scholarly journals High Levels of Antibodies to Multiple Domains and Strains of VAR2CSA Correlate with the Absence of Placental Malaria in Cameroonian Women Living in an Area of High Plasmodium falciparum Transmission

2012 ◽  
Vol 80 (4) ◽  
pp. 1479-1490 ◽  
Author(s):  
Yeung L. Tutterrow ◽  
Marion Avril ◽  
Kavita Singh ◽  
Carole A. Long ◽  
Robert J. Leke ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Chondroitin Sulfate ◽  
Malaria Transmission ◽  
Placental Malaria ◽  
Plasma Samples ◽  
High Antibody ◽  
Allelic Variants ◽  
Increased Risk ◽  
Antibody Levels ◽  
Chondroitin Sulfate A

ABSTRACTPlacental malaria, caused by sequestration ofPlasmodium falciparum-infected erythrocytes in the placenta, is associated with increased risk of maternal morbidity and poor birth outcomes. The parasite antigen VAR2CSA (variant surface antigen 2-chondroitin sulfate A) is expressed on infected erythrocytes and mediates binding to chondroitin sulfate A, initiating inflammation and disrupting homeostasis at the maternal-fetal interface. Although antibodies can prevent sequestration, it is unclear whether parasite clearance is due to antibodies to a single Duffy binding-like (DBL) domain or to an extensive repertoire of antibodies to multiple DBL domains and allelic variants. Accordingly, plasma samples collected longitudinally from pregnant women were screened for naturally acquired antibodies against an extensive panel of VAR2CSA proteins, including 2 to 3 allelic variants for each of 5 different DBL domains. Analyses were performed on plasma samples collected from 3 to 9 months of pregnancy from women living in areas in Cameroon with high and low malaria transmission. The results demonstrate that high antibody levels to multiple VAR2CSA domains, rather than a single domain, were associated with the absence of placental malaria when antibodies were present from early in the second trimester until term. Absence of placental malaria was associated with increasing antibody breadth to different DBL domains and allelic variants in multigravid women. Furthermore, the antibody responses of women in the lower-transmission site had both lower magnitude and lesser breadth than those in the high-transmission site. These data suggest that immunity to placental malaria results from high antibody levels to multiple VAR2CSA domains and allelic variants and that antibody breadth is influenced by malaria transmission intensity.

scholarly journals Antibodies That Inhibit Binding of Plasmodium falciparum-Infected Erythrocytes to Chondroitin Sulfate A and to the C Terminus of Merozoite Surface Protein 1 Correlate with Reduced Placental Malaria in Cameroonian Women

2004 ◽  
Vol 72 (3) ◽  
pp. 1603-1607 ◽  
Author(s):  
Diane Wallace Taylor ◽  
Aniong Zhou ◽  
Lauren E. Marsillio ◽  
Lucy W. Thuita ◽  
Efua B. Leke ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Chondroitin Sulfate ◽  
Placental Malaria ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Liver Stage ◽  
Merozoite Surface Protein 1 ◽  
Erythrocyte Surface ◽  
Antibody Levels ◽  
Chondroitin Sulfate A

ABSTRACT Plasmodium falciparum-infected erythrocytes often sequester in the placenta of pregnant women, producing placental malaria, a condition that can compromise the health of the developing fetus. Scientists are hopeful that a vaccine can be developed to prevent this condition. Immunological mechanisms responsible for eliminating parasites from the placenta remain unclear, but antibodies to the carboxyl-terminal 19-kDa segment of the merozoite surface protein 1 (MSP1-19), the ring-infected erythrocyte surface antigen (RESA), and an erythrocyte-surface ligand that binds chondroitin sulfate A (CSA-L) have been implicated. In addition, antibodies to sporozoite and liver-stage antigens could reduce initial parasite burdens. This study sought to determine if antibodies to the circumsporozoite protein (CSP), liver-stage antigen 1 (LSA1), RESA, MSP1-19, or CSA-L correlated with either the absence of placental parasites or low placental parasitemias. Using a frequency-matched case-control study design, we compared antibody levels in women (gravidity 1 to 11) with and without placental malaria. Results showed that women who were antibody negative for MSP1-19 were at a higher risk of having placental malaria than women with antibodies (P < 0.007). Furthermore, an association between high levels of antibodies that blocked the binding of infected erythrocytes to CSA and low placental parasitemias was observed (P = 0.02). On the other hand, women with high antibody levels at term to CSP, LSA1, and RESA were more likely to have placental malaria than antibody-negative women. Since antibodies to MSP1-19 and CSA-L were associated with reduced placental malaria, both antigens show promise for inclusion in a vaccine for women of child-bearing age.

