Antibody Targets on the Surface of Plasmodium Falciparum-Infected Erythrocytes That Are Associated With Immunity to Severe Malaria in Young Children

Overview

Journal J Infect Dis

Publisher Oxford University Press

Specialty Infectious Diseases

Date 2018 Oct 27

PMID 30365004

Citations 24

Authors

Jo-Anne Chan

Michelle J Boyle

Kerryn A Moore

Linda Reiling

Zaw Lin

Wina Hasang

Marion Avril

Laurens Manning

Ivo Mueller

Moses Laman

Timothy Davis

Joseph D Smith

Stephen J Rogerson

Julie A Simpson

Freya J I Fowkes

James G Beeson

Affiliations

Soon will be listed here.

Abstract

Background: Sequestration of Plasmodium falciparum-infected erythrocytes (IEs) in the microvasculature contributes to pathogenesis of severe malaria in children. This mechanism is mediated by antigens expressed on the IE surface. However, knowledge of specific targets and functions of antibodies to IE surface antigens that protect against severe malaria is limited.

Methods: Antibodies to IE surface antigens were examined in a case-control study of young children in Papua New Guinea presenting with severe or uncomplicated malaria (n = 448), using isolates with a virulent phenotype associated with severe malaria, and functional opsonic phagocytosis assays. We used genetically modified isolates and recombinant P. falciparum erythrocyte membrane protein 1 (PfEMP1) domains to quantify PfEMP1 as a target of antibodies associated with disease severity.

Results: Antibodies to the IE surface and recombinant PfEMP1 domains were significantly higher in uncomplicated vs severe malaria and were boosted following infection. The use of genetically modified P. falciparum revealed that PfEMP1 was a major target of antibodies and that PfEMP1-specific antibodies were associated with reduced odds of severe malaria. Furthermore, antibodies promoting the opsonic phagocytosis of IEs by monocytes were lower in those with severe malaria.

Conclusions: Findings suggest that PfEMP1 is a dominant target of antibodies associated with reduced risk of severe malaria, and function in part by promoting opsonic phagocytosis.

Citing Articles

Acquisition of Fc-afucosylation of PfEMP1-specific IgG is age-dependent and associated with clinical protection against malaria.

Lopez-Perez M, Seidu Z, Larsen M, Wang W, Nouta J, Wuhrer M Nat Commun. 2025; 16(1):237.

PMID: 39747065 PMC: 11696684. DOI: 10.1038/s41467-024-55543-w.

Antibodies to specific domains of erythrocyte membrane protein-1 and its relationship with protection from severe malarial anemia: A prospective study among Ghanaian children.

Nkansah C, Osei-Boakye F, Abbam G, Appiah S, Derigubah C, Bani S Health Sci Rep. 2024; 7(10):e70123.

PMID: 39385763 PMC: 11462291. DOI: 10.1002/hsr2.70123.

A systems serology approach to identifying key antibody correlates of protection from cerebral malaria in Malawian children.

Walker I, Dini S, Aitken E, Damelang T, Hasang W, Alemu A BMC Med. 2024; 22(1):388.

PMID: 39267089 PMC: 11396342. DOI: 10.1186/s12916-024-03604-8.

Hyper-diverse antigenic variation and resilience to transmission-reducing intervention in falciparum malaria.

Zhan Q, He Q, Tiedje K, Day K, Pascual M Nat Commun. 2024; 15(1):7343.

PMID: 39187488 PMC: 11347654. DOI: 10.1038/s41467-024-51468-6.

Antibodies to PfEMP1 and variant surface antigens: Protection after controlled human malaria infection in semi-immune Kenyan adults.

Kinyua A, Turner L, Kimingi H, Mwai K, Mwikali K, Andisi C J Infect. 2024; 89(4):106252.

PMID: 39182654 PMC: 11409615. DOI: 10.1016/j.jinf.2024.106252.

References

Claessens A, Adams Y, Ghumra A, Lindergard G, Buchan C, Andisi C . A subset of group A-like var genes encodes the malaria parasite ligands for binding to human brain endothelial cells. Proc Natl Acad Sci U S A. 2012; 109(26):E1772-81. PMC: 3387129. DOI: 10.1073/pnas.1120461109. View

Turner G, Morrison H, Jones M, Davis T, Looareesuwan S, Buley I . An immunohistochemical study of the pathology of fatal malaria. Evidence for widespread endothelial activation and a potential role for intercellular adhesion molecule-1 in cerebral sequestration. Am J Pathol. 1994; 145(5):1057-69. PMC: 1887431. View

Nilsson Bark S, Ahmad R, Dantzler K, Lukens A, De Niz M, Szucs M . Quantitative Proteomic Profiling Reveals Novel Surface Antigens and Possible Vaccine Candidates. Mol Cell Proteomics. 2017; 17(1):43-60. PMC: 5750850. DOI: 10.1074/mcp.RA117.000076. View

Ataide R, Hasang W, Wilson D, Beeson J, Mwapasa V, Molyneux M . Using an improved phagocytosis assay to evaluate the effect of HIV on specific antibodies to pregnancy-associated malaria. PLoS One. 2010; 5(5):e10807. PMC: 2876038. DOI: 10.1371/journal.pone.0010807. View

