Structural basis for antibody binding to adenylate cyclase toxin reveals RTX linkers as neutralization-sensitive epitopes.

RTX leukotoxins are a diverse family of prokaryotic virulence factors that are secreted by the type 1 secretion system (T1SS) and target leukocytes to subvert host defenses. T1SS substrates all contain a C-terminal RTX domain that mediates recruitment to the T1SS and drives secretion via a Brownian...

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Autores principales:	Jory A Goldsmith, Andrea M DiVenere, Jennifer A Maynard, Jason S McLellan
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/3057eb12420046989f002dc99abb491f
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spelling	oai:doaj.org-article:3057eb12420046989f002dc99abb491f2021-12-02T20:00:08ZStructural basis for antibody binding to adenylate cyclase toxin reveals RTX linkers as neutralization-sensitive epitopes.1553-73661553-737410.1371/journal.ppat.1009920https://doaj.org/article/3057eb12420046989f002dc99abb491f2021-09-01T00:00:00Zhttps://doi.org/10.1371/journal.ppat.1009920https://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374RTX leukotoxins are a diverse family of prokaryotic virulence factors that are secreted by the type 1 secretion system (T1SS) and target leukocytes to subvert host defenses. T1SS substrates all contain a C-terminal RTX domain that mediates recruitment to the T1SS and drives secretion via a Brownian ratchet mechanism. Neutralizing antibodies against the Bordetella pertussis adenylate cyclase toxin, an RTX leukotoxin essential for B. pertussis colonization, have been shown to target the RTX domain and prevent binding to the αMβ2 integrin receptor. Knowledge of the mechanisms by which antibodies bind and neutralize RTX leukotoxins is required to inform structure-based design of bacterial vaccines, however, no structural data are available for antibody binding to any T1SS substrate. Here, we determine the crystal structure of an engineered RTX domain fragment containing the αMβ2-binding site bound to two neutralizing antibodies. Notably, the receptor-blocking antibodies bind to the linker regions of RTX blocks I-III, suggesting they are key neutralization-sensitive sites within the RTX domain and are likely involved in binding the αMβ2 receptor. As the engineered RTX fragment contained these key epitopes, we assessed its immunogenicity in mice and showed that it elicits similar neutralizing antibody titers to the full RTX domain. The results from these studies will support the development of bacterial vaccines targeting RTX leukotoxins, as well as next-generation B. pertussis vaccines.Jory A GoldsmithAndrea M DiVenereJennifer A MaynardJason S McLellanPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 17, Iss 9, p e1009920 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Jory A Goldsmith Andrea M DiVenere Jennifer A Maynard Jason S McLellan Structural basis for antibody binding to adenylate cyclase toxin reveals RTX linkers as neutralization-sensitive epitopes.
description	RTX leukotoxins are a diverse family of prokaryotic virulence factors that are secreted by the type 1 secretion system (T1SS) and target leukocytes to subvert host defenses. T1SS substrates all contain a C-terminal RTX domain that mediates recruitment to the T1SS and drives secretion via a Brownian ratchet mechanism. Neutralizing antibodies against the Bordetella pertussis adenylate cyclase toxin, an RTX leukotoxin essential for B. pertussis colonization, have been shown to target the RTX domain and prevent binding to the αMβ2 integrin receptor. Knowledge of the mechanisms by which antibodies bind and neutralize RTX leukotoxins is required to inform structure-based design of bacterial vaccines, however, no structural data are available for antibody binding to any T1SS substrate. Here, we determine the crystal structure of an engineered RTX domain fragment containing the αMβ2-binding site bound to two neutralizing antibodies. Notably, the receptor-blocking antibodies bind to the linker regions of RTX blocks I-III, suggesting they are key neutralization-sensitive sites within the RTX domain and are likely involved in binding the αMβ2 receptor. As the engineered RTX fragment contained these key epitopes, we assessed its immunogenicity in mice and showed that it elicits similar neutralizing antibody titers to the full RTX domain. The results from these studies will support the development of bacterial vaccines targeting RTX leukotoxins, as well as next-generation B. pertussis vaccines.
format	article
author	Jory A Goldsmith Andrea M DiVenere Jennifer A Maynard Jason S McLellan
author_facet	Jory A Goldsmith Andrea M DiVenere Jennifer A Maynard Jason S McLellan
author_sort	Jory A Goldsmith
title	Structural basis for antibody binding to adenylate cyclase toxin reveals RTX linkers as neutralization-sensitive epitopes.
title_short	Structural basis for antibody binding to adenylate cyclase toxin reveals RTX linkers as neutralization-sensitive epitopes.
title_full	Structural basis for antibody binding to adenylate cyclase toxin reveals RTX linkers as neutralization-sensitive epitopes.
title_fullStr	Structural basis for antibody binding to adenylate cyclase toxin reveals RTX linkers as neutralization-sensitive epitopes.
title_full_unstemmed	Structural basis for antibody binding to adenylate cyclase toxin reveals RTX linkers as neutralization-sensitive epitopes.
title_sort	structural basis for antibody binding to adenylate cyclase toxin reveals rtx linkers as neutralization-sensitive epitopes.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/3057eb12420046989f002dc99abb491f
work_keys_str_mv	AT joryagoldsmith structuralbasisforantibodybindingtoadenylatecyclasetoxinrevealsrtxlinkersasneutralizationsensitiveepitopes AT andreamdivenere structuralbasisforantibodybindingtoadenylatecyclasetoxinrevealsrtxlinkersasneutralizationsensitiveepitopes AT jenniferamaynard structuralbasisforantibodybindingtoadenylatecyclasetoxinrevealsrtxlinkersasneutralizationsensitiveepitopes AT jasonsmclellan structuralbasisforantibodybindingtoadenylatecyclasetoxinrevealsrtxlinkersasneutralizationsensitiveepitopes
_version_	1718375712630505472

Structural basis for antibody binding to adenylate cyclase toxin reveals RTX linkers as neutralization-sensitive epitopes.

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