scholarly journals Antibodies That Inhibit Plasmodium falciparum Adhesion to Chondroitin Sulfate A Are Associated with Increased Birth Weight and the Gestational Age of Newborns

2003 ◽  
Vol 71 (11) ◽  
pp. 6620-6623 ◽  
Author(s):  
Patrick E. Duffy ◽  
Michal Fried
Keyword(s):  
Plasmodium Falciparum ◽  
Birth Weight ◽  
Chondroitin Sulfate ◽  
Pregnancy Outcomes ◽  
Placental Malaria ◽  
Western Kenya ◽  
Antibody Levels ◽  
Pregnancy Malaria ◽  
Reduced Risk ◽  
Chondroitin Sulfate A

ABSTRACT Antibodies that inhibit Plasmodium falciparum adhesion to the placental receptor chondroitin sulfate A are associated with a reduced risk of placental malaria, but whether these antibodies lead to improved pregnancy outcomes is unknown. We measured antiadhesion antibody levels in parturient women in western Kenya, where malaria transmission is intense. Secundigravid women with antiadhesion activity in their plasma delivered babies that were on average 398 g heavier (P = 0.019) and 2 weeks more mature (P = 0.002) than babies delivered to secundigravidas without antiadhesion activity. Our findings support the development of antiadhesion vaccines to prevent poor fetal outcomes due to pregnancy malaria.

scholarly journals Antibodies to Escherichia coli-Expressed C-Terminal Domains of Plasmodium falciparum Variant Surface Antigen 2-Chondroitin Sulfate A (VAR2CSA) Inhibit Binding of CSA-Adherent Parasites to Placental Tissue

2013 ◽  
Vol 81 (4) ◽  
pp. 1031-1039 ◽  
Author(s):  
Tracy Saveria ◽  
Andrew V. Oleinikov ◽  
Kathryn Wiliamson ◽  
Richa Chaturvedi ◽  
Joe Lograsso ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Plasmodium Falciparum ◽  
Chondroitin Sulfate ◽  
Surface Antigen ◽  
Transmembrane Protein ◽  
Placental Malaria ◽  
Placental Tissue ◽  
Content Type ◽  
Variant Surface Antigen ◽  
Chondroitin Sulfate A

ABSTRACTPlacental malaria (PM) is characterized by infected erythrocytes (IEs) that selectively bind to chondroitin sulfate A (CSA) and sequester in placental tissue. Variant surface antigen 2-CSA (VAR2CSA), aPlasmodium falciparumerythrocyte membrane protein 1 (PfEMP1) protein family member, is expressed on the surface of placental IEs and mediates adherence to CSA on the surface of syncytiotrophoblasts. This transmembrane protein contains 6 Duffy binding-like (DBL) domains which might contribute to the specific adhesive properties of IEs. Here, we use laboratory isolate 3D7 VAR2CSA DBL domains expressed inEscherichia colito generate antibodies specific for this protein. Flow cytometry results showed that antibodies generated against DBL4ε, DBL5ε, DBL6ε, and tandem double domains of DBL4-DBL5 and DBL5-DBL6 all bind to placental parasite isolates and to lab strains selected for CSA binding but do not bind to children's parasites. Antisera to DBL4ε and to DBL5ε inhibit maternal IE binding to placental tissue in a manner comparable to that for plasma collected from multigravid women. These antibodies also inhibit binding to CSA of several field isolates derived from pregnant women, while antibodies to double domains do not enhance the functional immune response. These data support DBL4ε and DBL5ε as vaccine candidates for pregnancy malaria and demonstrate thatE. coliis a feasible tool for the large-scale manufacture of a vaccine based on these VAR2CSA domains.

