Structural Basis for a Neutralizing Antibody Response Elicited by a Recombinant Hantaan Virus Gn Immunogen
ABSTRACT Hantaviruses are a group of emerging pathogens capable of causing severe disease upon zoonotic transmission to humans. The mature hantavirus surface presents higher-order tetrameric assemblies of two glycoproteins, Gn and Gc, which are responsible for negotiating host cell entry and constit...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2021-08-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mBio.02531-20 |
| _version_ | 1818754444621250560 |
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| author | Ilona Rissanen Stefanie A. Krumm Robert Stass Annalis Whitaker James E. Voss Emily A. Bruce Sylvia Rothenberger Stefan Kunz Dennis R. Burton Juha T. Huiskonen Jason W. Botten Thomas A. Bowden Katie J. Doores |
| author_facet | Ilona Rissanen Stefanie A. Krumm Robert Stass Annalis Whitaker James E. Voss Emily A. Bruce Sylvia Rothenberger Stefan Kunz Dennis R. Burton Juha T. Huiskonen Jason W. Botten Thomas A. Bowden Katie J. Doores |
| author_sort | Ilona Rissanen |
| collection | DOAJ |
| description | ABSTRACT Hantaviruses are a group of emerging pathogens capable of causing severe disease upon zoonotic transmission to humans. The mature hantavirus surface presents higher-order tetrameric assemblies of two glycoproteins, Gn and Gc, which are responsible for negotiating host cell entry and constitute key therapeutic targets. Here, we demonstrate that recombinantly derived Gn from Hantaan virus (HTNV) elicits a neutralizing antibody response (serum dilution that inhibits 50% infection [ID50], 1:200 to 1:850) in an animal model. Using antigen-specific B cell sorting, we isolated monoclonal antibodies (mAbs) exhibiting neutralizing and non-neutralizing activity, termed mAb HTN-Gn1 and mAb nnHTN-Gn2, respectively. Crystallographic analysis reveals that these mAbs target spatially distinct epitopes at disparate sites of the N-terminal region of the HTNV Gn ectodomain. Epitope mapping onto a model of the higher order (Gn-Gc)4 spike supports the immune accessibility of the mAb HTN-Gn1 epitope, a hypothesis confirmed by electron cryo-tomography of the antibody with virus-like particles. These data define natively exposed regions of the hantaviral Gn that can be targeted in immunogen design. IMPORTANCE The spillover of pathogenic hantaviruses from rodent reservoirs into the human population poses a continued threat to human health. Here, we show that a recombinant form of the Hantaan virus (HTNV) surface-displayed glycoprotein, Gn, elicits a neutralizing antibody response in rabbits. We isolated a neutralizing (HTN-Gn1) and a non-neutralizing (nnHTN-Gn2) monoclonal antibody and provide the first molecular-level insights into how the Gn glycoprotein may be targeted by the antibody-mediated immune response. These findings may guide rational vaccine design approaches focused on targeting the hantavirus glycoprotein envelope. |
| first_indexed | 2024-12-18T05:23:21Z |
| format | Article |
| id | doaj.art-1f67558141a14b57a4f6668f7781b182 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-18T05:23:21Z |
| publishDate | 2021-08-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-1f67558141a14b57a4f6668f7781b1822022-12-21T21:19:35ZengAmerican Society for MicrobiologymBio2150-75112021-08-0112410.1128/mBio.02531-20Structural Basis for a Neutralizing Antibody Response Elicited by a Recombinant Hantaan Virus Gn ImmunogenIlona Rissanen0Stefanie A. Krumm1Robert Stass2Annalis Whitaker3James E. Voss4Emily A. Bruce5Sylvia Rothenberger6Stefan Kunz7Dennis R. Burton8Juha T. Huiskonen9Jason W. Botten10Thomas A. Bowden11Katie J. Doores12Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford, United KingdomDepartment of Infectious Diseases, King's College London, London, United KingdomDivision of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford, United KingdomDivision of Immunobiology, Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, Vermont, USADepartment