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Therapeutic administration of a recombinant human monoclonal antibody reduces the severity of chikungunya virus disease in rhesus macaques.
Broeckel R, Fox JM, Haese N, Kreklywich CN, Sukulpovi-Petty S, Legasse A, Smith PP, Denton M, Corvey C, Krishnan S, Colgin LMA, Ducore RM, Lewis AD, Axthelm MK, Mandron M, Cortez P, Rothblatt J, Rao E, Focken I, Carter K, Sapparapau G, Crowe JE, Diamond MS, Streblow DN
(2017) PLoS Negl Trop Dis 11: e0005637
MeSH Terms: Animals, Antibodies, Monoclonal, Antibodies, Viral, B-Lymphocytes, Chikungunya Fever, Chikungunya virus, Disease Models, Animal, Drug Evaluation, Preclinical, Immunologic Factors, Macaca mulatta, T-Lymphocytes, Treatment Outcome
Show Abstract · Added March 14, 2018
Chikungunya virus (CHIKV) is a mosquito-borne virus that causes a febrile syndrome in humans associated with acute and chronic debilitating joint and muscle pain. Currently no licensed vaccines or therapeutics are available to prevent or treat CHIKV infections. We recently isolated a panel of potently neutralizing human monoclonal antibodies (mAbs), one (4N12) of which exhibited prophylactic and post-exposure therapeutic activity against CHIKV in immunocompromised mice. Here, we describe the development of an engineered CHIKV mAb, designated SVIR001, that has similar antigen binding and neutralization profiles to its parent, 4N12. Because therapeutic administration of SVIR001 in immunocompetent mice significantly reduced viral load in joint tissues, we evaluated its efficacy in a rhesus macaque model of CHIKV infection. Rhesus macaques that were treated after infection with SVIR001 showed rapid elimination of viremia and less severe joint infiltration and disease compared to animals treated with SVIR002, an isotype control mAb. SVIR001 reduced viral burden at the site of infection and at distant sites and also diminished the numbers of activated innate immune cells and levels of pro-inflammatory cytokines and chemokines. SVIR001 therapy; however, did not substantively reduce the induction of CHIKV-specific B or T cell responses. Collectively, these results show promising therapeutic activity of a human anti-CHIKV mAb in rhesus macaques and provide proof-of-principle for its possible use in humans to treat active CHIKV infections.
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12 MeSH Terms
The Molecular Basis for the Lack of Inflammatory Responses in Mouse Embryonic Stem Cells and Their Differentiated Cells.
D'Angelo W, Gurung C, Acharya D, Chen B, Ortolano N, Gama V, Bai F, Guo YL
(2017) J Immunol 198: 2147-2155
MeSH Terms: Animals, Cell Differentiation, Chikungunya Fever, Chikungunya virus, Embryonic Stem Cells, Immunity, Inflammation, Interferons, Lipopolysaccharides, Mice, Mice, Inbred DBA, NF-kappa B, RAW 264.7 Cells, Tumor Necrosis Factor-alpha, Virus Diseases
Show Abstract · Added July 10, 2017
We reported previously that mouse embryonic stem cells do not have a functional IFN-based antiviral mechanism. The current study extends our investigation to the inflammatory response in mouse embryonic stem cells and mouse embryonic stem cell-differentiated cells. We demonstrate that LPS, TNF-α, and viral infection, all of which induce robust inflammatory responses in naturally differentiated cells, failed to activate NF-κB, the key transcription factor that mediates inflammatory responses, and were unable to induce the expression of inflammatory genes in mouse embryonic stem cells. Similar results were obtained in human embryonic stem cells. In addition to the inactive state of NF-κB, the deficiency in the inflammatory response in mouse embryonic stem cells is also attributed to the lack of functional receptors for LPS and TNF-α. In vitro differentiation can trigger the development of the inflammatory response mechanism, as indicated by the transition of NF-κB from its inactive to active state. However, a limited response to TNF-α and viral infection, but not to LPS, was observed in mouse embryonic stem cell-differentiated fibroblasts. We conclude that the inflammatory response mechanism is not active in mouse embryonic stem cells, and in vitro differentiation promotes only partial development of this mechanism. Together with our previous studies, the findings described in this article demonstrate that embryonic stem cells are fundamentally different from differentiated somatic cells in their innate immunity, which may have important implications in developmental biology, immunology, and embryonic stem cell-based regenerative medicine.
