17 results on '"Scott D. Speer"'
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2. Molecular and phenotypic characteristics of RSV infections in infants during two nirsevimab randomized clinical trials
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Bahar Ahani, Kevin M. Tuffy, Anastasia A. Aksyuk, Deidre Wilkins, Michael E. Abram, Ron Dagan, Joseph B. Domachowske, Johnathan D. Guest, Hong Ji, Anna Kushnir, Amanda Leach, Shabir A. Madhi, Vaishali S. Mankad, Eric A. F. Simões, Benjamin Sparklin, Scott D. Speer, Ann Marie Stanley, David E. Tabor, Ulrika Wählby Hamrén, Elizabeth J. Kelly, and Tonya Villafana
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Science - Abstract
Abstract Nirsevimab is a monoclonal antibody that binds to the respiratory syncytial virus (RSV) fusion protein. During the Phase 2b (NCT02878330) and MELODY (NCT03979313) clinical trials, infants received one dose of nirsevimab or placebo before their first RSV season. In this pre-specified analysis, isolates from RSV infections were subtyped, sequenced and analyzed for nirsevimab binding site substitutions; subsequently, recombinant RSVs were engineered for microneutralization susceptibility testing. Here we show that the frequency of infections caused by subtypes A and B is similar across and within the two trials. In addition, RSV A had one and RSV B had 10 fusion protein substitutions occurring at >5% frequency. Notably, RSV B binding site substitutions were rare, except for the highly prevalent I206M:Q209R, which increases nirsevimab susceptibility; RSV B isolates from two participants had binding site substitutions that reduce nirsevimab susceptibility. Overall, >99% of isolates from the Phase 2b and MELODY trials retained susceptibility to nirsevimab.
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- 2023
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3. Fc-mediated functions of nirsevimab complement direct respiratory syncytial virus neutralization but are not required for optimal prophylactic protection
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Tyler Brady, Corinne Cayatte, Tiffany L. Roe, Scott D. Speer, Hong Ji, LeeAnn Machiesky, Tianhui Zhang, Deidre Wilkins, Kevin M. Tuffy, and Elizabeth J. Kelly
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nirsevimab ,respiratory syncytial virus ,Fc-mediated effector function ,anti-RSV F protein monoclonal antibodies ,RSV immunoprophylaxis ,Immunologic diseases. Allergy ,RC581-607 - Abstract
IntroductionNirsevimab is an extended half-life (M252Y/S254T/T256E [YTE]-modified) monoclonal antibody to the pre-fusion conformation of the respiratory syncytial virus (RSV) Fusion protein, with established efficacy in preventing RSV-associated lower respiratory tract infection in infants for the duration of a typical RSV season. Previous studies suggest that nirsevimab confers protection via direct virus neutralization. Here we use preclinical models to explore whether fragment crystallizable (Fc)-mediated effector functions contribute to nirsevimab-mediated protection.MethodsNirsevimab, MEDI8897* (i.e., nirsevimab without the YTE modification), and MEDI8897*-TM (i.e., MEDI8897* without Fc effector functions) binding to Fc γ receptors (FcγRs) was evaluated using surface plasmon resonance. Antibody-dependent neutrophil phagocytosis (ADNP), antibody-dependent cellular phagocytosis (ADCP), antibody-dependent complement deposition (ADCD), and antibody-dependent cellular cytotoxicity (ADCC) were assessed through in vitro and ex vivo serological analyses. A cotton rat challenge study was performed with MEDI8897* and MEDI8897*-TM to explore whether Fc effector functions contribute to protection from RSV.ResultsNirsevimab and MEDI8897* exhibited binding to a range of FcγRs, with expected reductions in FcγR binding affinities observed for MEDI8897*-TM. Nirsevimab exhibited in vitro ADNP, ADCP, ADCD, and ADCC activity above background levels, and similar ADNP, ADCP, and ADCD activity to palivizumab. Nirsevimab administration increased ex vivo ADNP, ADCP, and ADCD activity in participant serum from the MELODY study (NCT03979313). However, ADCC levels remained similar between nirsevimab and placebo. MEDI8897* and MEDI8897*-TM exhibited similar dose-dependent reduction in lung and nasal turbinate RSV titers in the cotton rat model.ConclusionNirsevimab possesses Fc effector activity comparable with the current standard of care, palivizumab. However, despite possessing the capacity for Fc effector activity, data from RSV challenge experiments illustrate that nirsevimab-mediated protection is primarily dependent on direct virus neutralization.
