Opsonic phagocytosis of Plasmodium falciparum merozoites: mechanism in human immunity and a correlate of protection against malaria

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Abstract

Background

An understanding of the mechanisms mediating protective immunity against malaria in humans is currently lacking, but critically important to advance the development of highly efficacious vaccines. Antibodies play a key role in acquired immunity, but the functional basis for their protective effect remains unclear. Furthermore, there is a strong need for immune correlates of protection against malaria to guide vaccine development.

Methods

Using a validated assay to measure opsonic phagocytosis of Plasmodium falciparum merozoites, we investigated the potential role of this functional activity in human immunity against clinical episodes of malaria in two independent cohorts (n = 109 and n = 287) experiencing differing levels of malaria transmission and evaluated its potential as a correlate of protection.

Results

Antibodies promoting opsonic phagocytosis of merozoites were cytophilic immunoglobulins (IgG1 and IgG3), induced monocyte activation and production of pro-inflammatory cytokines, and were directed against major merozoite surface proteins (MSPs). Consistent with protective immunity in humans, opsonizing antibodies were acquired with increasing age and malaria exposure, were boosted on re-infection, and levels were related to malaria transmission intensity. Opsonic phagocytosis was strongly associated with a reduced risk of clinical malaria in longitudinal studies in children with current or recent infections. In contrast, antibodies to the merozoite surface in standard immunoassays, or growth-inhibitory antibodies, were not significantly associated with protection. In multivariate analyses including several antibody responses, opsonic phagocytosis remained significantly associated with protection against malaria, highlighting its potential as a correlate of immunity. Furthermore, we demonstrate that human antibodies against MSP2 and MSP3 that are strongly associated with protection in this population are effective in opsonic phagocytosis of merozoites, providing a functional link between these antigen-specific responses and protection for the first time.

Conclusions

Opsonic phagocytosis of merozoites appears to be an important mechanism contributing to protective immunity in humans. The opsonic phagocytosis assay appears to be a strong correlate of protection against malaria, a valuable biomarker of immunity, and provides a much-needed new tool for assessing responses to blood-stage malaria vaccines and measuring immunity in populations.

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Most cited references 46

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Gamma-globulin and acquired immunity to human malaria.

S. Cohen, I A McGregor, S Carrington (1961)

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Parasitologic and clinical human response to immunoglobulin administration in falciparum malaria.

Arunee Sabchareon, Hasnaa Bouharoun-Tayoun, Tan Chongsuphajaisiddhi … (1991)

The protective effect of African IgG antibodies against Plasmodium falciparum malaria was investigated by passive transfer in Thai patients. Sera from 333 African adults were collected in the Cote d'Ivoire and subjected to extensive screening. One hundred fifty-three samples were discarded for safety reasons, and IgG was extracted from those remaining under conditions allowing their use by the intravenous (iv) route. Eight Thai patients with P. falciparum parasitemia were treated by iv inoculation of the IgG: six with a 100 mg/kg dose given over three days, one with a single 20 mg/kg dose, and one with a single 200 mg/kg dose. To ensure a safety margin of at least 48 hours, subjects were chosen among patients having a recrudescent parasitemia following quinine treatment failure at the RI level. At that stage, symptoms were mild or absent and parasitemia was low but increasing (range 4, 200-9,000/microliters). The IgG pool exerted a profound, stage-specific, but non-sterilizing effect on each of the strains tested, and proved to be safe. Asexual parasitemia decreased by a mean 728-fold (range 46-1,086), while gametocytes were unaffected. Clearance of parasites and symptoms was as fast or faster than with drugs, and was consistent in the eight patients treated, suggesting that target antigens were equally expressed in geographically remote isolates. In peripheral blood smears, no mature forms were seen at any time during the followup, which does not support the hypothesis that reversal of cytoadherence occurred. After the disappearance of the transferred antibodies, recrudescent parasites from three patients were found to be susceptible to the same extent (mean decrease of 1,310-fold) to the same IgG preparation, indicating that selection of parasites able to escape the effect of antibodies had not occurred. No adverse side-effects were detected during the followup, which lasted one year.

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Isolation of viable Plasmodium falciparum merozoites to define erythrocyte invasion events and advance vaccine and drug development.

