Role of the Antigen Capture Pathway in the Induction of a Neutralizing Antibody Response to Anthrax Protective Antigen

ABSTRACT Toxin neutralizing antibodies represent the major mode of protective immunity against a number of toxin-mediated bacterial diseases, including anthrax; however, the cellular mechanisms that lead to optimal neutralizing antibody responses remain ill defined. Here we show that the cellular bi...

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Autores principales:	Anita Verma, Miriam M. Ngundi, Gregory A. Price, Kazuyo Takeda, James Yu, Drusilla L. Burns
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	anthrax protective antigen antigen capture neutralizing antibodies toxin neutralization Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/7cec29e401294f60999abd85e8cfa46e
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spelling	oai:doaj.org-article:7cec29e401294f60999abd85e8cfa46e2021-11-15T15:53:25ZRole of the Antigen Capture Pathway in the Induction of a Neutralizing Antibody Response to Anthrax Protective Antigen10.1128/mBio.00209-182150-7511https://doaj.org/article/7cec29e401294f60999abd85e8cfa46e2018-03-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00209-18https://doaj.org/toc/2150-7511ABSTRACT Toxin neutralizing antibodies represent the major mode of protective immunity against a number of toxin-mediated bacterial diseases, including anthrax; however, the cellular mechanisms that lead to optimal neutralizing antibody responses remain ill defined. Here we show that the cellular binding pathway of anthrax protective antigen (PA), the binding component of anthrax toxin, determines the toxin neutralizing antibody response to this antigen. PA, which binds cellular receptors and efficiently enters antigen-presenting cells by receptor-mediated endocytosis, was found to elicit robust anti-PA IgG and toxin neutralizing antibody responses. In contrast, a receptor binding-deficient mutant of PA, which does not bind receptors and only inefficiently enters antigen-presenting cells by macropinocytosis, elicited very poor antibody responses. A chimeric protein consisting of the receptor binding-deficient PA mutant tethered to the binding subunit of cholera toxin, which efficiently enters cells using the cholera toxin receptor rather than the PA receptor, elicited an anti-PA IgG antibody response similar to that elicited by wild-type PA; however, the chimeric protein elicited a poor toxin neutralizing antibody response. Taken together, our results demonstrate that the antigen capture pathway can dictate the magnitudes of the total IgG and toxin neutralizing antibody responses to PA as well as the ratio of the two responses. IMPORTANCE Neutralizing antibodies provide protection against a number of toxin-mediated bacterial diseases by inhibiting toxin action. Therefore, many bacterial vaccines are designed to induce a toxin neutralizing antibody response. We have used protective antigen (PA), the binding component of anthrax toxin, as a model antigen to investigate immune mechanisms important for the induction of robust toxin neutralizing antibody responses. We found that the pathway used by antigen-presenting cells to capture PA dictates the robustness of the neutralizing antibody response to this antigen. These results provide new insights into immune mechanisms that play an important role in the induction of toxin neutralizing antibody responses and may be useful in the design of new vaccines against toxin-mediated bacterial diseases.Anita VermaMiriam M. NgundiGregory A. PriceKazuyo TakedaJames YuDrusilla L. BurnsAmerican Society for Microbiologyarticleanthrax protective antigenantigen captureneutralizing antibodiestoxin neutralizationMicrobiologyQR1-502ENmBio, Vol 9, Iss 1 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	anthrax protective antigen antigen capture neutralizing antibodies toxin neutralization Microbiology QR1-502
spellingShingle	anthrax protective antigen antigen capture neutralizing antibodies toxin neutralization Microbiology QR1-502 Anita Verma Miriam M. Ngundi Gregory A. Price Kazuyo Takeda James Yu Drusilla L. Burns Role of the Antigen Capture Pathway in the Induction of a Neutralizing Antibody Response to Anthrax Protective Antigen
description	ABSTRACT Toxin neutralizing antibodies represent the major mode of protective immunity against a number of toxin-mediated bacterial diseases, including anthrax; however, the cellular mechanisms that lead to optimal neutralizing antibody responses remain ill defined. Here we show that the cellular binding pathway of anthrax protective antigen (PA), the binding component of anthrax toxin, determines the toxin neutralizing antibody response to this antigen. PA, which binds cellular receptors and efficiently enters antigen-presenting cells by receptor-mediated endocytosis, was found to elicit robust anti-PA IgG and toxin neutralizing antibody responses. In contrast, a receptor binding-deficient mutant of PA, which does not bind receptors and only inefficiently enters antigen-presenting cells by macropinocytosis, elicited very poor antibody responses. A chimeric protein consisting of the receptor binding-deficient PA mutant tethered to the binding subunit of cholera toxin, which efficiently enters cells using the cholera toxin receptor rather than the PA receptor, elicited an anti-PA IgG antibody response similar to that elicited by wild-type PA; however, the chimeric protein elicited a poor toxin neutralizing antibody response. Taken together, our results demonstrate that the antigen capture pathway can dictate the magnitudes of the total IgG and toxin neutralizing antibody responses to PA as well as the ratio of the two responses. IMPORTANCE Neutralizing antibodies provide protection against a number of toxin-mediated bacterial diseases by inhibiting toxin action. Therefore, many bacterial vaccines are designed to induce a toxin neutralizing antibody response. We have used protective antigen (PA), the binding component of anthrax toxin, as a model antigen to investigate immune mechanisms important for the induction of robust toxin neutralizing antibody responses. We found that the pathway used by antigen-presenting cells to capture PA dictates the robustness of the neutralizing antibody response to this antigen. These results provide new insights into immune mechanisms that play an important role in the induction of toxin neutralizing antibody responses and may be useful in the design of new vaccines against toxin-mediated bacterial diseases.
format	article
author	Anita Verma Miriam M. Ngundi Gregory A. Price Kazuyo Takeda James Yu Drusilla L. Burns
author_facet	Anita Verma Miriam M. Ngundi Gregory A. Price Kazuyo Takeda James Yu Drusilla L. Burns
author_sort	Anita Verma
title	Role of the Antigen Capture Pathway in the Induction of a Neutralizing Antibody Response to Anthrax Protective Antigen
title_short	Role of the Antigen Capture Pathway in the Induction of a Neutralizing Antibody Response to Anthrax Protective Antigen
title_full	Role of the Antigen Capture Pathway in the Induction of a Neutralizing Antibody Response to Anthrax Protective Antigen
title_fullStr	Role of the Antigen Capture Pathway in the Induction of a Neutralizing Antibody Response to Anthrax Protective Antigen
title_full_unstemmed	Role of the Antigen Capture Pathway in the Induction of a Neutralizing Antibody Response to Anthrax Protective Antigen
title_sort	role of the antigen capture pathway in the induction of a neutralizing antibody response to anthrax protective antigen
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/7cec29e401294f60999abd85e8cfa46e
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Role of the Antigen Capture Pathway in the Induction of a Neutralizing Antibody Response to Anthrax Protective Antigen

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