scholarly journals Analysis of Human Antibodies to Erythrocyte Binding Antigen 175 of Plasmodium falciparum

2000 ◽  
Vol 68 (10) ◽  
pp. 5559-5566 ◽  
Author(s):  
Daniel M. N. Okenu ◽  
Eleanor M. Riley ◽  
Quentin D. Bickle ◽  
Philip U. Agomo ◽  
Arnoldo Barbosa ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Recombinant Proteins ◽  
Large Population ◽  
Clinical Malaria ◽  
Ligand Interaction ◽  
Human Antibodies ◽  
Multistep Process ◽  
Erythrocyte Binding ◽  
Igg3 Subclass ◽  
Region Ii

ABSTRACT Invasion of human erythrocytes by Plasmodium falciparummerozoites is a multistep process. For many strains of the parasite, part of this process requires that the erythrocyte binding antigen 175 (EBA-175) of the merozoite binds to sialic acid residues of glycophorin A on the erythrocyte surface, a receptor-ligand interaction which represents a potential target for inhibition by antibodies. This study characterizes the reactivity of naturally acquired human antibodies with four recombinant proteins representing parts of EBA-175 (region II, regions III to V, and the dimorphic C and F segment region) in populations in which the organism is endemic. Serum immunoglobulin G (IgG) recognizing the recombinant proteins is predominantly of the IgG1 and IgG3 subclasses, and its prevalence increases with age. In a large population study in The Gambia, serum positivity for IgG or IgG1 and IgG3 subclass antibodies to each of the EBA-175 recombinant antigens was not significantly associated with subsequent protection from clinical malaria. However, there was a trend indicating that individuals with high levels of IgG to region II may have some protection.

Plasmodium falciparum EBA-175 kDa protein peptides which bind to human red blood cells

Parasitology ◽  
2000 ◽  
Vol 120 (3) ◽  
pp. 225-235 ◽  
Author(s):  
L. E. RODRIGUEZ ◽  
M. URQUIZA ◽  
M. OCAMPO ◽  
J. SUAREZ ◽  
H. CURTIDOR ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Binding Activity ◽  
Ligand Interaction ◽  
Merozoite Invasion ◽  
Human Red Blood Cells ◽  
Affinity Constants ◽  
Region I ◽  
Binding Peptides ◽  
V Region ◽  
Region Ii

Solid experimental evidence indicates that EBA-175 is used as a ligand by the Plasmodium falciparum merozoite to bind to human RBC, via different binding processing fragments. Using synthetic peptides and specific receptor-ligand interaction methodology, we have identified 6 high-activity binding sequences from the EBA-175 CAMP strain; peptide 1758 (KSYGTPDNIDKNMSLIHKHN), located in the so-called region I for which no binding activity has been reported before, peptides 1779 (NIDRIYDKNLLMIKEHILAI) and 1783 (HRNKKNDKLYRDEWWKVIKK), located in region II, in a sub-region known as 5′ Cys F2, previously reported as being a binding region, and peptides 1814 (DRNSNTLHLKDYRNEENERH), 1815 (YTNQNINISQERDLQKHGFH) and 1818 (NNNFNNIPSRYNLYDKKLDL), in region III–V where antibodies inhibit merozoite invasion of erythrocytes. The affinity constants were between 60 and 180 nM and the critical amino acids involved in the binding were identified. The binding of these peptides to enzyme-treated RBC was analysed; binding of peptide 1814, located in the III–V region, was found to be sialic acid dependent. Some of these high binding peptides were able to inhibit in vitro merozoite invasion and to block the binding of recombinant RII-EBA to RBC. Several of these peptides are located in regions recognized by protective immune clusters of merozoites (ICMs) eluted antibodies.

scholarly journals Antibodies to Plasmodium falciparum Erythrocyte-binding Antigen-175 are Associated With Protection From Clinical Malaria

2011 ◽  
Vol 30 (12) ◽  
pp. 1037-1042 ◽  
Author(s):  
Matthew B. McCarra ◽  
George Ayodo ◽  
Peter O. Sumba ◽  
James W. Kazura ◽  
Ann M. Moormann ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Clinical Malaria ◽  
Erythrocyte Binding

scholarly journals Measurement of Antibody Levels against Region II of the Erythrocyte-Binding Antigen 175 of Plasmodium falciparum in an Area of Malaria Holoendemicity in Western Kenya