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- 2023
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4. Broadly Neutralizing Activity of Zika Virus-Immune Sera Identifies a Single Viral Serotype
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Kimberly A. Dowd, Christina R. DeMaso, Rebecca S. Pelc, Scott D. Speer, Alexander R.Y. Smith, Leslie Goo, Derek J. Platt, John R. Mascola, Barney S. Graham, Mark J. Mulligan, Michael S. Diamond, Julie E. Ledgerwood, and Theodore C. Pierson
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Biology (General) ,QH301-705.5 - Abstract
Recent epidemics of Zika virus (ZIKV) have been associated with congenital malformation during pregnancy and Guillain-Barré syndrome. There are two ZIKV lineages (African and Asian) that share >95% amino acid identity. Little is known regarding the ability of neutralizing antibodies elicited against one lineage to protect against the other. We investigated the breadth of the neutralizing antibody response following ZIKV infection by measuring the sensitivity of six ZIKV strains to neutralization by ZIKV-confirmed convalescent human serum or plasma samples. Contemporary Asian and early African ZIKV strains were similarly sensitive to neutralization regardless of the cellular source of virus. Furthermore, mouse immune serum generated after infection with African or Asian ZIKV strains was capable of neutralizing homologous and heterologous ZIKV strains equivalently. Because our study only defines a single ZIKV serotype, vaccine candidates eliciting robust neutralizing antibody responses should inhibit infection of both ZIKV lineages, including strains circulating in the Americas.
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- 2016
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5. ISG15 deficiency and increased viral resistance in humans but not mice
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Scott D. Speer, Zhi Li, Sofija Buta, Béatrice Payelle-Brogard, Li Qian, Frederic Vigant, Erminia Rubino, Thomas J. Gardner, Tim Wedeking, Mark Hermann, James Duehr, Ozden Sanal, Ilhan Tezcan, Nahal Mansouri, Payam Tabarsi, Davood Mansouri, Véronique Francois-Newton, Coralie F. Daussy, Marisela R. Rodriguez, Deborah J. Lenschow, Alexander N. Freiberg, Domenico Tortorella, Jacob Piehler, Benhur Lee, Adolfo García-Sastre, Sandra Pellegrini, and Dusan Bogunovic
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Science - Abstract
ISG15 is a ubiquitin-like protein which has important immune-related functions in mice and humans. Here the authors demonstrate that, unlike in mice, human ISG15 stabilizes UPS18 and that ISG15-deficient human cells are more resistant to viral infection.
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- 2016
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6. prM-reactive antibodies reveal a role for partially mature virions in dengue virus pathogenesis
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Kimberly A. Dowd, Devika Sirohi, Scott D. Speer, Laura A. VanBlargan, Rita E. Chen, Swati Mukherjee, Bradley M. Whitener, Jennifer Govero, Maya Aleshnick, Bridget Larman, Soila Sukupolvi-Petty, Madhumati Sevvana, Andrew S. Miller, Thomas Klose, Aihua Zheng, Scott Koenig, Margaret Kielian, Richard J. Kuhn, Michael S. Diamond, and Theodore C. Pierson
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Multidisciplinary - Abstract
Cleavage of the flavivirus premembrane (prM) structural protein during maturation can be inefficient. The contribution of partially mature flavivirus virions that retain uncleaved prM to pathogenesis during primary infection is unknown. To investigate this question, we characterized the functional properties of newly-generated dengue virus (DENV) prM-reactive monoclonal antibodies (mAbs) in vitro and using a mouse model of DENV disease. Anti-prM mAbs neutralized DENV infection in a virion maturation state–dependent manner. Alanine scanning mutagenesis and cryoelectron microscopy of anti-prM mAbs in complex with immature DENV defined two modes of attachment to a single antigenic site. In vivo, passive transfer of intact anti-prM mAbs resulted in an antibody-dependent enhancement of disease. However, protection against DENV-induced lethality was observed when the transferred mAbs were genetically modified to inhibit their ability to interact with Fcγ receptors. These data establish that in addition to mature forms of the virus, partially mature infectious prM + virions can also contribute to pathogenesis during primary DENV infections.
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- 2023
7. Distinct neutralizing antibody correlates of protection among related Zika virus vaccines identify a role for antibody quality
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Vicky Roy, Kathryn E. Foulds, Tracy J. Ruckwardt, John Paul Todd, Sonia Maciejewski, Bryant M. Foreman, Kimberly A. Dowd, Maya Aleshnick, Scott D. Speer, Rebecca S. Pelc, Deepika Nair, Martha Nason, Wing Pui Kong, Nigel Bourne, John R. Mascola, Julie E. Ledgerwood, Galit Alter, Theodore C. Pierson, Katherine E. Burgomaster, Martin R. Gaudinski, Sung Youl Ko, Barney S. Graham, David N. Gordon, Kaitlyn M. Morabito, Alan D.T. Barrett, Mario Roederer, Christina R. DeMaso, Brian E. Fisher, Eun Sung Yang, and Grace L. Chen
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biology ,Zika Virus Infection ,Viral Vaccine ,Viral Vaccines ,General Medicine ,Zika Virus ,biology.organism_classification ,Antibodies, Viral ,Virology ,Antibodies, Neutralizing ,Neutralization ,Zika virus ,DNA vaccination ,Titer ,Mice ,Immunity ,biology.protein ,Animals ,Antibody ,Neutralizing antibody - Abstract
The emergence of Zika virus (ZIKV) in the Americas stimulated the development of multiple ZIKV vaccine candidates. We previously developed two related DNA vaccine candidates encoding ZIKV structural proteins that were immunogenic in animal models and humans. We sought to identify neutralizing antibody (NAb) properties induced by each vaccine that correlated with protection in nonhuman primates (NHPs). Despite eliciting equivalent NAb titers in NHPs, these vaccines were not equally protective. The transfer of equivalent titers of vaccine-elicited NAb into AG129 mice also revealed nonequivalent protection, indicating qualitative differences among antibodies (Abs) elicited by these vaccines. Both vaccines elicited Abs with similar binding titers against envelope protein monomers and those incorporated into virus-like particles, as well as a comparable capacity to orchestrate phagocytosis. Functional analysis of vaccine-elicited NAbs from NHPs and humans revealed a capacity to neutralize the structurally mature form of the ZIKV virion that varied in magnitude among vaccine candidates. Conversely, sensitivity to the virion maturation state was not a characteristic of NAbs induced by natural or experimental infection. Passive transfer experiments in mice revealed that neutralization of mature ZIKV virions more accurately predicts protection from ZIKV infection. These findings demonstrate that NAb correlates of protection may differ among vaccine antigens when assayed using standard neutralization platforms and suggest that measurements of Ab quality, including the capacity to neutralize mature virions, will be critical for defining correlates of ZIKV vaccine-induced immunity.