Lau C, Turner L, Jespersen J, Lowe E, Petersen B, Wang C . Structural conservation despite huge sequence diversity allows EPCR binding by the PfEMP1 family implicated in severe childhood malaria. Cell Host Microbe. 2014; 17(1):118-29. PMC: 4297295. DOI: 10.1016/j.chom.2014.11.007. View

Gupta S, Snow R, Donnelly C, Marsh K, Newbold C . Immunity to non-cerebral severe malaria is acquired after one or two infections. Nat Med. 1999; 5(3):340-3. DOI: 10.1038/6560. View

Travassos M, Niangaly A, Bailey J, Ouattara A, Coulibaly D, Lyke K . Children with cerebral malaria or severe malarial anaemia lack immunity to distinct variant surface antigen subsets. Sci Rep. 2018; 8(1):6281. PMC: 5908851. DOI: 10.1038/s41598-018-24462-4. View

Rottmann M, Lavstsen T, Mugasa J, Kaestli M, Jensen A, Muller D . Differential expression of var gene groups is associated with morbidity caused by Plasmodium falciparum infection in Tanzanian children. Infect Immun. 2006; 74(7):3904-11. PMC: 1489729. DOI: 10.1128/IAI.02073-05. View

Shabani E, Hanisch B, Opoka R, Lavstsen T, John C . Plasmodium falciparum EPCR-binding PfEMP1 expression increases with malaria disease severity and is elevated in retinopathy negative cerebral malaria. BMC Med. 2017; 15(1):183. PMC: 5639490. DOI: 10.1186/s12916-017-0945-y. View

10.

Jespersen J, Wang C, Mkumbaye S, Minja D, Petersen B, Turner L . Plasmodium falciparum var genes expressed in children with severe malaria encode CIDRα1 domains. EMBO Mol Med. 2016; 8(8):839-50. PMC: 4967939. DOI: 10.15252/emmm.201606188. View

11.

Lavstsen T, Salanti A, Jensen A, Arnot D, Theander T . Sub-grouping of Plasmodium falciparum 3D7 var genes based on sequence analysis of coding and non-coding regions. Malar J. 2003; 2:27. PMC: 222925. DOI: 10.1186/1475-2875-2-27. View

12.

Aikawa M . Human cerebral malaria. Am J Trop Med Hyg. 1988; 39(1):3-10. DOI: 10.4269/ajtmh.1988.39.3. View

13.

Pongponratn E, Riganti M, Punpoowong B, Aikawa M . Microvascular sequestration of parasitized erythrocytes in human falciparum malaria: a pathological study. Am J Trop Med Hyg. 1991; 44(2):168-75. DOI: 10.4269/ajtmh.1991.44.168. View

14.

Voss T, Healer J, Marty A, Duffy M, Thompson J, Beeson J . A var gene promoter controls allelic exclusion of virulence genes in Plasmodium falciparum malaria. Nature. 2005; 439(7079):1004-8. DOI: 10.1038/nature04407. View

15.

Abdi A, Hodgson S, Muthui M, Kivisi C, Kamuyu G, Kimani D . Plasmodium falciparum malaria parasite var gene expression is modified by host antibodies: longitudinal evidence from controlled infections of Kenyan adults with varying natural exposure. BMC Infect Dis. 2017; 17(1):585. PMC: 5569527. DOI: 10.1186/s12879-017-2686-0. View

16.

Griffin J, Hollingsworth T, Reyburn H, Drakeley C, Riley E, Ghani A . Gradual acquisition of immunity to severe malaria with increasing exposure. Proc Biol Sci. 2015; 282(1801):20142657. PMC: 4309004. DOI: 10.1098/rspb.2014.2657. View

17.

Chan J, Stanisic D, Duffy M, Robinson L, Lin E, Kazura J . Patterns of protective associations differ for antibodies to P. falciparum-infected erythrocytes and merozoites in immunity against malaria in children. Eur J Immunol. 2017; 47(12):2124-2136. PMC: 5893221. DOI: 10.1002/eji.201747032. View

18.

Rambhatla J, Turner L, Manning L, Laman M, Davis T, Beeson J . Acquisition of Antibodies Against Endothelial Protein C Receptor-Binding Domains of Plasmodium falciparum Erythrocyte Membrane Protein 1 in Children with Severe Malaria. J Infect Dis. 2018; 219(5):808-818. DOI: 10.1093/infdis/jiy564. View

19.

Reiling L, Richards J, Fowkes F, Barry A, Triglia T, Chokejindachai W . Evidence that the erythrocyte invasion ligand PfRh2 is a target of protective immunity against Plasmodium falciparum malaria. J Immunol. 2010; 185(10):6157-67. DOI: 10.4049/jimmunol.1001555. View

20.

Turner L, Lavstsen T, Mmbando B, Wang C, Magistrado P, Vestergaard L . IgG antibodies to endothelial protein C receptor-binding cysteine-rich interdomain region domains of Plasmodium falciparum erythrocyte membrane protein 1 are acquired early in life in individuals exposed to malaria. Infect Immun. 2015; 83(8):3096-103. PMC: 4496620. DOI: 10.1128/IAI.00271-15. View