2004 ◽  
Vol 72 (2) ◽  
pp. 735-741 ◽  
Author(s):  
Eunita A. Ohas ◽  
John H. Adams ◽  
John N. Waitumbi ◽  
Alloys S. S. Orago ◽  
Arnoldo Barbosa ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Sialic Acid ◽  
Inhibitory Activity ◽  
Western Kenya ◽  
Transmission Season ◽  
High Transmission ◽  
Exposed Population ◽  
Erythrocyte Binding ◽  
Antibody Levels ◽  
Region Ii

ABSTRACT Region II of the 175-kDa erythrocyte-binding antigen (EBA-175RII) of Plasmodium falciparum is functionally important in sialic acid-dependent erythrocyte invasion and is considered a prime target for an invasion-blocking vaccine. The objectives of this study were to (i) determine the prevalence of anti-EBA-175RII antibodies in a naturally exposed population, (ii) determine whether naturally acquired antibodies have a functional role by inhibiting binding of EBA-175RII to erythrocytes, and (iii) determine whether antibodies against EBA-175RII correlate with immunity to clinical malaria. We treated 301 lifelong residents of an area of malaria holoendemicity in western Kenya for malaria, monitored them during a high-transmission season, and identified 33 individuals who were asymptomatic despite parasitemia (clinically immune). We also identified 50 clinically susceptible individuals to serve as controls. These 83 individuals were treated and monitored again during the subsequent low-transmission season. Anti-EBA-175RII antibodies were present in 98.7% of the individuals studied. The antibody levels were relatively stable between the beginning and end of the high-transmission season and correlated with the plasma EBA-175RII erythrocyte-binding-inhibitory activity. There was no difference in anti-EBA-175RII levels or plasma EBA-175RII erythrocyte-binding-inhibitory activity between clinically immune and clinically susceptible groups. However, these parameters were higher in nonparasitemic than in parasitemic individuals at enrollment. These results suggest that although antibodies against EBA-175RII may be effective in suppressing some of the wild parasite strains, EBA-175RII is unlikely to be effective as a monovalent vaccine against malaria, perhaps due to allelic heterogeneity and/or presence of sialic acid-independent strains.

scholarly journals Invasion Profiles of Brazilian Field Isolates of Plasmodium falciparum: Phenotypic and Genotypic Analyses

2004 ◽  
Vol 72 (10) ◽  
pp. 5886-5891 ◽  
Author(s):  
Cheryl-Ann Lobo ◽  
Karla de Frazao ◽  
Marilis Rodriguez ◽  
Marion Reid ◽  
Mariano Zalis ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Invasion Pathways ◽  
Parasite Invasion ◽  
Specific Amino Acid ◽  
Field Isolates ◽  
Erythrocyte Invasion ◽  
Erythrocyte Binding ◽  
Normal Enzyme ◽  
Region Ii ◽  
Distinct Field

ABSTRACT The invasion of red blood cells (RBCs) by Plasmodium falciparum is dependent on multiple molecular interactions between erythrocyte receptors and parasite ligands. Invasion studies using culture-adapted parasite strains have indicated significant receptor heterogeneity. It is not known whether this heterogeneity reflects the parasite invasion arsenal in the field. We have studied the invasion phenotypes of 14 distinct field isolates from the Legal Amazon areas of Brazil by using erythrocyte invasion assays to investigate invasion into normal, enzyme-treated, and clinical-mutant RBCs. Analysis of these isolates revealed four distinct invasion profiles. Using En(a−) cells to get an unequivocal estimate of the use of glycophorin A (GPA) as a receptor, we found that the 175-kDa erythrocyte-binding antigen (EBA-175)/GPA pathway was used by a minority of the parasite isolates studied. Although polymorphism of region II domains at specific amino acid positions in both EBA-140 and EBA-181 was found in these field isolates, this did not correlate with invasion profiles and thus receptor selectivity. These studies have further confirmed the existence of a significant diversity of invasion pathways in nature and suggest that additional parasite ligands will have to be targeted to devise global vaccines that will work in the field.

Baculovirus-mediated expression of Plasmodium falciparum erythrocyte binding antigen 175 polypeptides and their recognition by human antibodies.

