIV envelope trimers facilitate a novel method for generating human neutralizing monoclonal antibodies against HIV.
Hicar MD, Chen X, Briney B, Hammonds J, Wang JJ, Kalams S, Spearman PW, Crowe JE
(2010) J Acquir Immune Defic Syndr 54: 223-35
MeSH Terms: AIDS Vaccines, Amino Acid Sequence, Antibodies, Monoclonal, Antibody Specificity, Antigens, CD19, B-Lymphocytes, Cells, Cultured, Gene Expression Regulation, Green Fluorescent Proteins, HIV, Humans, Hybridomas, Immunoglobulins, Molecular Sequence Data, Protein Multimerization, Virion, env Gene Products, Human Immunodeficiency Virus, gag Gene Products, Human Immunodeficiency Virus
Show Abstract · Added August 6, 2012
Monomeric HIV envelope vaccines fail to elicit broadly neutralizing antibodies or to protect against infection. Neutralizing antibodies against HIV bind to native functionally active Env trimers on the virion surface. Gag-Env pseudovirions recapitulate the native trimer and could serve as an effective epitope presentation platform for study of the neutralizing antibody response in HIV-infected individuals. To address if pseudovirions can recapitulate native HIV virion epitope structures, we carefully characterized these particles, concentrating on the antigenic structure of the coreceptor binding site. By blue native gel shift assays, Gag-Env pseudovirions were shown to contain native trimers that were competent for binding to neutralizing monoclonal antibodies. In enzyme-linked immunosorbent assay, pseudovirions exhibited increased binding of known CD4-induced antibodies after addition of CD4. Using flow cytometric analysis, fluorescently labeled pseudovirions specifically identified a subset of antigen-specific B cells in HIV-infected subjects. Interestingly, the sequence of one of these novel human antibodies, identified during cloning of single HIV-specific B cells and designated 2C6, exhibited homology to mAb 47e, a known anti-CD4-induced coreceptor binding site antibody. The secreted monoclonal antibody 2C6 did not bind monomeric gp120, but specifically bound envelope on pseudovirions. A recombinant form of the antibody 2C6 acted as a CD4-induced epitope-specific antibody in neutralization assays, yet did not bind monomeric gp120. These findings imply specificity against a quaternary epitope presented on the pseudovirion envelope spike. These data demonstrate that Gag-Env pseudovirions recapitulate CD4 and coreceptor binding pocket antigenic structures and can facilitate identification of B-cell clones that secrete neutralizing antibodies.
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18 MeSH Terms
From touchdown to transcription: the reovirus cell entry pathway.
Danthi P, Guglielmi KM, Kirchner E, Mainou B, Stehle T, Dermody TS
(2010) Curr Top Microbiol Immunol 343: 91-119
MeSH Terms: Animals, Capsid Proteins, Cell Adhesion Molecules, Endocytosis, Humans, Immunity, Innate, Immunoglobulins, Integrin beta1, Receptors, Cell Surface, Reoviridae, Virion, Virus Assembly, Virus Attachment, Virus Internalization
Show Abstract · Added December 10, 2013
Mammalian orthoreoviruses (reoviruses) are prototype members of the Reoviridae family of nonenveloped viruses. Reoviruses contain ten double-stranded RNA gene segments enclosed in two concentric protein shells, outer capsid and core. These viruses serve as a versatile experimental system for studies of virus cell entry, innate immunity, and organ-specific disease. Reoviruses engage cells by binding to cell-surface carbohydrates and the immunoglobulin superfamily member, junctional adhesion molecule-A (JAM-A). JAM-A is a homodimer formed by extensive contacts between its N-terminal immunoglobulin-like domains. Reovirus attachment protein σ1 disrupts the JAM-A dimer, engaging a single JAM-A molecule by virtually the same interface used for JAM-A homodimerization. Following attachment to JAM-A and carbohydrate, reovirus internalization is promoted by β1 integrins, most likely via clathrin-dependent endocytosis. In the endocytic compartment, reovirus outer-capsid protein σ3 is removed by cathepsin proteases, which exposes the viral membrane-penetration protein, μ1. Proteolytic processing and conformational rearrangements of μ1 mediate endosomal membrane rupture and delivery of transcriptionally active reovirus core particles into the host cell cytoplasm. These events also allow the φ cleavage fragment of μ1 to escape into the cytoplasm where it activates NF-κB and elicits apoptosis. This review will focus on mechanisms of reovirus cell entry and activation of innate immune response signaling pathways.
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14 MeSH Terms
p120-Catenin is required for mouse vascular development.