Copyright © 2017 by The American Association of Immunologists, Inc.
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15 MeSH Terms
Pathogenic Chikungunya Virus Evades B Cell Responses to Establish Persistence.
Hawman DW, Fox JM, Ashbrook AW, May NA, Schroeder KMS, Torres RM, Crowe JE, Dermody TS, Diamond MS, Morrison TE
(2016) Cell Rep 16: 1326-1338
MeSH Terms: Amino Acids, Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, B-Lymphocytes, Chikungunya Fever, Chikungunya virus, Glycoproteins, Humans, Mice, Mice, Inbred C57BL, Viral Envelope Proteins
Show Abstract · Added April 13, 2017
Chikungunya virus (CHIKV) and related alphaviruses cause epidemics of acute and chronic musculoskeletal disease. To investigate the mechanisms underlying the failure of immune clearance of CHIKV, we studied mice infected with an attenuated CHIKV strain (181/25) and the pathogenic parental strain (AF15561), which differ by five amino acids. Whereas AF15561 infection of wild-type mice results in viral persistence in joint tissues, 181/25 is cleared. In contrast, 181/25 infection of μMT mice lacking mature B cells results in viral persistence in joint tissues, suggesting that virus-specific antibody is required for clearance of infection. Mapping studies demonstrated that a highly conserved glycine at position 82 in the A domain of the E2 glycoprotein impedes clearance and neutralization of multiple CHIKV strains. Remarkably, murine and human antibodies targeting E2 domain B failed to neutralize pathogenic CHIKV strains efficiently. Our data suggest that pathogenic CHIKV strains evade E2 domain-B-neutralizing antibodies to establish persistence.
Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.
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13 MeSH Terms
Broadly Neutralizing Alphavirus Antibodies Bind an Epitope on E2 and Inhibit Entry and Egress.
Fox JM, Long F, Edeling MA, Lin H, van Duijl-Richter MKS, Fong RH, Kahle KM, Smit JM, Jin J, Simmons G, Doranz BJ, Crowe JE, Fremont DH, Rossmann MG, Diamond MS
(2015) Cell 163: 1095-1107
MeSH Terms: Alphavirus, Alphavirus Infections, Amino Acid Sequence, Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Chikungunya virus, Cryoelectron Microscopy, Epitopes, Glycoproteins, Humans, Immunoglobulin Fab Fragments, Mice, Models, Molecular, Molecular Sequence Data, Protein Structure, Tertiary, Sequence Alignment, Viral Envelope Proteins, Viral Vaccines, Virus Internalization
Show Abstract · Added January 26, 2016
We screened a panel of mouse and human monoclonal antibodies (MAbs) against chikungunya virus and identified several with inhibitory activity against multiple alphaviruses. Passive transfer of broadly neutralizing MAbs protected mice against infection by chikungunya, Mayaro, and O'nyong'nyong alphaviruses. Using alanine-scanning mutagenesis, loss-of-function recombinant proteins and viruses, and multiple functional assays, we determined that broadly neutralizing MAbs block multiple steps in the viral lifecycle, including entry and egress, and bind to a conserved epitope on the B domain of the E2 glycoprotein. A 16 Å resolution cryo-electron microscopy structure of a Fab fragment bound to CHIKV E2 B domain provided an explanation for its neutralizing activity. Binding to the B domain was associated with repositioning of the A domain of E2 that enabled cross-linking of neighboring spikes. Our results suggest that B domain antigenic determinants could be targeted for vaccine or antibody therapeutic development against multiple alphaviruses of global concern.
Copyright © 2015 Elsevier Inc. All rights reserved.
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21 MeSH Terms
Cryo-EM structures elucidate neutralizing mechanisms of anti-chikungunya human monoclonal antibodies with therapeutic activity.