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- 2019
8. Broadly Neutralizing Activity of Zika Virus-Immune Sera Identifies a Single Viral Serotype
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Julie E. Ledgerwood, Scott D. Speer, Rebecca S. Pelc, Kimberly A. Dowd, Leslie Goo, Mark J. Mulligan, Michael S. Diamond, Christina R. DeMaso, Theodore C. Pierson, John R. Mascola, Derek J. Platt, Barney S. Graham, and Alexander R. Y. Smith
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0301 basic medicine ,Serotype ,Antibodies, Viral ,Serogroup ,Immune sera ,Article ,General Biochemistry, Genetics and Molecular Biology ,Neutralization ,Virus ,Zika virus ,03 medical and health sciences ,Humans ,Neutralizing antibody ,lcsh:QH301-705.5 ,biology ,Plasma samples ,Zika Virus Infection ,Immune Sera ,Zika Virus ,biology.organism_classification ,Antibodies, Neutralizing ,Virology ,030104 developmental biology ,lcsh:Biology (General) ,biology.protein ,Antibody - Abstract
SummaryRecent epidemics of Zika virus (ZIKV) have been associated with congenital malformation during pregnancy and Guillain-Barré syndrome. There are two ZIKV lineages (African and Asian) that share >95% amino acid identity. Little is known regarding the ability of neutralizing antibodies elicited against one lineage to protect against the other. We investigated the breadth of the neutralizing antibody response following ZIKV infection by measuring the sensitivity of six ZIKV strains to neutralization by ZIKV-confirmed convalescent human serum or plasma samples. Contemporary Asian and early African ZIKV strains were similarly sensitive to neutralization regardless of the cellular source of virus. Furthermore, mouse immune serum generated after infection with African or Asian ZIKV strains was capable of neutralizing homologous and heterologous ZIKV strains equivalently. Because our study only defines a single ZIKV serotype, vaccine candidates eliciting robust neutralizing antibody responses should inhibit infection of both ZIKV lineages, including strains circulating in the Americas.
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- 2016
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9. VIROLOGY. Diagnostics for Zika virus on the horizon
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Scott D, Speer and Theodore C, Pierson
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Aedes ,Zika Virus Infection ,Animals ,Humans ,Zika Virus - Published
- 2016
10. Structural Basis of Zika Virus-Specific Antibody Protection
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Theodore C. Pierson, Michael S. Diamond, Derek J. Platt, Estefania Fernandez, Christopher A. Nelson, Haiyan Zhao, Matthew J. Gorman, Daved H. Fremont, Kimberly A. Dowd, Jennifer Govero, and Scott D. Speer
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0301 basic medicine ,Models, Molecular ,medicine.drug_class ,Monoclonal antibody ,Antibodies, Viral ,General Biochemistry, Genetics and Molecular Biology ,Epitope ,Article ,Zika virus ,03 medical and health sciences ,Epitopes ,Mice ,Viral Envelope Proteins ,Fab Fragments ,medicine ,Animals ,biology ,Zika Virus Infection ,Antibodies, Monoclonal ,Zika Virus ,biology.organism_classification ,Virology ,Antibodies, Neutralizing ,Mice, Inbred C57BL ,Specific antibody ,030104 developmental biology ,Epitope mapping ,biology.protein ,Antibody ,Congenital disease ,Epitope Mapping - Abstract
Zika virus (ZIKV) infection during pregnancy has emerged as a global public health problem because of its ability to cause severe congenital disease. Here, we developed six mouse monoclonal antibodies (mAbs) against ZIKV including four (ZV-48, ZV-54, ZV-64, and ZV-67) that were ZIKV specific and neutralized infection of African, Asian, and American strains to varying degrees. X-ray crystallographic and competition binding analyses of Fab fragments and scFvs defined three spatially distinct epitopes in DIII of the envelope protein corresponding to the lateral ridge (ZV-54 and ZV-67), C-C' loop (ZV-48 and ZV-64), and ABDE sheet (ZV-2) regions. In vivo passive transfer studies revealed protective activity of DIII-lateral ridge specific neutralizing mAbs in a mouse model of ZIKV infection. Our results suggest that DIII is targeted by multiple type-specific antibodies with distinct neutralizing activity, which provides a path for developing prophylactic antibodies for use in pregnancy or designing epitope-specific vaccines against ZIKV.