Oas RG, Xiao K, Summers S, Wittich KB, Chiasson CM, Martin WD, Grossniklaus HE, Vincent PA, Reynolds AB, Kowalczyk AP
(2010) Circ Res 106: 941-51
MeSH Terms: Animals, Antigens, CD, Blood Vessels, Body Patterning, CD8 Antigens, Cadherins, Catenins, Cell Proliferation, Cells, Cultured, Embryo Loss, Endothelial Cells, Gestational Age, Hemorrhage, Immunoglobulins, Integrases, Mice, Mice, Inbred C57BL, Mice, Knockout, Microvessels, Pericytes, Promoter Regions, Genetic, Receptor Protein-Tyrosine Kinases, Receptor, TIE-2
Show Abstract · Added March 5, 2014
RATIONALE - p120-catenin (p120) is an armadillo family protein that binds to the cytoplasmic domain of classical cadherins and prevents cadherin endocytosis. The role of p120 in vascular development is unknown.
OBJECTIVE - The purpose of this study is to examine the role of p120 in mammalian vascular development by generating a conditionally mutant mouse lacking endothelial p120 and determining the effects of the knockout on vasculogenesis, angiogenic remodeling, and the regulation of endothelial cadherin levels.
METHODS AND RESULTS - A conditional Cre/loxP gene deletion strategy was used to ablate p120 expression, using the Tie2 promoter to drive endothelial Cre recombinase expression. Mice lacking endothelial p120 died embryonically beginning at embryonic day 11.5. Major blood vessels appeared normal at embryonic day 9.5. However, both embryonic and extraembryonic vasculature of mutant animals were disorganized and displayed decreased microvascular density by embryonic day 11.5. Importantly, both vascular endothelial cadherin and N-cadherin levels were significantly reduced in vessels lacking p120. This decrease in cadherin expression was accompanied by reduced pericyte recruitment and hemorrhaging. Furthermore, p120-null cultured endothelial cells exhibited proliferation defects that could be rescued by exogenous expression of vascular endothelial cadherin.
CONCLUSIONS - These findings reveal a fundamental role for p120 in regulating endothelial cadherin levels during vascular development, as well as microvascular patterning, vessel integrity, and endothelial cell proliferation. Loss of endothelial p120 results in lethality attributable to decreased microvascular density and hemorrhages.
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23 MeSH Terms
Immunoglobulin superfamily virus receptors and the evolution of adaptive immunity.
Dermody TS, Kirchner E, Guglielmi KM, Stehle T
(2009) PLoS Pathog 5: e1000481
MeSH Terms: Adaptive Immunity, Animals, Evolution, Molecular, Humans, Immunoglobulins, Ligands, Receptors, Virus
Added December 10, 2013
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7 MeSH Terms
Aberrant DNA methylation occurs in colon neoplasms arising in the azoxymethane colon cancer model.
Borinstein SC, Conerly M, Dzieciatkowski S, Biswas S, Washington MK, Trobridge P, Henikoff S, Grady WM
(2010) Mol Carcinog 49: 94-103
MeSH Terms: Adaptor Proteins, Signal Transducing, Animals, Apoptosis Regulatory Proteins, Azoxymethane, Calcium-Calmodulin-Dependent Protein Kinases, Cell Adhesion Molecule-1, Cell Adhesion Molecules, Colonic Neoplasms, Connexins, Cyclin-Dependent Kinase Inhibitor p16, DNA Methylation, DNA Modification Methylases, DNA Repair Enzymes, DNA-Binding Proteins, Death-Associated Protein Kinases, Disease Models, Animal, Humans, Immunoglobulins, Inhibitor of Differentiation Proteins, Insulin-Like Growth Factor Binding Protein 3, Intestinal Mucosa, Membrane Proteins, Mice, MutL Protein Homolog 1, Nuclear Proteins, Receptors, CXCR4, Repressor Proteins, Transcription Factors, Tumor Suppressor Proteins
Show Abstract · Added April 12, 2016
Mouse models of intestinal tumors have advanced our understanding of the role of gene mutations in colorectal malignancy. However, the utility of these systems for studying the role of epigenetic alterations in intestinal neoplasms remains to be defined. Consequently, we assessed the role of aberrant DNA methylation in the azoxymethane (AOM) rodent model of colon cancer. AOM induced tumors display global DNA hypomethylation, which is similar to human colorectal cancer. We next assessed the methylation status of a panel of candidate genes previously shown to be aberrantly methylated in human cancer or in mouse models of malignant neoplasms. This analysis revealed different patterns of DNA methylation that were gene specific. Zik1 and Gja9 demonstrated cancer-specific aberrant DNA methylation, whereas, Cdkn2a/p16, Igfbp3, Mgmt, Id4, and Cxcr4 were methylated in both the AOM tumors and normal colon mucosa. No aberrant methylation of Dapk1 or Mlt1 was detected in the neoplasms, but normal colon mucosa samples displayed methylation of these genes. Finally, p19(Arf), Tslc1, Hltf, and Mlh1 were unmethylated in both the AOM tumors and normal colon mucosa. Thus, aberrant DNA methylation does occur in AOM tumors, although the frequency of aberrantly methylated genes appears to be less common than in human colorectal cancer. Additional studies are necessary to further characterize the patterns of aberrantly methylated genes in AOM tumors.