Long F, Fong RH, Austin SK, Chen Z, Klose T, Fokine A, Liu Y, Porta J, Sapparapu G, Akahata W, Doranz BJ, Crowe JE, Diamond MS, Rossmann MG
(2015) Proc Natl Acad Sci U S A 112: 13898-903
MeSH Terms: Antibodies, Monoclonal, Antibodies, Neutralizing, Chikungunya Fever, Chikungunya virus, Cryoelectron Microscopy, Humans, Protein Conformation
Show Abstract · Added January 26, 2016
Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes severe acute and chronic disease in humans. Although highly inhibitory murine and human monoclonal antibodies (mAbs) have been generated, the structural basis of their neutralizing activity remains poorly characterized. Here, we determined the cryo-EM structures of chikungunya virus-like particles complexed with antibody fragments (Fab) of two highly protective human mAbs, 4J21 and 5M16, that block virus fusion with host membranes. Both mAbs bind primarily to sites within the A and B domains, as well as to the B domain's β-ribbon connector of the viral glycoprotein E2. The footprints of these antibodies on the viral surface were consistent with results from loss-of-binding studies using an alanine scanning mutagenesis-based epitope mapping approach. The Fab fragments stabilized the position of the B domain relative to the virus, particularly for the complex with 5M16. This finding is consistent with a mechanism of neutralization in which anti-CHIKV mAbs that bridge the A and B domains impede movement of the B domain away from the underlying fusion loop on the E1 glycoprotein and therefore block the requisite pH-dependent fusion of viral and host membranes.
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7 MeSH Terms
Isolation and Characterization of Broad and Ultrapotent Human Monoclonal Antibodies with Therapeutic Activity against Chikungunya Virus.
Smith SA, Silva LA, Fox JM, Flyak AI, Kose N, Sapparapu G, Khomandiak S, Khomadiak S, Ashbrook AW, Kahle KM, Fong RH, Swayne S, Doranz BJ, McGee CE, Heise MT, Pal P, Brien JD, Austin SK, Diamond MS, Dermody TS, Crowe JE
(2015) Cell Host Microbe 18: 86-95
MeSH Terms: Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Chemoprevention, Chikungunya Fever, Chikungunya virus, Disease Models, Animal, Humans, Immunization, Passive, Inhibitory Concentration 50, Mice, Protein Binding, Survival Analysis, Treatment Outcome, Viral Envelope Proteins, Virus Internalization
Show Abstract · Added January 26, 2016
Chikungunya virus (CHIKV) is a mosquito-transmitted RNA virus that causes acute febrile infection associated with polyarthralgia in humans. Mechanisms of protective immunity against CHIKV are poorly understood, and no effective therapeutics or vaccines are available. We isolated and characterized human monoclonal antibodies (mAbs) that neutralize CHIKV infectivity. Among the 30 mAbs isolated, 13 had broad and ultrapotent neutralizing activity (IC50 < 10 ng/ml), and all of these mapped to domain A of the E2 envelope protein. Potent inhibitory mAbs blocked post-attachment steps required for CHIKV membrane fusion, and several were protective in a lethal challenge model in immunocompromised mice, even when administered at late time points after infection. These highly protective mAbs could be considered for prevention or treatment of CHIKV infection, and their epitope location in domain A of E2 could be targeted for rational structure-based vaccine development.
Copyright © 2015 Elsevier Inc. All rights reserved.
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17 MeSH Terms
Serotonin Receptor Agonist 5-Nonyloxytryptamine Alters the Kinetics of Reovirus Cell Entry.