of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USADivision of Immunobiology, Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, Vermont, USAInstitute of Microbiology, Lausanne University Hospital and University of Lausanne, Lausanne, SwitzerlandInstitute of Microbiology, Lausanne University Hospital and University of Lausanne, Lausanne, SwitzerlandDepartment of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USADivision of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford, United KingdomDivision of Immunobiology, Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, Vermont, USADivision of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford, United KingdomDepartment of Infectious Diseases, King's College London, London, United KingdomABSTRACT Hantaviruses are a group of emerging pathogens capable of causing severe disease upon zoonotic transmission to humans. The mature hantavirus surface presents higher-order tetrameric assemblies of two glycoproteins, Gn and Gc, which are responsible for negotiating host cell entry and constitute key therapeutic targets. Here, we demonstrate that recombinantly derived Gn from Hantaan virus (HTNV) elicits a neutralizing antibody response (serum dilution that inhibits 50% infection [ID50], 1:200 to 1:850) in an animal model. Using antigen-specific B cell sorting, we isolated monoclonal antibodies (mAbs) exhibiting neutralizing and non-neutralizing activity, termed mAb HTN-Gn1 and mAb nnHTN-Gn2, respectively. Crystallographic analysis reveals that these mAbs target spatially distinct epitopes at disparate sites of the N-terminal region of the HTNV Gn ectodomain. Epitope mapping onto a model of the higher order (Gn-Gc)4 spike supports the immune accessibility of the mAb HTN-Gn1 epitope, a hypothesis confirmed by electron cryo-tomography of the antibody with virus-like particles. These data define natively exposed regions of the hantaviral Gn that can be targeted in immunogen design. IMPORTANCE The spillover of pathogenic hantaviruses from rodent reservoirs into the human population poses a continued threat to human health. Here, we show that a recombinant form of the Hantaan virus (HTNV) surface-displayed glycoprotein, Gn, elicits a neutralizing antibody response in rabbits. We isolated a neutralizing (HTN-Gn1) and a non-neutralizing (nnHTN-Gn2) monoclonal antibody and provide the first molecular-level insights into how the Gn glycoprotein may be targeted by the antibody-mediated immune response. These findings may guide rational vaccine design approaches focused on targeting the hantavirus glycoprotein envelope.https://journals.asm.org/doi/10.1128/mBio.02531-20glycoproteinhantavirusneutralizing antibodystructurezoonosis |
| spellingShingle | Ilona Rissanen Stefanie A. Krumm Robert Stass Annalis Whitaker James E. Voss Emily A. Bruce Sylvia Rothenberger Stefan Kunz Dennis R. Burton Juha T. Huiskonen Jason W. Botten Thomas A. Bowden Katie J. Doores Structural Basis for a Neutralizing Antibody Response Elicited by a Recombinant Hantaan Virus Gn Immunogen mBio glycoprotein hantavirus neutralizing antibody structure zoonosis |
| title | Structural Basis for a Neutralizing Antibody Response Elicited by a Recombinant Hantaan Virus Gn Immunogen |
| title_full | Structural Basis for a Neutralizing Antibody Response Elicited by a Recombinant Hantaan Virus Gn Immunogen |
| title_fullStr | Structural Basis for a Neutralizing Antibody Response Elicited by a Recombinant Hantaan Virus Gn Immunogen |
| title_full_unstemmed | Structural Basis for a Neutralizing Antibody Response Elicited by a Recombinant Hantaan Virus Gn Immunogen |
| title_short | Structural Basis for a Neutralizing Antibody Response Elicited by a Recombinant Hantaan Virus Gn Immunogen |
| title_sort | structural basis for a neutralizing antibody response elicited by a recombinant hantaan virus gn immunogen |
| topic | glycoprotein hantavirus neutralizing antibody structure zoonosis |
| url | https://journals.asm.org/doi/10.1128/mBio.02531-20 |
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