2009 Wiley-Liss, Inc.
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29 MeSH Terms
The Kir channel immunoglobulin domain is essential for Kir1.1 (ROMK) thermodynamic stability, trafficking and gating.
Fallen K, Banerjee S, Sheehan J, Addison D, Lewis LM, Meiler J, Denton JS
(2009) Channels (Austin) 3: 57-68
MeSH Terms: Amino Acid Sequence, Animals, Cell Line, Computer Simulation, Hot Temperature, Humans, Hydrophobic and Hydrophilic Interactions, Immunoglobulins, Ion Channel Gating, Membrane Potentials, Models, Molecular, Molecular Sequence Data, Mutation, Potassium, Potassium Channels, Inwardly Rectifying, Protein Conformation, Protein Denaturation, Protein Stability, Protein Structure, Tertiary, Protein Transport, Rats, Structure-Activity Relationship, Transfection
Show Abstract · Added April 25, 2013
The renal inward rectifying potassium channel Kir1.1 plays key roles in regulating electrolyte homeostasis and blood pressure. Loss-of-function mutations in the channel cause a life-threatening salt and water balance disorder in infants called antenatal Bartter syndrome (ABS). Of more than 30 ABS mutations identified, approximately half are located in the intracellular domain of the channel. The mechanisms underlying channel dysfunction for most of these mutations are unknown. By mapping intracellular mutations onto an atomic model of Kir1.1, we found that several of these are localized to a phylogenetically ancient immunoglobulin (Ig)-like domain (IgLD) that has not been characterized previously, prompting us to examine this structure in detail. The IgLD is assembled from two beta-pleated sheets packed face-to-face, creating a beta-sheet interface or core, populated by highly conserved side chains. Thermodynamic calculations on computationally mutated channels suggest that IgLD core residues are among the most important residues for determining cytoplasmic domain stability. Consistent with this notion, we show that two ABS mutations (A198T and Y314C) located within the IgLD core impair channel biosynthesis and trafficking in mammalian cells. A fraction of core mutant channels reach the cell surface, but are electrically silent due to closure of the helix-bundle gate. Compensatory mutation-induced rescue of channel function revealed that IgLD core mutants fail to rectify. Our study sheds new light on the pathogenesis of ABS and establishes the IgLD as an essential structure within the Kir channel family.
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23 MeSH Terms
Structure of reovirus sigma1 in complex with its receptor junctional adhesion molecule-A.
Kirchner E, Guglielmi KM, Strauss HM, Dermody TS, Stehle T
(2008) PLoS Pathog 4: e1000235
MeSH Terms: Binding Sites, Capsid Proteins, Cell Adhesion Molecules, Crystallography, X-Ray, HeLa Cells, Humans, Hydrogen-Ion Concentration, Immunoglobulins, Models, Molecular, Orthoreovirus, Mammalian, Protein Interaction Domains and Motifs, Protein Multimerization, Protein Stability, Receptors, Cell Surface, Static Electricity, Surface Plasmon Resonance
Show Abstract · Added December 10, 2013
Viral attachment to specific host receptors is the first step in viral infection and serves an essential function in the selection of target cells. Mammalian reoviruses are highly useful experimental models for studies of viral pathogenesis and show promise as vectors for oncolytics and vaccines. Reoviruses engage cells by binding to carbohydrates and the immunoglobulin superfamily member, junctional adhesion molecule-A (JAM-A). JAM-A exists at the cell surface as a homodimer formed by extensive contacts between its N-terminal immunoglobulin-like domains. We report the crystal structure of reovirus attachment protein sigma1 in complex with a soluble form of JAM-A. The sigma1 protein disrupts the JAM-A dimer, engaging a single JAM-A molecule via virtually the same interface that is used for JAM-A homodimerization. Thus, reovirus takes advantage of the adhesive nature of an immunoglobulin-superfamily receptor by usurping the ligand-binding site of this molecule to attach to the cell surface. The dissociation constant (K(D)) of the interaction between sigma1 and JAM-A is 1,000-fold lower than that of the homophilic interaction between JAM-A molecules, indicating that JAM-A strongly prefers sigma1 as a ligand. Analysis of reovirus mutants engineered by plasmid-based reverse genetics revealed residues in sigma1 required for binding to JAM-A and infectivity of cultured cells. These studies define biophysical mechanisms of reovirus cell attachment and provide a platform for manipulating reovirus tropism to enhance vector targeting.