Mainou BA, Ashbrook AW, Smith EC, Dorset DC, Denison MR, Dermody TS
(2015) J Virol 89: 8701-12
MeSH Terms: Animals, Antiviral Agents, Biological Transport, Cell Line, Cell Survival, Chikungunya virus, Chlorocebus aethiops, Cholera Toxin, Cricetinae, Cytoskeleton, Endosomes, HeLa Cells, Humans, Interferon-gamma, L Cells, Methiothepin, Mice, Murine hepatitis virus, Reoviridae, Reoviridae Infections, Serotonin Antagonists, Transferrin, Tryptamines, Vero Cells, Virus Assembly, Virus Attachment, Virus Internalization
Show Abstract · Added February 4, 2016
UNLABELLED - Mammalian orthoreoviruses (reoviruses) are nonenveloped double-stranded RNA viruses that infect most mammalian species, including humans. Reovirus binds to cell surface glycans, junctional adhesion molecule A (JAM-A), and the Nogo-1 receptor (depending on the cell type) and enters cells by receptor-mediated endocytosis. Within the endocytic compartment, reovirus undergoes stepwise disassembly, which is followed by release of the transcriptionally active viral core into the cytoplasm. In a small-molecule screen to identify host mediators of reovirus infection, we found that treatment of cells with 5-nonyloxytryptamine (5-NT), a prototype serotonin receptor agonist, diminished reovirus cytotoxicity. 5-NT also blocked reovirus infection. In contrast, treatment of cells with methiothepin mesylate, a serotonin antagonist, enhanced infection by reovirus. 5-NT did not alter cell surface expression of JAM-A or attachment of reovirus to cells. However, 5-NT altered the distribution of early endosomes with a concomitant impairment of reovirus transit to late endosomes and a delay in reovirus disassembly. Consistent with an inhibition of viral disassembly, 5-NT treatment did not alter infection by in vitro-generated infectious subvirion particles, which bind to JAM-A but bypass a requirement for proteolytic uncoating in endosomes to infect cells. We also found that treatment of cells with 5-NT decreased the infectivity of alphavirus chikungunya virus and coronavirus mouse hepatitis virus. These data suggest that serotonin receptor signaling influences cellular activities that regulate entry of diverse virus families and provides a new, potentially broad-spectrum target for antiviral drug development.
IMPORTANCE - Identification of well-characterized small molecules that modulate viral infection can accelerate development of antiviral therapeutics while also providing new tools to increase our understanding of the cellular processes that underlie virus-mediated cell injury. We conducted a small-molecule screen to identify compounds capable of inhibiting cytotoxicity caused by reovirus, a prototype double-stranded RNA virus. We found that 5-nonyloxytryptamine (5-NT) impairs reovirus infection by altering viral transport during cell entry. Remarkably, 5-NT also inhibits infection by an alphavirus and a coronavirus. The antiviral properties of 5-NT suggest that serotonin receptor signaling is an important regulator of infection by diverse virus families and illuminate a potential new drug target.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
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27 MeSH Terms
Residue 82 of the Chikungunya virus E2 attachment protein modulates viral dissemination and arthritis in mice.
Ashbrook AW, Burrack KS, Silva LA, Montgomery SA, Heise MT, Morrison TE, Dermody TS
(2014) J Virol 88: 12180-92
MeSH Terms: Amino Acid Substitution, Animals, Arthritis, CHO Cells, Chikungunya virus, Cricetulus, Disease Models, Animal, Mice, Inbred C57BL, Mutant Proteins, Viral Envelope Proteins, Viral Tropism, Virulence Factors, Virus Replication
Show Abstract · Added January 21, 2015
UNLABELLED - Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that has reemerged to cause profound epidemics of fever, rash, and arthralgia throughout sub-Saharan Africa, Southeast Asia, and the Caribbean. Like other arthritogenic alphaviruses, mechanisms of CHIKV pathogenesis are not well defined. Using the attenuated CHIKV strain 181/25 and virulent strain AF15561, we identified a residue in the E2 viral attachment protein that is a critical determinant of viral replication in cultured cells and pathogenesis in vivo. Viruses containing an arginine at E2 residue 82 displayed enhanced infectivity in mammalian cells but reduced infectivity in mosquito cells and diminished virulence in a mouse model of CHIKV disease. Mice inoculated with virus containing an arginine at this position exhibited reduced swelling at the site of inoculation with a concomitant decrease in the severity of necrosis in joint-associated tissues. Viruses containing a glycine at E2 residue 82 produced higher titers in the spleen and serum at early times postinfection. Using wild-type and glycosaminoglycan (GAG)-deficient Chinese hamster ovary (CHO) cell lines and soluble GAGs, we found that an arginine at residue 82 conferred greater dependence on GAGs for infection of mammalian cells. These data suggest that CHIKV E2 interactions with GAGs diminish dissemination to lymphoid tissue, establishment of viremia, and activation of inflammatory responses early in infection. Collectively, these results suggest a function for GAG utilization in regulating CHIKV tropism and host responses that contribute to arthritis.