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- 2016
11. ISG15 deficiency and increased viral resistance in humans but not mice
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Zhi Li, Benhur Lee, Ilhan Tezcan, Payam Tabarsi, Sofija Buta, Nahal Mansouri, Frederic Vigant, Domenico Tortorella, James Duehr, Béatrice Payelle-Brogard, Sandra Pellegrini, Li Qian, Scott D. Speer, Véronique Francois-Newton, Davood Mansouri, Jacob Piehler, Alexander N. Freiberg, Mark Hermann, Thomas J. Gardner, Marisela R. Rodriguez, Ozden Sanal, Tim Wedeking, Adolfo García-Sastre, Coralie F. Daussy, Deborah J. Lenschow, Erminia Rubino, Dusan Bogunovic, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Signalisation des Cytokines, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Osnabrück University, Hacettepe University = Hacettepe Üniversitesi, Shahid Beheshti University of Medical Sciences [Tehran] (SBUMS), Shahid Beheshti University, University of Washington School of Medicine, The University of Texas Medical Branch (UTMB), This was supported in part by NIH grant R00 AI106942-02 to D.B., NIH grant R01 AI101820 to D.T., an American Heart Association pre-doctoral fellowship and a USPHS Institutional Research Training Award T32-AI07647 to T.J.G., NRSA T32 AR07279-30 to M.R.R., NIH grant RO1 A1080672 and Pew Scholar Award to D.J.L., funding by the DFG (SFB 944) to J.P., NIH grant R33 AI102267 to A.N.F. and B.L., CRIP (Center for Research on Influenza Pathogenesis), and NIAID funded Center of Excellence for Influenza Research and Surveillance (contract #HHSN272201400008C) to AGS. Experimental support was provided by the Speed Congenics Facility of the Rheumatic Disease Core Center (P30 AR048335). Work in the Cytokine Signaling Unit was supported by Institut Pasteur, CNRS, INSERM and an Amgen Scholarship to E.R., Çocuk Sağlığı ve Hastalıkları, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Universität Osnabrück - Osnabrück University
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0301 basic medicine ,Animals ,Cell Line ,Cytokines/genetics ,Cytokines/immunology ,Cytokines/metabolism ,Female ,Gene Expression Regulation ,Humans ,Interferons/metabolism ,Mice ,Primary Cell Culture ,Ubiquitin Thiolesterase/metabolism ,Ubiquitins/genetics ,Ubiquitins/immunology ,Ubiquitins/metabolism ,Virus Diseases/immunology ,Science ,General Physics and Astronomy ,Biology ,Viral resistance ,Viral infection ,General Biochemistry, Genetics and Molecular Biology ,Article ,MESH: Primary Cell Culture ,03 medical and health sciences ,MESH: Ubiquitins ,MESH: Animals ,MESH: Interferons ,MESH: Mice ,Ubiquitins ,MESH: Cytokines ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Multidisciplinary ,MESH: Humans ,General Chemistry ,MESH: Ubiquitin Thiolesterase ,ISG15 ,Virology ,MESH: Gene Expression Regulation ,3. Good health ,MESH: Cell Line ,MESH: Virus Diseases ,030104 developmental biology ,Virus Diseases ,Immunology ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Cytokines ,Interferons ,MESH: Female ,Ubiquitin Thiolesterase - Abstract
ISG15 is an interferon (IFN)-α/β-induced ubiquitin-like protein. It exists as a free molecule, intracellularly and extracellularly, and conjugated to target proteins. Studies in mice have demonstrated a role for Isg15 in antiviral immunity. By contrast, human ISG15 was shown to have critical immune functions, but not in antiviral immunity. Namely, free extracellular ISG15 is crucial in IFN-γ-dependent antimycobacterial immunity, while free intracellular ISG15 is crucial for USP18-mediated downregulation of IFN-α/β signalling. Here we describe ISG15-deficient patients who display no enhanced susceptibility to viruses in vivo, in stark contrast to Isg15-deficient mice. Furthermore, fibroblasts derived from ISG15-deficient patients display enhanced antiviral protection, and expression of ISG15 attenuates viral resistance to WT control levels. The species-specific gain-of-function in antiviral immunity observed in ISG15 deficiency is explained by the requirement of ISG15 to sustain USP18 levels in humans, a mechanism not operating in mice., ISG15 is a ubiquitin-like protein which has important immune-related functions in mice and humans. Here the authors demonstrate that, unlike in mice, human ISG15 stabilizes UPS18 and that ISG15-deficient human cells are more resistant to viral infection.
