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Structural Basis for a Neutralizing Antibody Response Elicited by a Recombinant Hantaan Virus Gn Immunogen

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العنوان: Structural Basis for a Neutralizing Antibody Response Elicited by a Recombinant Hantaan Virus Gn Immunogen
المؤلفون: Rissanen, Ilona, Krumm, Stefanie A., Stass, Robert, Whitaker, Annalis, Voss, James E., Bruce, Emily A., Rothenberger, Sylvia, Kunz, Stefan, Burton, Dennis R., Huiskonen, Juha T., Botten, Jason W., Bowden, Thomas A., Doores, Katie J.
المساهمون: Institute of Biotechnology, Molecular and Integrative Biosciences Research Programme, Helsinki Institute of Life Science HiLIFE
بيانات النشر: American Society for Microbiology
سنة النشر: 2022
المجموعة: Helsingfors Universitet: HELDA – Helsingin yliopiston digitaalinen arkisto
مصطلحات موضوعية: glycoprotein, hantavirus, neutralizing antibody, structure, zoonosis, HANTAVIRUS PULMONARY SYNDROME, HEMORRHAGIC-FEVER, PUUMALA VIRUS, NEPHROPATHIA-EPIDEMICA, MONOCLONAL-ANTIBODIES, NUCLEOCAPSID PROTEIN, GLYCOPROTEINS, VACCINES, ANTIGEN, SYSTEM, 11832 Microbiology and virology
الوصف: 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 nn-ITN-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 (nn-ITN-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. ; Peer reviewed
نوع الوثيقة: article in journal/newspaper
وصف الملف: application/pdf
اللغة: English
العلاقة: This work was funded by the MRC (MR/L009528/1 and MR/S007555/1 to T.A.B., MR/ N002091/1 to K.J.D. and T.A.B., MR/K024426/1 and MRC Discovery Award MC/PC/15068 to K.J.D.), the Academy of Finland (grant 309605 to I.R.), the European Research Council under the European Union’s Horizon 2020 research and innovation program (grant 649053 to J.T.H.), and National Institutes of Health (NIH) grants R41AI132047, R41AI132047-01S1, and R43AI142911 to J.W.B. The Wellcome Centre for Human Genetics (WCHG) is supported by Wellcome Centre grant 203141/Z/16/Z. Computation used the Oxford Biomedical Research Computing (BMRC) facility, a joint development between the WCHG and the Big Data Institute supported by Health Data Research UK and the National Institute of Health Research (NIHR) Oxford Biomedical Research Centre. Oxford Particle Imaging Centre was founded by a Wellcome JIF award (060208/Z/00/Z) and is supported by grants from Wellcome (093305/Z/10/Z) and the MRC. We thank Bilal Qureshi for support with electron microscopy and Jingshan Ren for advice on crystallographic data processing. We also thank Diamond Light Source (DLS) for beamtime (proposal MX19946) and the staff of beamline i03 at DLS for assistance with X-ray data collection. We further acknowledge Diamond Light Source for time on beamline Krios I under proposal EM20223-7 for access and support and for the use of cryo-EM facilities at the United Kingdom?s National Electron Bio-Imaging Centre (eBIC), funded by Wellcome, Medical Research Council (MRC) and Biotechnology and Biological Sciences Research Council (BBRSC). We acknowledge CSC?IT Center for Science, Finland, for computational resources. The following reagent was obtained through the NIH Biodefense and Emerging Infections Research Resources Repository, National Institute of Allergy and Infectious Diseases, NIH: rabbit anti-ANDV N polyclonal antibody (NR-12152). This work was funded by the MRC (MR/L009528/1 and MR/S007555/1 to T.A.B., MR/ N002091/1 to K.J.D. and T.A.B., MR/K024426/1 and MRC Discovery Award MC/PC/15068 to K.J.D.), the Academy of Finland (grant 309605 to I.R.), the European Research Council under the European Union?s Horizon 2020 research and innovation program (grant 649053 to J.T.H.), and National Institutes of Health (NIH) grants R41AI132047, R41AI132047-01S1, and R43AI142911 to J.W.B. The Wellcome Centre for Human Genetics (WCHG) is supported by Wellcome Centre grant 203141/Z/16/Z. Computation used the Oxford Biomedical Research Computing (BMRC) facility, a joint development between the WCHG and the Big Data Institute supported by Health Data Research UK and the National Institute of Health Research (NIHR) Oxford Biomedical Research Centre. Oxford Particle Imaging Centre was founded by a Wellcome JIF award (060208/Z/00/Z) and is supported by grants from Wellcome (093305/Z/10/Z) and the MRC.; Rissanen , I , Krumm , S A , Stass , R , Whitaker , A , Voss , J E , Bruce , E A , Rothenberger , S , Kunz , S , Burton , D R , Huiskonen , J T , Botten , J W , Bowden , T A & Doores , K J 2021 , ' Structural Basis for a Neutralizing Antibody Response Elicited by a Recombinant Hantaan Virus Gn Immunogen ' , mBio , vol. 12 , no. 4 , 02531 . https://doi.org/10.1128/mBio.02531-20Test; ORCID: /0000-0002-0348-7323/work/156150863; http://hdl.handle.net/10138/341549Test; f7410e78-5e80-4664-b7e8-4b0d72d83370; 000695211800002
الإتاحة: http://hdl.handle.net/10138/341549Test
حقوق: cc_by ; info:eu-repo/semantics/openAccess ; openAccess
رقم الانضمام: edsbas.BA3BA1ED
قاعدة البيانات: BASE
الوصف
الوصف غير متاح.