Michelle J. Boyle, Danny Wilson, Jack Richards … (2010)

During blood-stage infection by Plasmodium falciparum, merozoites invade RBCs. Currently there is limited knowledge of cellular and molecular invasion events, and no established assays are available to readily measure and quantify invasion-inhibitory antibodies or compounds for vaccine and drug studies. We report the isolation of viable merozoites that retain their invasive capacity, at high purity and yield, purified by filtration of highly synchronous populations of schizonts. We show that the half-life of merozoite invasive capacity after rupture is 5 min at 37 degrees C, and 15 min at room temperature. Studying the kinetics of invasion revealed that 80% of invasion events occur within 10 min of mixing merozoites and RBCs. Invasion efficiency was maximum at low merozoite-to-RBC ratios and occurred efficiently in the absence of serum and with high concentrations of dialyzed nonimmune serum. We developed and optimized an invasion assay by using purified merozoites that enabled invasion-inhibitory activity of antibodies and compounds to be measured separately from other mechanisms of growth inhibition; the assay was more sensitive for detecting inhibitory activity than established growth-inhibition assays. Furthermore, with the use of purified merozoites it was possible to capture and fix merozoites at different stages of invasion for visualization by immunofluorescence microscopy and EM. We thereby demonstrate that processing of the major merozoite antigen merozoite surface protein-1 occurs at the time of RBC invasion. These findings have important implications for defining invasion events and molecular interactions, understanding immune interactions, and identifying and evaluating inhibitors to advance vaccine and drug development.

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Author and article information

Contributors

Faith HA Osier

Gaoqian Feng

Michelle J Boyle

Christine Langer

Jingling Zhou

Jack S Richards

Fiona J McCallum

Linda Reiling

Anthony Jaworowski

Robin F Anders

Kevin Marsh

James G Beeson

Journal

Journal ID (nlm-ta): BMC Med

Journal ID (iso-abbrev): BMC Med

Title: BMC Medicine

Publisher: BioMed Central

ISSN (Electronic): 1741-7015

Publication date Collection: 2014

Publication date (Electronic): 1 July 2014

Volume: 12

Page: 108

Affiliations

[1 ]KEMRI Centre for Geographic Medicine Research-Coast, Kilifi, Kenya

[2 ]Centre for Biomedical Research, The Burnet Institute, 85 Commercial Road, 3004 Melbourne, Victoria, Australia

[3 ]Australian Army Malaria Institute, Enoggera, Queensland, Australia

[4 ]Department of Biochemistry, La Trobe University, Melbourne, Australia

[5 ]Department of Microbiology, Monash University, Wellington Rd, Clayton, VIC 3800, Australia

Article

Publisher ID: 1741-7015-12-108

DOI: 10.1186/1741-7015-12-108

PMC ID: 4098671

PubMed ID: 24980799

SO-VID: bfb48605-b4f0-491e-89b8-7a1a4e78d5c7

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. 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.

History

Date received : 16 March 2014

Date accepted : 6 June 2014

Comments

Camila França wrote:

Malaria vaccine development collection topic 2) Plasmodium life-cycle and immunological responses.

See: https://www.scienceopen.com/collection/malariavaccine

Our understanding of the mechanisms mediating protective immunity against malaria is still incomplete. This is, however, critically important to advance the development of highly efficacious vaccines.

This study by Osier and colleagues showing that opsonic phagocytosis of merozoites is an important mechanism contributing to protective immunity in humans represents a big step forward in our understanding of how antibodies mediate protection. In addition to contributing to the development of efficacious vaccines, this knowledge is also useful as a correlate of protective/effective immunity, which can be helpful to distinguish between immune and susceptible individuals.

2018-10-03 18:27 UTC

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Opsonic phagocytosis of Plasmodium falciparum merozoites: mechanism in human immunity and a correlate of protection against malaria

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Abstract

Background

Methods

Results

Conclusions

Related collections

Malaria vaccine development

Most cited references 46

Gamma-globulin and acquired immunity to human malaria.

Parasitologic and clinical human response to immunoglobulin administration in falciparum malaria.

Isolation of viable Plasmodium falciparum merozoites to define erythrocyte invasion events and advance vaccine and drug development.

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Cited by 118