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- 2016
12. Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome
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Daphne Heijsman, Rachel Schot, Grazia M.S. Mancini, Scott D. Speer, Frans W. Verheijen, Leontine van Unen, Rob Willemsen, Zhi Li, Johan M. Kros, Femke A.T. de Vries, Grétel Oudesluijs, Aida Bertoli Avella, Dusan Bogunovic, Marije E.C. Meuwissen, Marta Martín-Fernández, Rutger W W Brouwer, Maarten H. Lequin, Irenaeus F.M. de Coo, Yanick J. Crow, Sigrid Tinschert, Wilfred F. J. van IJcken, Jeroen Dudink, Tobias Goldmann, Mark Hermann, Sofija Buta, Wendy Stam, Marco Prinz, Sandra Pellegrini, Li, Zhi, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Medical Faculty Carl Gustav Carus, Technische Universität Dresden = Dresden University of Technology (TU Dresden), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Signalisation des Cytokines, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Signalisation des Cytokines - Cytokine Signaling, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), institute of neuropathology, University of Freiburg [Freiburg], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Manchester Centre for Genomic Medicine [Manchester, UK] (MCGM), St Mary's Hospital Manchester-Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester], Financial support was obtained by NutsOhra Funds project 1203-030 to G.M.S. Mancini. D. Bogunovic is supported by the National Institute of Allergy and Infectious Diseases grant number R00AI106942-02. Z. Li and S. Pellegrini acknowledge institutional support from Institut Pasteur, Centre National de la Recherche Scientifique, and Institut National de la Santé et de la Recherche Médicale. Y.J. Crow acknowledges the European Research Council (GA 309449)., Innsbruck Medical University [Austria] (IMU), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Manchester Centre for Genomic Medicine (MCGM), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-St Mary's Hospital Manchester, Clinical Genetics, Pathology, Radiology & Nuclear Medicine, Cell biology, Neurology, and Pediatrics
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Male ,0301 basic medicine ,MESH: Signal Transduction ,MESH: Interferon Type I ,Microcephaly ,[SDV.GEN] Life Sciences [q-bio]/Genetics ,MESH: Calcinosis ,Torch syndrome ,Polymicrogyria ,Immunology and Allergy ,MESH: Endopeptidases ,Research Articles ,Genetic disorder ,Brain ,Calcinosis ,3. Good health ,MESH: Microglia ,Interferon Type I ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Female ,MESH: Immunity, Innate ,Microglia ,medicine.symptom ,Ubiquitin Thiolesterase ,Signal Transduction ,medicine.drug ,[SDV.IMM] Life Sciences [q-bio]/Immunology ,Immunology ,Inflammation ,Biology ,Nervous System Malformations ,MESH: Nervous System Malformations ,03 medical and health sciences ,MESH: Brain ,Autoimmune Diseases of the Nervous System ,Endopeptidases ,medicine ,Journal Article ,Humans ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Innate immune system ,MESH: Humans ,Brief Definitive Report ,medicine.disease ,Immunity, Innate ,MESH: Male ,MESH: Autoimmune Diseases of the Nervous System ,030104 developmental biology ,Human medicine ,MESH: Female ,Interferon type I ,Calcification - Abstract
Meuwissen and collaborators define a novel genetic cause of pseudo-TORCH syndrome, which resembles the sequelae of congenital infection and represents a novel type I interferonopathy., Pseudo-TORCH syndrome (PTS) is characterized by microcephaly, enlarged ventricles, cerebral calcification, and, occasionally, by systemic features at birth resembling the sequelae of congenital infection but in the absence of an infectious agent. Genetic defects resulting in activation of type 1 interferon (IFN) responses have been documented to cause Aicardi-Goutières syndrome, which is a cause of PTS. Ubiquitin-specific peptidase 18 (USP18) is a key negative regulator of type I IFN signaling. In this study, we identified loss-of-function recessive mutations of USP18 in five PTS patients from two unrelated families. Ex vivo brain autopsy material demonstrated innate immune inflammation with calcification and polymicrogyria. In vitro, patient fibroblasts displayed severely enhanced IFN-induced inflammation, which was completely rescued by lentiviral transduction of USP18. These findings add USP18 deficiency to the list of genetic disorders collectively termed type I interferonopathies. Moreover, USP18 deficiency represents the first genetic disorder of PTS caused by dysregulation of the response to type I IFNs. Therapeutically, this places USP18 as a promising target not only for genetic but also acquired IFN-mediated CNS disorders.