1997 ◽  
Vol 65 (9) ◽  
pp. 3631-3637 ◽  
Author(s):  
J R Daugherty ◽  
C I Murphy ◽  
L A Doros-Richert ◽  
A Barbosa ◽  
L O Kashala ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Human Antibodies ◽  
Erythrocyte Binding

scholarly journals Population Genetic Analysis of the Plasmodium Falciparum Erythrocyte Binding Antigen-175 (EBA-175) Gene in Equatorial Guinea

2021 ◽  
Author(s):  
Pei-Kui Yang ◽  
Xue-Yan Liang ◽  
Min Lin ◽  
Jiang-Tao Chen ◽  
Hui-Ying Huang ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Plasmodium Falciparum ◽  
Natural Selection ◽  
Malaria Vaccine ◽  
Blood Stage ◽  
Equatorial Guinea ◽  
Bioko Island ◽  
Erythrocyte Binding ◽  
Region Ii ◽  
Blood Stage Malaria

Abstract Background: Plasmodium falciparum erythrocyte binding antigen-175 (PfEBA-175) is a candidate antigen for a blood-stage malaria vaccine, while various polymorphisms in the PfEBA-175 gene among global P. falciparum populations have prevented the development of effective vaccines based on this gene. At the same time, the dimorphism of the F- and C-fragments associated with high endemic of severe malaria has been described. This study aimed to investigate the dimorphism of PfEBA-175 on both the Bioko island and continent of Equatorial Guinea, as well as the genetic polymorphism and natural selection of global PfEBA-175.Methods: A total of 218 blood samples were collected from patients with P. falciparum malaria on Bioko Island and Bata district in 2018 and 2019. The allelic dimorphism of PfEBA-175 region II was investigated by nested polymerase chain reaction and sequencing. Polymorphic characteristics and the effect of natural selection were analyzed using MEGA 7.0, DnaSP 6.0 and PopART programs. Genetic diversity in 312 global PfEBA-175 region II sequences was also analyzed. Protein function prediction of new amino acid mutation sites was performed using PolyPhen-2 and Foldx program.Results: Allelic dimorphism of PfEBA-175 was identified in the study area, and the frequency of the F-fragment was higher than that of the C-fragment in both Bioko Island and Bata district populations. Additionally, single infections (87.80%) were more frequent than mixed infections (12.20%). A total of 49 monoclonal PfEBA-175 region II sequences of Bioko Island and Bata district were sequenced successfully. PfEBA-175 of Bioko Island and Bata district isolates showed a high degree of genetic variability and heterogeneity, with π values of 0.00407 & 0.00411 and Hd values of 0.958 & 0.976 for nucleotide diversity, respectively. The values of Tajima's D of PfEBA-175 on Bata district and Bioko Island were 0.56395 and -0.27018, respectively. Globally, PfEBA-175 isolates from Asia were more diverse than those from Africa and South America, and genetic differentiation quantified by the fixation index between Asian and South American countries populations was significant (Fst>0.15, P<0.05). A total of 312 global isolates clustered in 92 haplotypes, and only one cluster contained isolates from three continents. The mutations A34T, K109E, D278Y, K301N, L305V and D329N were predicted as probably damaging by PolyPhen-2. Among them, mutations A34T, K301N and L305V led to significant increases in the free energy difference (ΔΔG>1), indicating destabilization of the protein structure.Conclusions: This study proved the dimorphism of PfEBA-175, and also demonstrated that the F-fragment was remarkably predominant in the study area. The distribution patterns and genetic diversity of PfEBA-175 in Equatorial Guinea isolates were similar to those of isolates worldwide. High levels of recombination events were observed in PfEBA-175 isolates globally, suggesting that natural selection and intragenic recombination might be the main drivers of genetic diversity in global PfEBA-175. These results have important reference value for the development of blood-stage malaria vaccine based on this antigen.

scholarly journals Cytophilic Immunoglobulin Responses to Plasmodium falciparum Glutamate-Rich Protein Are Correlated with Protection against Clinical Malaria in Dielmo, Senegal

2000 ◽  
Vol 68 (5) ◽  
pp. 2617-2620 ◽  
Author(s):  
Claude Oeuvray ◽  
Michael Theisen ◽  
Christophe Rogier ◽  
Jean-Francois Trape ◽  
Søren Jepsen ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Protective Immunity ◽  
Clinical Malaria ◽  
Parasite Growth ◽  
Antibody Responses ◽  
Plasma Samples ◽  
Confounding Effect ◽  
Human Antibodies ◽  
Age Related ◽  
Effect Of Age

