NadA3 Structures Reveal Undecad Coiled Coils and LOX1 Binding Regions Competed by Meningococcus B Vaccine-Elicited Human Antibodies

ABSTRACT Neisseria meningitidis serogroup B (MenB) is a major cause of sepsis and invasive meningococcal disease. A multicomponent vaccine, 4CMenB, is approved for protection against MenB. Neisserial adhesin A (NadA) is one of the main vaccine antigens, acts in host cell adhesion, and may influence...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Alessia Liguori, Lucia Dello Iacono, Giulietta Maruggi, Barbara Benucci, Marcello Merola, Paola Lo Surdo, Jacinto López-Sagaseta, Mariagrazia Pizza, Enrico Malito, Matthew J. Bottomley
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	LOX-1 receptor neisserial adhesin A monoclonal antibody epitopes three-dimensional structure vaccine antigen Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/27786e9b8cd34730b7b46d70ceb020ba
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:27786e9b8cd34730b7b46d70ceb020ba
record_format	dspace
spelling	oai:doaj.org-article:27786e9b8cd34730b7b46d70ceb020ba2021-11-15T15:58:20ZNadA3 Structures Reveal Undecad Coiled Coils and LOX1 Binding Regions Competed by Meningococcus B Vaccine-Elicited Human Antibodies10.1128/mBio.01914-182150-7511https://doaj.org/article/27786e9b8cd34730b7b46d70ceb020ba2018-11-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01914-18https://doaj.org/toc/2150-7511ABSTRACT Neisseria meningitidis serogroup B (MenB) is a major cause of sepsis and invasive meningococcal disease. A multicomponent vaccine, 4CMenB, is approved for protection against MenB. Neisserial adhesin A (NadA) is one of the main vaccine antigens, acts in host cell adhesion, and may influence colonization and invasion. Six major genetic variants of NadA exist and can be classified into immunologically distinct groups I and II. Knowledge of the crystal structure of the 4CMenB vaccine component NadA3 (group I) would improve understanding of its immunogenicity, folding, and functional properties and might aid antigen design. Here, X-ray crystallography, biochemical, and cellular studies were used to deeply characterize NadA3. The NadA3 crystal structure is reported; it revealed two unexpected regions of undecad coiled-coil motifs and other conformational differences from NadA5 (group II) not predicted by previous analyses. Structure-guided engineering was performed to increase NadA3 thermostability, and a second crystal structure confirmed the improved packing. Functional NadA3 residues mediating interactions with human receptor LOX-1 were identified. Also, for two protective vaccine-elicited human monoclonal antibodies (5D11, 12H11), we mapped key NadA3 epitopes. These vaccine-elicited human MAbs competed binding of NadA3 to LOX-1, suggesting their potential to inhibit host-pathogen colonizing interactions. The data presented provide a significant advance in the understanding of the structure, immunogenicity and function of NadA, one of the main antigens of the multicomponent meningococcus B vaccine. IMPORTANCE The bacterial microbe Neisseria meningitidis serogroup B (MenB) is a major cause of devastating meningococcal disease. An approved multicomponent vaccine, 4CMenB, protects against MenB. Neisserial adhesin A (NadA) is a key vaccine antigen and acts in host cell-pathogen interactions. We investigated the 4CMenB vaccine component NadA3 in order to improve the understanding of its immunogenicity, structure, and function and to aid antigen design. We report crystal structures of NadA3, revealing unexpected structural motifs, and other conformational differences from the NadA5 orthologue studied previously. We performed structure-based antigen design to engineer increased NadA3 thermostability. Functional NadA3 residues mediating interactions with the human receptor LOX-1 and vaccine-elicited human antibodies were identified. These antibodies competed binding of NadA3 to LOX-1, suggesting their potential to inhibit host-pathogen colonizing interactions. Our data provide a significant advance in the overall understanding of the 4CMenB vaccine antigen NadA.Alessia LiguoriLucia Dello IaconoGiulietta MaruggiBarbara BenucciMarcello MerolaPaola Lo SurdoJacinto López-SagasetaMariagrazia PizzaEnrico MalitoMatthew J. BottomleyAmerican Society for MicrobiologyarticleLOX-1 receptorneisserial adhesin Amonoclonal antibody epitopesthree-dimensional structurevaccine antigenMicrobiologyQR1-502ENmBio, Vol 9, Iss 5 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	LOX-1 receptor neisserial adhesin A monoclonal antibody epitopes three-dimensional structure vaccine antigen Microbiology QR1-502
spellingShingle	LOX-1 receptor neisserial adhesin A monoclonal antibody epitopes three-dimensional structure vaccine antigen Microbiology QR1-502 Alessia Liguori Lucia Dello Iacono Giulietta Maruggi Barbara Benucci Marcello Merola Paola Lo Surdo Jacinto López-Sagaseta Mariagrazia Pizza Enrico Malito Matthew J. Bottomley NadA3 Structures Reveal Undecad Coiled Coils and LOX1 Binding Regions Competed by Meningococcus B Vaccine-Elicited Human Antibodies