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- 2016
13. Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation
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Nahal Mansouri, Bertrand Boisson, Xianqin Zhang, Qing Kenneth Wang, Gillian I. Rice, Xing Wang, Seyed Alireza Mahdaviani, Chao Yuan, Yuval Itan, Flore Rozenberg, Satoshi Okada, Gilles Uzé, Dusan Bogunovic, Mugen Liu, Tao Ma, Pierre Lebon, Lilliana Radoshevich, Jingyu Liu, Wenqiang Liu, Tiantian Han, Davood Mansouri, Delin Liu, Jean-Laurent Casanova, Béatrice Payelle-Brogard, Yanick J. Crow, Dilek Yalnizoglu, Stefano Volpi, Zhi Li, Ozden Sanal, Lu Zeng, Bo Wang, Chunyuan Chen, Sandra Pellegrini, Shen-Ying Zhang, Emmanuelle Jouanguy, Luigi D. Notarangelo, Adolfo García-Sastre, Philippe Gros, Hui Jiang, Stéphanie Boisson-Dupuis, Véronique Francois-Newton, Laurent Abel, Scott D. Speer, Ilhan Tezcan, Jacinta Bustamante, Li, Zhi, Host and microbial molecular dissection of pathogenesis and immunity in tuberculosis - HOMITB - - EC:FP7:HEALTH2008-11-01 - 2012-04-30 - 200732 - VALID, A system view on the differential activities of human type I interferons - IFNACTION - - EC:FP7:HEALTH2009-01-01 - 2012-12-31 - 223608 - VALID, Huazhong University of Science and Technology [Wuhan] (HUST), Signalisation des Cytokines, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Istituto Giannina Gaslini, Genova, Immunologia Clinica e Sperimentale, Ankara University School of Medicine [Turkey], University of Manchester [Manchester], Shahid Beheshti University of Medical Sciences [Tehran] (SBUMS), Shahid Beheshti University, St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Institut des sciences du végétal (ISV), Centre National de la Recherche Scientifique (CNRS), Department of Mathematics [Nanjing], Nanjing University of Aeronautics and Astronautics [Nanjing] (NUAA), Institut de Recherche en Communications Optiques et Microondes (IRCOM), Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS), Hunan Institute of Science and Technology, Interactions Bactéries-Cellules (UIBC), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Dynamique des interactions membranaires normales et pathologiques (DIMNP), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Département de Physique des Particules (ex SPP) (DPhP), Institut de Recherches sur les lois Fondamentales de l'Univers (IRFU), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Laboratoire de Virologie, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique Humaine des Maladies Infectieuses (Inserm U980), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Service de virologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Saint-Vincent de Paul, Università degli Studi di Brescia = University of Brescia (UniBs), The Laboratory of Human Genetics of Infectious Diseases is supported by grants from the French National Agency for Research (ANR), the EU grant HOMITB (HEALTH-F32008-200732), the St Giles Foundation, the National Center for Research Resources and the National Center for Advancing Sciences (NCATS), National Institutes of Health grant number 8UL1TR000043, the Rockefeller University, the National Institute of Allergy and Infectious Diseases grant number R37AI095983, Institut Merieux research grant and the Empire State Stem Cell fund through NYSDOH Contract #C023046 to Flow Cytometry Research Core at the Rockefeller University. The Cytokine Signaling Unit is supported by the Institut Pasteur, CNRS and INSERM. S.P. and G.U. received funding from the EU Seventh Framework Programme under grant agreement 223608. V.F.-N. was supported by the Ligue contre le Cancer. L.R. is a Human Frontier Science Program long-term fellow. L.D.N. was supported by the National Institute of Allergy and Infectious Diseases grant number 1PO1AI076210-01A1. Y.J.C. thanks the Manchester Biomedical Research Centre and the Greater Manchester Comprehensive Local Research Network, the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement 241779, and the European Research Council (GA 309449). A.G.-S. acknowledges NIAID grants U19AI083025 and P01AI090935 for support. We thank C. Daussy for technical assistance, E. Bianchi and F. Michel for discussions. We thank D. Zhang and the members of the Zhang laboratory for assistance, advice and discussions. This work was supported by Chinese National Natural Science Foundation grants (81000079, 81170165) to X.Z. D.B. is supported by the National Institute of Allergy and Infectious Diseases grant number R00AI106942-02., European Project: 200732,EC:FP7:HEALTH,FP7-HEALTH-2007-A,HOMITB(2008), European Project: 223608,EC:FP7:HEALTH,FP7-HEALTH-2007-B,IFNACTION(2009), Çocuk ve Ergen Ruh Sağlığı ve Hastalıkları, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Shahid Beheshti University of Medical Sciences, The Rockefeller University, St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, rockefeller university, Department of Mathematics (Nanjing University of Aeronautics and Astronautics), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]-Institut National de la Recherche Agronomique (INRA), Département de Physique des Particules (ex SPP) (DPP), CHU Cochin [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Saint-Vincent de Paul, Department of Pediatrics and Institute for Molecular Medicine Angello Nocivelli, University of Brescia, Centre National de la Recherche Scientifique (CNRS)-Université de Limoges (UNILIM), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Università degli Studi di Brescia [Brescia], and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1)
