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Human antibodies activate complement against Plasmodium falciparum sporozoites, and are associated with protection against malaria in children

BACKGROUND: Antibodies targeting Plasmodium falciparum sporozoites play a key role in human immunity to malaria. However, antibody mechanisms that neutralize sporozoites are poorly understood. This has been a major constraint in developing highly efficacious vaccines, as we lack strong correlates of...

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Autores principales: Kurtovic, Liriye, Behet, Marije C., Feng, Gaoqian, Reiling, Linda, Chelimo, Kiprotich, Dent, Arlene E., Mueller, Ivo, Kazura, James W., Sauerwein, Robert W., Fowkes, Freya J. I., Beeson, James G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5925837/
https://www.ncbi.nlm.nih.gov/pubmed/29706136
http://dx.doi.org/10.1186/s12916-018-1054-2
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author Kurtovic, Liriye
Behet, Marije C.
Feng, Gaoqian
Reiling, Linda
Chelimo, Kiprotich
Dent, Arlene E.
Mueller, Ivo
Kazura, James W.
Sauerwein, Robert W.
Fowkes, Freya J. I.
Beeson, James G.
author_facet Kurtovic, Liriye
Behet, Marije C.
Feng, Gaoqian
Reiling, Linda
Chelimo, Kiprotich
Dent, Arlene E.
Mueller, Ivo
Kazura, James W.
Sauerwein, Robert W.
Fowkes, Freya J. I.
Beeson, James G.
author_sort Kurtovic, Liriye
collection PubMed
description BACKGROUND: Antibodies targeting Plasmodium falciparum sporozoites play a key role in human immunity to malaria. However, antibody mechanisms that neutralize sporozoites are poorly understood. This has been a major constraint in developing highly efficacious vaccines, as we lack strong correlates of protective immunity. METHODS: We quantified the ability of human antibodies from malaria-exposed populations to interact with human complement, examined the functional effects of complement activity against P. falciparum sporozoites in vitro, and identified targets of functional antibodies. In children and adults from malaria-endemic regions, we determined the acquisition of complement-fixing antibodies to sporozoites and their relationship with antibody isotypes and subclasses. We also investigated associations with protective immunity in a longitudinal cohort of children (n = 206) residing in a malaria-endemic region. RESULTS: We found that antibodies to the major sporozoite surface antigen, circumsporozoite protein (CSP), were predominately IgG1, IgG3, and IgM, and could interact with complement through recruitment of C1q and activation of the classical pathway. The central repeat region of CSP, included in leading vaccines, was a key target of complement-fixing antibodies. We show that antibodies activate human complement on P. falciparum sporozoites, which consequently inhibited hepatocyte cell traversal that is essential for establishing liver-stage infection, and led to sporozoite death in vitro. The natural acquisition of complement-fixing antibodies in malaria-exposed populations was age-dependent, and was acquired more slowly to sporozoite antigens than to merozoite antigens. In a longitudinal cohort of children, high levels of complement-fixing antibodies were significantly associated with protection against clinical malaria. CONCLUSIONS: These novel findings point to complement activation by antibodies as an important mechanism of anti-sporozoite human immunity, thereby enabling new strategies for developing highly efficacious malaria vaccines. We also present evidence that complement-fixing antibodies may be a valuable correlate of protective immunity in humans. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12916-018-1054-2) contains supplementary material, which is available to authorized users.
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spelling pubmed-59258372018-05-01 Human antibodies activate complement against Plasmodium falciparum sporozoites, and are associated with protection against malaria in children Kurtovic, Liriye Behet, Marije C. Feng, Gaoqian Reiling, Linda Chelimo, Kiprotich Dent, Arlene E. Mueller, Ivo Kazura, James W. Sauerwein, Robert W. Fowkes, Freya J. I. Beeson, James G. BMC Med Research Article BACKGROUND: Antibodies targeting Plasmodium falciparum sporozoites play a key role in human immunity to malaria. However, antibody mechanisms that neutralize sporozoites are poorly understood. This has been a major constraint in developing highly efficacious vaccines, as we lack strong correlates of protective immunity. METHODS: We quantified the ability of human antibodies from malaria-exposed populations to interact with human complement, examined the functional effects of complement activity against P. falciparum sporozoites in vitro, and identified targets of functional antibodies. In children and adults from malaria-endemic regions, we determined the acquisition of complement-fixing antibodies to sporozoites and their relationship with antibody isotypes and subclasses. We also investigated associations with protective immunity in a longitudinal cohort of children (n = 206) residing in a malaria-endemic region. RESULTS: We found that antibodies to the major sporozoite surface antigen, circumsporozoite protein (CSP), were predominately IgG1, IgG3, and IgM, and could interact with complement through recruitment of C1q and activation of the classical pathway. The central repeat region of CSP, included in leading vaccines, was a key target of complement-fixing antibodies. We show that antibodies activate human complement on P. falciparum sporozoites, which consequently inhibited hepatocyte cell traversal that is essential for establishing liver-stage infection, and led to sporozoite death in vitro. The natural acquisition of complement-fixing antibodies in malaria-exposed populations was age-dependent, and was acquired more slowly to sporozoite antigens than to merozoite antigens. In a longitudinal cohort of children, high levels of complement-fixing antibodies were significantly associated with protection against clinical malaria. CONCLUSIONS: These novel findings point to complement activation by antibodies as an important mechanism of anti-sporozoite human immunity, thereby enabling new strategies for developing highly efficacious malaria vaccines. We also present evidence that complement-fixing antibodies may be a valuable correlate of protective immunity in humans. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12916-018-1054-2) contains supplementary material, which is available to authorized users. BioMed Central 2018-04-30 /pmc/articles/PMC5925837/ /pubmed/29706136 http://dx.doi.org/10.1186/s12916-018-1054-2 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Kurtovic, Liriye
Behet, Marije C.
Feng, Gaoqian
Reiling, Linda
Chelimo, Kiprotich
Dent, Arlene E.
Mueller, Ivo
Kazura, James W.
Sauerwein, Robert W.
Fowkes, Freya J. I.
Beeson, James G.
Human antibodies activate complement against Plasmodium falciparum sporozoites, and are associated with protection against malaria in children
title Human antibodies activate complement against Plasmodium falciparum sporozoites, and are associated with protection against malaria in children
title_full Human antibodies activate complement against Plasmodium falciparum sporozoites, and are associated with protection against malaria in children
title_fullStr Human antibodies activate complement against Plasmodium falciparum sporozoites, and are associated with protection against malaria in children
title_full_unstemmed Human antibodies activate complement against Plasmodium falciparum sporozoites, and are associated with protection against malaria in children
title_short Human antibodies activate complement against Plasmodium falciparum sporozoites, and are associated with protection against malaria in children
title_sort human antibodies activate complement against plasmodium falciparum sporozoites, and are associated with protection against malaria in children
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5925837/
https://www.ncbi.nlm.nih.gov/pubmed/29706136
http://dx.doi.org/10.1186/s12916-018-1054-2
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