description	ABSTRACT Neisseria meningitidis serogroup B (MenB) is a major cause of sepsis and invasive meningococcal disease. A multicomponent vaccine, 4CMenB, is approved for protection against MenB. Neisserial adhesin A (NadA) is one of the main vaccine antigens, acts in host cell adhesion, and may influence colonization and invasion. Six major genetic variants of NadA exist and can be classified into immunologically distinct groups I and II. Knowledge of the crystal structure of the 4CMenB vaccine component NadA3 (group I) would improve understanding of its immunogenicity, folding, and functional properties and might aid antigen design. Here, X-ray crystallography, biochemical, and cellular studies were used to deeply characterize NadA3. The NadA3 crystal structure is reported; it revealed two unexpected regions of undecad coiled-coil motifs and other conformational differences from NadA5 (group II) not predicted by previous analyses. Structure-guided engineering was performed to increase NadA3 thermostability, and a second crystal structure confirmed the improved packing. Functional NadA3 residues mediating interactions with human receptor LOX-1 were identified. Also, for two protective vaccine-elicited human monoclonal antibodies (5D11, 12H11), we mapped key NadA3 epitopes. These vaccine-elicited human MAbs competed binding of NadA3 to LOX-1, suggesting their potential to inhibit host-pathogen colonizing interactions. The data presented provide a significant advance in the understanding of the structure, immunogenicity and function of NadA, one of the main antigens of the multicomponent meningococcus B vaccine. IMPORTANCE The bacterial microbe Neisseria meningitidis serogroup B (MenB) is a major cause of devastating meningococcal disease. An approved multicomponent vaccine, 4CMenB, protects against MenB. Neisserial adhesin A (NadA) is a key vaccine antigen and acts in host cell-pathogen interactions. We investigated the 4CMenB vaccine component NadA3 in order to improve the understanding of its immunogenicity, structure, and function and to aid antigen design. We report crystal structures of NadA3, revealing unexpected structural motifs, and other conformational differences from the NadA5 orthologue studied previously. We performed structure-based antigen design to engineer increased NadA3 thermostability. Functional NadA3 residues mediating interactions with the human receptor LOX-1 and vaccine-elicited human antibodies were identified. These antibodies competed binding of NadA3 to LOX-1, suggesting their potential to inhibit host-pathogen colonizing interactions. Our data provide a significant advance in the overall understanding of the 4CMenB vaccine antigen NadA.
format	article
author	Alessia Liguori Lucia Dello Iacono Giulietta Maruggi Barbara Benucci Marcello Merola Paola Lo Surdo Jacinto López-Sagaseta Mariagrazia Pizza Enrico Malito Matthew J. Bottomley
author_facet	Alessia Liguori Lucia Dello Iacono Giulietta Maruggi Barbara Benucci Marcello Merola Paola Lo Surdo Jacinto López-Sagaseta Mariagrazia Pizza Enrico Malito Matthew J. Bottomley
author_sort	Alessia Liguori
title	NadA3 Structures Reveal Undecad Coiled Coils and LOX1 Binding Regions Competed by Meningococcus B Vaccine-Elicited Human Antibodies
title_short	NadA3 Structures Reveal Undecad Coiled Coils and LOX1 Binding Regions Competed by Meningococcus B Vaccine-Elicited Human Antibodies
title_full	NadA3 Structures Reveal Undecad Coiled Coils and LOX1 Binding Regions Competed by Meningococcus B Vaccine-Elicited Human Antibodies
title_fullStr	NadA3 Structures Reveal Undecad Coiled Coils and LOX1 Binding Regions Competed by Meningococcus B Vaccine-Elicited Human Antibodies
title_full_unstemmed	NadA3 Structures Reveal Undecad Coiled Coils and LOX1 Binding Regions Competed by Meningococcus B Vaccine-Elicited Human Antibodies
title_sort	nada3 structures reveal undecad coiled coils and lox1 binding regions competed by meningococcus b vaccine-elicited human antibodies
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/27786e9b8cd34730b7b46d70ceb020ba
work_keys_str_mv	AT alessialiguori nada3structuresrevealundecadcoiledcoilsandlox1bindingregionscompetedbymeningococcusbvaccineelicitedhumanantibodies AT luciadelloiacono nada3structuresrevealundecadcoiledcoilsandlox1bindingregionscompetedbymeningococcusbvaccineelicitedhumanantibodies AT giuliettamaruggi nada3structuresrevealundecadcoiledcoilsandlox1bindingregionscompetedbymeningococcusbvaccineelicitedhumanantibodies AT barbarabenucci nada3structuresrevealundecadcoiledcoilsandlox1bindingregionscompetedbymeningococcusbvaccineelicitedhumanantibodies AT marcellomerola nada3structuresrevealundecadcoiledcoilsandlox1bindingregionscompetedbymeningococcusbvaccineelicitedhumanantibodies AT paolalosurdo nada3structuresrevealundecadcoiledcoilsandlox1bindingregionscompetedbymeningococcusbvaccineelicitedhumanantibodies AT jacintolopezsagaseta nada3structuresrevealundecadcoiledcoilsandlox1bindingregionscompetedbymeningococcusbvaccineelicitedhumanantibodies AT mariagraziapizza nada3structuresrevealundecadcoiledcoilsandlox1bindingregionscompetedbymeningococcusbvaccineelicitedhumanantibodies AT enricomalito nada3structuresrevealundecadcoiledcoilsandlox1bindingregionscompetedbymeningococcusbvaccineelicitedhumanantibodies AT matthewjbottomley nada3structuresrevealundecadcoiledcoilsandlox1bindingregionscompetedbymeningococcusbvaccineelicitedhumanantibodies
_version_	1718427019273830400

NadA3 Structures Reveal Undecad Coiled Coils and LOX1 Binding Regions Competed by Meningococcus B Vaccine-Elicited Human Antibodies

Ejemplares similares