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Male ,MESH: Signal Transduction ,MESH: Inflammation ,MESH: Interferon Type I ,Intracellular Space ,0302 clinical medicine ,Interferon ,MESH: Child ,Child ,MESH: Endopeptidases ,S-Phase Kinase-Associated Proteins ,0303 health sciences ,MESH: Cytokines ,Multidisciplinary ,Effector ,MESH: Gene Expression Regulation ,Pedigree ,3. Good health ,Cell biology ,030220 oncology & carcinogenesis ,Interferon Type I ,Viruses ,Cytokines ,Science & Technology - Other Topics ,MESH: Intracellular Space ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Female ,Signal transduction ,MESH: S-Phase Kinase-Associated Proteins ,Ubiquitin Thiolesterase ,Intracellular ,Signal Transduction ,medicine.drug ,Adolescent ,[SDV.IMM] Life Sciences [q-bio]/Immunology ,MESH: Pedigree ,Biology ,[SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics ,MESH: Viruses ,03 medical and health sciences ,Immunity ,Endopeptidases ,medicine ,Humans ,MESH: Ubiquitins ,Ubiquitins ,Alleles ,030304 developmental biology ,Inflammation ,MESH: Adolescent ,MESH: Humans ,MESH: Alleles ,Ubiquitination ,ISG15 ,MESH: Male ,Neuroimmunology ,Gene Expression Regulation ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,Immunology ,MESH: Ubiquitination ,MESH: Female ,Interferon type I - Abstract
Intracellular ISG15 is an interferon (IFN)-alpha/beta-inducible ubiquitin-like modifier which can covalently bind other proteins in a process called ISGylation; it is an effector of IFN-alpha/beta-dependent antiviral immunity in mice(1-4). We previously published a study describing humans with inherited ISG15deficiency but without unusually severe viral diseases(5). We showed that these patients were prone to mycobacterial disease and that human ISG15 was non-redundant as an extracellular IFN-gamma-inducing molecule. We show here that ISG15-deficient patients also display unanticipated cellular, immunological and clinical signs of enhanced IFN-alpha/beta immunity, reminiscent of the Mendelian autoinflammatory interferonopathies Aicardi-Goutieres syndrome and spondyloenchondrodysplasia(6-9). We further show that an absence of intracellular ISG15 in the patients' cells prevents the accumulation of USP18(10,11), a potent negative regulator of IFN-alpha/beta signalling, resulting in the enhancement and amplification of IFN-alpha/beta responses. Human ISG15, therefore, is not only redundant for antiviral immunity, but is a key negative regulator of IFN-alpha/beta immunity. In humans, intracellular ISG15 is IFN-alpha/beta-inducible not to serve as a substrate for ISGylation-dependent antiviral immunity, but to ensure USP18-dependent regulation of IFN-alpha/beta and prevention of IFN-alpha/beta-dependent autoinflammation.
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- 2015
14. Diagnostics for Zika virus on the horizon
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Scott D. Speer and Theodore C. Pierson
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0301 basic medicine ,Aedes ,Multidisciplinary ,biology ,viruses ,030231 tropical medicine ,Yellow fever ,Outbreak ,biology.organism_classification ,medicine.disease ,Virology ,Zika virus ,Dengue fever ,Serology ,03 medical and health sciences ,Flavivirus ,030104 developmental biology ,0302 clinical medicine ,Immunology ,medicine ,Global health - Abstract
Zika virus (ZIKV) is a mosquito-transmitted flavivirus that is related to other pathogens of clinical importance, including yellow fever and dengue (DENV) viruses. Although once infrequently associated with human disease, ZIKV has emerged as a global health threat with its introduction into South America during 2014 and 2015. Of concern, recent ZIKV outbreaks are linked to severe neuro-developmental complications in the children of women infected while pregnant, as well as Guillain-Barre syndrome in adults ( 1 ). Management of this epidemic has been complicated by extensive serological cross-reactivity among flaviviruses and the cocirculation of ZIKV and DENV in regions experiencing the greatest disease burden. Current serological diagnostics have a limited capacity to distinguish between DENV and ZIKV. On page 823 of this issue, Stettler et al. ( 2 ) characterize monoclonal antibodies (mAbs) isolated from ZIKV-infected humans that hold promise as diagnostics or therapeutics, and advance our understanding of the repertoire of antibodies elicited by ZIKV infection.
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- 2016
15. ID: 55
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Scott D. Speer, Mark Hermann, Sandra Pellegrini, Béatrice Payelle-Brogard, Adolfo García-Sastre, Sofija Buta, Dusan Bogunovic, and Zhi Li
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Immunology ,Hematology ,Biology ,Biochemistry ,ISG15 ,Transduction (genetics) ,Viral replication ,Downregulation and upregulation ,Interferon ,Immunity ,In vivo ,Extracellular ,medicine ,Immunology and Allergy ,Molecular Biology ,medicine.drug - Abstract
ISG15 is an interferon (IFN)- α / β -inducible protein that exists as a free molecule and conjugated to target proteins (ISGylation). In vivo studies in mice have demonstrated a critical role for ISG15 in antiviral immunity. By contrast, in humans, ISG15 has been shown to have critical functions, but not in antiviral immunity. Extracellular ISG15 is essential in IFN- γ -dependent antimycobacterial immunity, and intracellular ISG15 is essential for the USP18-mediated downregulation of IFN- α / β signaling. We describe ISG15-deficient patients, who, unlike Isg15-deficient mice, display no enhanced susceptibility to viruses in vivo . On the contrary, patients fibroblasts displayed enhanced antiviral protection and transduction of ISG15 restored viral replication to control levels. Difference in antiviral immunity in absence of ISG15 in humans vs. mice is mechanistically explained by ISG15 stabilizing USP18 in humans but not in mice. Thus, ISG15-deficient individuals present with gain-of-function in antiviral immunity at the expense of increased susceptibility to mycobacteria and auto-immunity.
