Human antibodies activate complement against Plasmodium falciparum sporozoites, and are associated with protection against malaria in children
Abstract 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 corre...
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doaj-5ea9b6e4dbcf409ca298b0588593785c2020-11-24T22:11:27ZengBMCBMC Medicine1741-70152018-04-0116111710.1186/s12916-018-1054-2Human antibodies activate complement against Plasmodium falciparum sporozoites, and are associated with protection against malaria in childrenLiriye Kurtovic0Marije C. Behet1Gaoqian Feng2Linda Reiling3Kiprotich Chelimo4Arlene E. Dent5Ivo Mueller6James W. Kazura7Robert W. Sauerwein8Freya J. I. Fowkes9James G. Beeson10Burnet InstituteDepartment of Medical Microbiology, Radboud University Medical CenterBurnet InstituteBurnet InstituteKenya Medical Research InstituteCenter for Global Health and Diseases, Case Western UniversityDivision of Population Health and Immunity, Walter and Eliza Hall InstituteCenter for Global Health and Diseases, Case Western UniversityDepartment of Medical Microbiology, Radboud University Medical CenterBurnet InstituteBurnet InstituteAbstract 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.http://link.springer.com/article/10.1186/s12916-018-1054-2AntibodiesCircumsporozoite proteinSporozoiteComplementMalariaPlasmodium falciparum |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Liriye Kurtovic Marije C. Behet Gaoqian Feng Linda Reiling Kiprotich Chelimo Arlene E. Dent Ivo Mueller James W. Kazura Robert W. Sauerwein Freya J. I. Fowkes James G. Beeson |
spellingShingle |
Liriye Kurtovic Marije C. Behet Gaoqian Feng Linda Reiling Kiprotich Chelimo Arlene E. Dent Ivo Mueller James W. Kazura Robert W. Sauerwein Freya J. I. Fowkes James G. Beeson Human antibodies activate complement against Plasmodium falciparum sporozoites, and are associated with protection against malaria in children BMC Medicine Antibodies Circumsporozoite protein Sporozoite Complement Malaria Plasmodium falciparum |
author_facet |
Liriye Kurtovic Marije C. Behet Gaoqian Feng Linda Reiling Kiprotich Chelimo Arlene E. Dent Ivo Mueller James W. Kazura Robert W. Sauerwein Freya J. I. Fowkes James G. Beeson |
author_sort |
Liriye Kurtovic |
title |
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_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_sort |
human antibodies activate complement against plasmodium falciparum sporozoites, and are associated with protection against malaria in children |
publisher |
BMC |
series |
BMC Medicine |
issn |
1741-7015 |
publishDate |
2018-04-01 |
description |
Abstract 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. |
topic |
Antibodies Circumsporozoite protein Sporozoite Complement Malaria Plasmodium falciparum |
url |
http://link.springer.com/article/10.1186/s12916-018-1054-2 |
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