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16 MeSH Terms
A critical role for protein kinase C-theta-mediated T cell survival in cardiac allograft rejection.
Manicassamy S, Yin D, Zhang Z, Molinero LL, Alegre ML, Sun Z
(2008) J Immunol 181: 513-20
MeSH Terms: Animals, Antibodies, Monoclonal, Antigens, CD, CD40 Ligand, CTLA-4 Antigen, Cell Survival, Cells, Cultured, Female, Graft Rejection, Heart Transplantation, Homeodomain Proteins, Immunoglobulins, Isoenzymes, Lymphocyte Culture Test, Mixed, Mice, Mice, Knockout, Protein Kinase C, Protein Kinase C-theta, T-Lymphocytes, Transplantation, Homologous, bcl-X Protein
Show Abstract · Added December 10, 2013
Protein kinase C (PKC)-theta mediates the critical TCR signals required for T cell activation. Previously, we have shown that in response to TCR stimulation, PKC-theta-/- T cells undergo apoptosis due to greatly reduced levels of the anti-apoptotic molecule, Bcl-xL. In this study, we demonstrate that PKC-theta-regulated expression of Bcl-xL is essential for T cell-mediated cardiac allograft rejection. Rag1-/- mice reconstituted with wild-type T cells readily rejected fully mismatched cardiac allografts, whereas Rag1-/- mice reconstituted with PKC-theta-/- T cells failed to promote rejection. Transgenic expression of Bcl-xL in PKC-theta-/- T cells was sufficient to restore cardiac allograft rejection, suggesting that PKC-theta-regulated survival is required for T cell-mediated cardiac allograft rejection in this adoptive transfer model. In contrast to adoptive transfer experiments, intact PKC-theta-/- mice displayed delayed, but successful cardiac allograft rejection, suggesting the potential compensation for PKC-theta function. Finally, a subtherapeutic dose of anti-CD154 Ab or CTLA4-Ig, which was not sufficient to prevent cardiac allograft rejection in the wild-type mice, prevented heart rejection in the PKC-theta-/- mice. Thus, in combination with other treatments, inhibition of PKC-theta may facilitate achieving long-term survival of allografts.
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21 MeSH Terms
Reovirus preferentially infects the basolateral surface and is released from the apical surface of polarized human respiratory epithelial cells.
Excoffon KJ, Guglielmi KM, Wetzel JD, Gansemer ND, Campbell JA, Dermody TS, Zabner J
(2008) J Infect Dis 197: 1189-97
MeSH Terms: Animals, Cell Adhesion Molecules, Cell Polarity, Electric Impedance, Humans, Immunoglobulins, Immunohistochemistry, L Cells, Mice, Microscopy, Confocal, Neuraminidase, Orthoreovirus, Mammalian, Reassortant Viruses, Receptors, Cell Surface, Reoviridae Infections, Respiratory Mucosa, Respiratory Tract Infections, Tight Junctions, Virus Shedding
Show Abstract · Added December 10, 2013
Mammalian reoviruses infect respiratory and gastrointestinal epithelia and cause disease in neonates. Junctional adhesion molecule-A (JAM-A) is a serotype-independent receptor for reovirus. JAM-A localizes to tight junctions and contributes to paracellular permeability in polarized epithelia. To investigate the mechanisms of reovirus infection of polarized epithelial cells, we assessed reovirus replication, release, and spread after apical and basolateral adsorption to primary human airway epithelial cultures. Reovirus infection of human airway epithelia was more efficient after adsorption to the basolateral surface than after adsorption to the apical surface, and it was dependent on JAM-A. Reovirus binding to carbohydrate coreceptor sialic acid inhibited apical infection, which was partially ameliorated by treatment of the cultures with neuraminidase. Despite the preference for basolateral infection, reovirus was released from the apical surface of respiratory epithelia and did not disrupt tight junctions. These results establish the existence of an infectious circuit for reovirus in polarized human respiratory epithelial cells.
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19 MeSH Terms
A patient with adult erythermalgia: evidence suggesting an autoimmune etiology.
Jackson AL, Oates JA
(2008) Am J Med Sci 335: 320-2
MeSH Terms: Autoimmune Diseases, Erythromelalgia, Female, Humans, Immunoglobulins, Intravenous, Middle Aged
Show Abstract · Added December 10, 2013
We report the case of a woman with a combination of erythermalgia, idiopathic thrombocytopenic purpura, and vitamin B-12 deficiency with positive parietal cell antibodies. The patient was treated with intravenous administration of immunoglobulins together with small doses of prednisone, which resulted in an improvement in her platelet counts, rise in her vitamin B12 levels, and resolution of her painful discolored digits. These findings suggest an underlying autoimmune component to the development of erythermalgia.
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6 MeSH Terms