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- 2015
16. Engineering temperature sensitive live attenuated influenza vaccines from emerging viruses
- Author
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David E. Wentworth, Bin Zhou, Yan Li, Xudong Lin, Anju Subba, and Scott D. Speer
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viruses ,Biology ,medicine.disease_cause ,Vaccines, Attenuated ,Virus Replication ,H5N1 genetic structure ,Virus ,Article ,Mice ,Influenza A Virus, H1N1 Subtype ,Orthomyxoviridae Infections ,Pandemic ,Influenza A virus ,medicine ,Live attenuated influenza vaccine ,Animals ,Lung ,Mice, Inbred BALB C ,Attenuated vaccine ,General Veterinary ,General Immunology and Microbiology ,Public Health, Environmental and Occupational Health ,Temperature ,Virology ,Disease Models, Animal ,Infectious Diseases ,Viral replication ,Influenza Vaccines ,Mutation ,Molecular Medicine ,Female ,Human Virus - Abstract
The licensed live attenuated influenza A vaccine (LAIV) in the United States is created by making a reassortant containing six internal genes from a cold-adapted master donor strain ( ca A/AA/6/60) and two surface glycoprotein genes from a circulating/emerging strain ( e.g. , A/CA/7/09 for the 2009/2010 H1N1 pandemic). Technologies to rapidly create recombinant viruses directly from patient specimens were used to engineer alternative LAIV candidates that have genomes composed entirely of vRNAs from pandemic or seasonal strains. Multiple mutations involved in the temperature-sensitive ( ts) phenotype of the ca A/AA/6/60 master donor strain were introduced into a 2009 H1N1 pandemic strain rA/New York/1682/2009 (rNY1682-WT) to create rNY1682-TS1, and additional mutations identified in other ts viruses were added to rNY1682-TS1 to create rNY1682-TS2. Both rNY1682-TS1 and rNY1682-TS2 replicated efficiently at 30 °C and 33 °C. However, rNY1682-TS1 was partially restricted, and rNY1682-TS2 was completely restricted at 39 °C. Additionally, engineering the TS1 or TS2 mutations into a distantly related human seasonal H1N1 influenza A virus also resulted pronounced restriction of replication in vitro . Clinical symptoms and virus replication in the lungs of mice showed that although rNY1682-TS2 and the licensed FluMist ® -H1N1pdm LAIV that was used to combat the 2009/2010 pandemic were similarly attenuated, the rNY1682-TS2 was more protective upon challenge with a virulent mutant of pandemic H1N1 virus or a heterologous H1N1 (A/PR/8/1934) virus. This study demonstrates that engineering key temperature sensitive mutations (PB1-K391E, D581G, A661T; PB2-P112S, N265S, N556D, Y658H) into the genomes of influenza A viruses attenuates divergent human virus lineages and provides an alternative strategy for the generation of LAIVs.
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- 2011
17. Erratum: Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation
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Xianqin Zhang, Seyed Alireza Mahdaviani, Chao Yuan, Tao Ma, Lilliana Radoshevich, Véronique Francois-Newton, Béatrice Payelle-Brogard, Davood Mansouri, Delin Liu, Nahal Mansouri, Stefano Volpi, Gilles Uzé, Philippe Gros, Hui Jiang, Bo Wang, Stéphanie Boisson-Dupuis, Ozden Sanal, Laurent Abel, Luigi D. Notarangelo, Dusan Bogunovic, Flore Rozenberg, Mugen Liu, Scott D. Speer, Yuval Itan, Jacinta Bustamante, Yanick J. Crow, Emmanuelle Jouanguy, Adolfo García-Sastre, Tiantian Han, Pierre Lebon, Dilek Yalnizoglu, Ilhan Tezcan, Sandra Pellegrini, Qing Kenneth Wang, Jean-Laurent Casanova, Wenqiang Liu, Xing Wang, Satoshi Okada, Chunyuan Chen, Shen-Ying Zhang, Lu Zeng, Jingyu Liu, Zhi Li, Bertrand Boisson, and Gillian I. Rice
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Multidisciplinary ,Chemistry ,Interferon α β ,medicine ,Inflammation ,Erratum ,medicine.symptom ,error ,ISG15 ,Molecular biology ,Intracellular - Abstract
Nature 517, 89–93 (2015); doi:10.1038/nature13801In this Letter, author J.-L.C. was inadvertently missing one of their affiliations; they should also have been associated with affiliation number 2 (St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York 10065, USA). This has been corrected in the online versions of the paper.
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- 2015
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