IMPORTANCE - CHIKV is a reemerging alphavirus of global significance with high potential to spread into new, immunologically naive populations. The severity of CHIKV disease, particularly its propensity for chronic musculoskeletal manifestations, emphasizes the need for identification of genetic determinants that dictate CHIKV virulence in the host. To better understand mechanisms of CHIKV pathogenesis, we probed the function of an amino acid polymorphism in the E2 viral attachment protein using a mouse model of CHIKV musculoskeletal disease. In addition to influencing glycosaminoglycan utilization, we identified roles for this polymorphism in differential infection of mammalian and mosquito cells and targeting of CHIKV to specific tissues within infected mice. These studies demonstrate a correlation between CHIKV tissue tropism and virus-induced pathology modulated by a single polymorphism in E2, which in turn illuminates potential targets for vaccine and antiviral drug development.
Copyright © 2014, American Society for Microbiology. All Rights Reserved.
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13 MeSH Terms
A single-amino-acid polymorphism in Chikungunya virus E2 glycoprotein influences glycosaminoglycan utilization.
Silva LA, Khomandiak S, Ashbrook AW, Weller R, Heise MT, Morrison TE, Dermody TS
(2014) J Virol 88: 2385-97
MeSH Terms: Alphavirus Infections, Amino Acid Substitution, Animals, CHO Cells, Chikungunya Fever, Chikungunya virus, Chlorocebus aethiops, Cricetinae, Cricetulus, Endosomes, Genotype, Glycosaminoglycans, Heparitin Sulfate, Humans, Hydrogen Bonding, Kinetics, Models, Molecular, Mutation, Polymorphism, Single Nucleotide, Protein Multimerization, Static Electricity, Vero Cells, Viral Envelope Proteins, Virus Attachment, Virus Internalization, Virus Replication
Show Abstract · Added May 20, 2014
UNLABELLED - Chikungunya virus (CHIKV) is a reemerging arbovirus responsible for outbreaks of infection throughout Asia and Africa, causing an acute illness characterized by fever, rash, and polyarthralgia. Although CHIKV infects a broad range of host cells, little is known about how CHIKV binds and gains access to the target cell interior. In this study, we tested whether glycosaminoglycan (GAG) binding is required for efficient CHIKV replication using CHIKV vaccine strain 181/25 and clinical isolate SL15649. Preincubation of strain 181/25, but not SL15649, with soluble GAGs resulted in dose-dependent inhibition of infection. While parental Chinese hamster ovary (CHO) cells are permissive for both strains, neither strain efficiently bound to or infected mutant CHO cells devoid of GAG expression. Although GAGs appear to be required for efficient binding of both strains, they exhibit differential requirements for GAGs, as SL15649 readily infected cells that express excess chondroitin sulfate but that are devoid of heparan sulfate, whereas 181/25 did not. We generated a panel of 181/25 and SL15649 variants containing reciprocal amino acid substitutions at positions 82 and 318 in the E2 glycoprotein. Reciprocal exchange at residue 82 resulted in a phenotype switch; Gly(82) results in efficient infection of mutant CHO cells but a decrease in heparin binding, whereas Arg(82) results in reduced infectivity of mutant cells and an increase in heparin binding. These results suggest that E2 residue 82 is a primary determinant of GAG utilization, which likely mediates attenuation of vaccine strain 181/25.
IMPORTANCE - Chikungunya virus (CHIKV) infection causes a debilitating rheumatic disease that can persist for months to years, and yet there are no licensed vaccines or antiviral therapies. Like other alphaviruses, CHIKV displays broad tissue tropism, which is thought to be influenced by virus-receptor interactions. In this study, we determined that cell-surface glycosaminoglycans are utilized by both a vaccine strain and a clinical isolate of CHIKV to mediate virus binding. We also identified an amino acid polymorphism in the viral E2 attachment protein that influences utilization of glycosaminoglycans. These data enhance an understanding of the viral and host determinants of CHIKV cell entry, which may foster development of new antivirals that act by blocking this key step in viral infection.
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26 MeSH Terms