Structure and mechanism of monoclonal antibody binding to the junctional epitope of Plasmodium falciparum circumsporozoite protein
| Autor: | Špela Binter, Daniel Emerling, Yevel Flores-Garcia, Sini Reponen, Andrew B. Ward, C. Richter King, Rachael S. Wash, Sean M. Carroll, Paul Kellam, Phillip C. Aoto, Jonathan L. Torres, David Oyen, Fidel Zavala, Allan Bradley, Emily Locke, Franck Lemiale, Ian A. Wilson, Qi Liang, T. Pholcharee |
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| Přispěvatelé: | Torres, Jonathan L [0000-0003-0137-8497], Aoto, Phillip C [0000-0001-6518-0899], Binter, Špela [0000-0003-2335-6336], Pholcharee, Tossapol [0000-0002-5347-1936], Locke, Emily [0000-0003-1944-8473], Bradley, Allan [0000-0002-2349-8839], Kellam, Paul [0000-0003-3166-4734], Ward, Andrew B [0000-0001-7153-3769], Wilson, Ian A [0000-0002-6469-2419], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
Plasmodium Physiology Protozoan Proteins Antibodies Protozoan Molecular Dynamics Biochemistry Physical Chemistry Epitope law.invention Binding Analysis Antibodies Monoclonal Murine-Derived Epitopes Mice Computational Chemistry law 1108 Medical Microbiology Immune Physiology Medicine and Health Sciences IMPLEMENTATION Biology (General) Enzyme-Linked Immunoassays 0303 health sciences Immune System Proteins Crystallography biology Physics 030302 biochemistry & molecular biology Condensed Matter Physics 3. Good health Circumsporozoite protein Chemistry Sporozoites 1107 Immunology Physical Sciences Recombinant DNA Crystal Structure Female Antibody Life Sciences & Biomedicine Research Article 0605 Microbiology medicine.drug_class QH301-705.5 Immunology ANTIGEN Plasmodium falciparum Mice Transgenic Monoclonal antibody Research and Analysis Methods Microbiology Antibodies 03 medical and health sciences Structure-Activity Relationship Antigen Virology Parasite Groups Genetics medicine Solid State Physics Animals Binding site Immunoassays Molecular Biology Chemical Characterization 030304 developmental biology Science & Technology Chemical Bonding MALARIA INFECTION Biology and Life Sciences Proteins Hydrogen Bonding RC581-607 biology.organism_classification Molecular biology biology.protein Immunologic Techniques Parasitology Binding Sites Antibody Immunologic diseases. Allergy Apicomplexa |
| Zdroj: | PLoS Pathogens PLoS Pathogens, Vol 16, Iss 3, p e1008373 (2020) |
| Popis: | Lasting protection has long been a goal for malaria vaccines. The major surface antigen on Plasmodium falciparum sporozoites, the circumsporozoite protein (PfCSP), has been an attractive target for vaccine development and most protective antibodies studied to date interact with the central NANP repeat region of PfCSP. However, it remains unclear what structural and functional characteristics correlate with better protection by one antibody over another. Binding to the junctional region between the N-terminal domain and central NANP repeats has been proposed to result in superior protection: this region initiates with the only NPDP sequence followed immediately by NANP. Here, we isolated antibodies in Kymab mice immunized with full-length recombinant PfCSP and two protective antibodies were selected for further study with reactivity against the junctional region. X-ray and EM structures of two monoclonal antibodies, mAb667 and mAb668, shed light on their differential affinity and specificity for the junctional region. Importantly, these antibodies also bind to the NANP repeat region with equal or better affinity. A comparison with an NANP-only binding antibody (mAb317) revealed roughly similar but statistically distinct levels of protection against sporozoite challenge in mouse liver burden models, suggesting that junctional antibody protection might relate to the ability to also cross-react with the NANP repeat region. Our findings indicate that additional efforts are necessary to isolate a true junctional antibody with no or much reduced affinity to the NANP region to elucidate the role of the junctional epitope in protection. Author summary The circumsporozoite protein (CSP) of Plasmodium falciparum malaria has been the foundation for the design of transmission blocking malaria vaccines. To date, the most promising CSP-based vaccine candidate is RTS,S, which consists of the central repeating NANP amino-acid sequence and the C-terminal domain of CSP fused to hepatitis B surface antigen that assembles into virus-like particles. Potential shortcomings of RTS,S includes the lack of other potential CSP epitopes such as the junctional epitope, which is located between the N-terminal domain of CSP and the start of the NANP repeat region. Here, we elicited antibodies against full-length CSP and screened for junctional epitope binding. We then used an array of biophysical techniques to elucidate the nature of the binding and tested the level of two protective antibodies in a mouse challenge model. Although the antibodies were able to bind both junctional and NANP epitopes, the in vivo data showed distinct levels of protection between themselves and also to an NANP-only binder. Our data suggest that their protection ability may be related to the strong cross-reactivity with NANP epitopes. Since all reported junctional antibodies to date have dual-specificity, we suggest that a true junctional binder with no or very low NANP affinity, if one can be found, is essential to evaluate the contribution of the junctional epitope to protection. |
| Databáze: | OpenAIRE |
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