ABSTRACT The goal of this study was to analyze antibody responses toPlasmodium falciparum glutamate-rich protein (GLURP) using clinical data and plasma samples obtained from villagers of Dielmo, Senegal. This molecule was chosen because it is targeted by human antibodies which induce parasite growth inhibition in antibody-dependent cellular inhibition (ADCI) assays. The results showed a strong correlation between protection against malaria attacks and levels of immunoglobulin G2 (IgG2) and IgG3 against GLURP94–489 (R0) and IgG3 against GLURP705–1178 (R2) when corrected for the confounding effect of age-related exposure to malaria. Thus, GLURP may play a role in the induction of protective immunity against P. falciparum malaria.

scholarly journals Antibodies against the Plasmodium falciparum Receptor Binding Domain of EBA-175 Block Invasion Pathways That Do Not Involve Sialic Acids

2000 ◽  
Vol 68 (4) ◽  
pp. 1964-1966 ◽  
Author(s):  
David L. Narum ◽  
J. David Haynes ◽  
Steven Fuhrmann ◽  
Kathy Moch ◽  
Hong Liang ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Growth Inhibition ◽  
Sialic Acids ◽  
Parasite Development ◽  
Invasion Pathways ◽  
Neuraminidase Treatment ◽  
Erythrocyte Binding ◽  
Vitro Analysis ◽  
Region Ii

ABSTRACT The 175-kDa Plasmodium falciparum erythrocyte binding protein (EBA-175) binds to its receptor, sialic acids on glycophorin A. The binding region within EBA-175 is a cysteine-rich region identified as region II. Antibodies against region II block the binding of native EBA-175 to erythrocytes. We identified a P. falciparum strain, FVO, that could not invade erythrocytes devoid of sialic acids due to prior neuraminidase treatment, and in addition, we used a strain, 3D7, that could invade such sialic acid-depleted erythrocytes. We used these two strains to study the capacity of anti-region II antibodies to inhibit FVO and 3D7 parasite development in vitro. Analysis of growth-inhibitory effects of purified FVO anti-region II immunoglobulin G (IgG) with the FVO and 3D7 strains resulted in similar levels of growth inhibition. FVO and 3D7 strains were inhibited between 28 and 56% compared to control IgG. There appeared to be no intracellular growth retardation or killing of either isolate, suggesting that invasion was indeed inhibited. Incubation of recombinant region II with anti-region II IgG reversed the growth inhibition. These results suggest that antibodies against region II can also interfere with merozoite invasion pathways that do not involve sialic acids. The fact that EBA-175 has such a universal and yet susceptible role in erythrocyte invasion clearly supports its inclusion in a multivalent malaria vaccine.

scholarly journals Polymorphisms in Erythrocyte Binding Antigens 140 and 181 Affect Function and Binding but Not Receptor Specificity in Plasmodium falciparum

2009 ◽  
Vol 77 (4) ◽  
pp. 1689-1699 ◽  
Author(s):  
Alexander G. Maier ◽  
Jake Baum ◽  
Brian Smith ◽  
David J. Conway ◽  
Alan F. Cowman
Keyword(s):  
Plasmodium Falciparum ◽  
Cell Receptor ◽  
Receptor Interaction ◽  
Glycophorin A ◽  
Sequence Variability ◽  
Receptor Specificity ◽  
Binding Domains ◽  
Erythrocyte Binding ◽  
Glycophorin C ◽  
Region Ii

ABSTRACT Invasion of human erythrocytes by the malaria parasite Plasmodium falciparum utilizes multiple ligand-receptor interactions involving erythrocyte receptors and parasite erythrocyte binding proteins of the Duffy binding-like family. Erythrocyte binding antigen 175 (EBA-175) binds to glycophorin A, the most abundant protein on the human erythrocyte surface and EBA-140 (also known as BAEBL) binds to glycophorin C, while the receptor for EBA-181 (also known as JESEBL) remains unknown. EBA binding is mediated via region II, a highly structured extracellular domain that shows a degree of sequence variability between different laboratory strains/isolates. Here, we determined the influence of region II polymorphisms on host cell receptor binding and overall function during invasion of EBA-140, EBA-175, and EBA-181. Polymorphisms in the binding domains of EBA-140 and EBA-181 have been suggested previously to alter their respective receptor specificities. In our hands, these polymorphisms affected the levels of EBA-140 and EBA-181 binding to receptors but, critically, not the receptor specificities of these proteins. The degree of EBA-140 binding to glycophorin C correlates with the level of function for this ligand-receptor interaction in merozoite invasion. In contrast, EBA-175, which is highly polymorphic in region II, shows no variability in its ability to bind to its receptor, glycophorin A. Combined, these data highlight the importance of sequence variability in EBAs as driven by immune selection but not by receptor specificity.

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