scholarly journals Placental Malaria Diminishes Development of Antibody Responses to Plasmodium falciparum Epitopes in Infants Residing in an Area of Western Kenya Where P. falciparum Is Endemic

2005 ◽  
Vol 12 (3) ◽  
pp. 375-379 ◽  
Author(s):  
Phillip Cullison Bonner ◽  
Zhiyong Zhou ◽  
Lisa B. Mirel ◽  
John G. Ayisi ◽  
Ya Ping Shi ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Immune Responses ◽  
Immunoglobulin G ◽  
Placental Malaria ◽  
Antibody Responses ◽  
Plasma Samples ◽  
Western Kenya ◽  
The Difference ◽  
Antibody Levels

ABSTRACT To determine the effect of placental malaria (PM) infection on the development of antibody responses to malaria in infants, we measured immunoglobulin G levels to seven different Plasmodium falciparum epitopes by using plasma samples collected at monthly intervals from infants born to mothers with and without PM. Overall, PM was associated with diminished antibody levels to all of the epitopes tested, especially with infants aged ≥4 to 12 months, and the difference was statistically significant for four of the seven epitopes (P < 0.0035). These findings suggest that PM can negatively influence the development of immune responses to malaria in infants.

scholarly journals Development of Antibodies against Chondroitin Sulfate A-Adherent Plasmodium falciparum in Pregnant Women

1999 ◽  
Vol 67 (10) ◽  
pp. 5367-5371 ◽  
Author(s):  
Bertrand Maubert ◽  
Nadine Fievet ◽  
Germaine Tami ◽  
Michel Cot ◽  
Christian Boudin ◽  
...  
Keyword(s):  
Immune Response ◽  
Plasmodium Falciparum ◽  
Pregnant Women ◽  
Chondroitin Sulfate ◽  
Cross Sectional Study ◽  
Sectional Study ◽  
Parasite Strain ◽  
Cross Sectional ◽  
Increased Risk ◽  
Chondroitin Sulfate A

ABSTRACT In areas where Plasmodium falciparum is endemic, pregnant women are at increased risk for malaria, and this risk is greatest during the first pregnancy. The placenta sequesters parasites that are able to cytoadhere to chondroitin sulfate A (CSA), a molecule expressed by the placental syncytiotrophoblast, while parasites from a nonpregnant host do not bind to CSA. Cytoadherence is mediated by the expression of variants of the P. falciparum-erythrocyte membrane protein 1 family. Each member of this molecule family induces antibodies that specifically agglutinate infected erythrocytes and inhibit their cytoadherence ability. We investigated whether the higher susceptibility of primigravidae was related to the lack of immune response towards CSA-binding parasites. In a cross-sectional study, primigravidae delivering with a noninfected placenta were less likely to have antibodies agglutinating CSA-binding parasites than multigravidae (P < 0.01). In contrast, parasites from nonpregnant hosts were as likely to be recognized by the sera from women of various parities. In a longitudinal study, at 6 months of pregnancy, antibodies against CSA-binding parasites were present in 31.8% of primigravidae and in 76.9% of secundigravidae (P = 0.02). The antibodies against CSA-binding parasites inhibited the cytoadherence of a CSA-adherent parasite strain to the human placental trophoblast. Our data support the idea that the higher susceptibility of primiparae is related to a lack of a specific immune response to placental parasites.

scholarly journals The Chondroitin Sulfate A-binding Site of the VAR2CSA Protein Involves Multiple N-terminal Domains

2011 ◽  
Vol 286 (18) ◽  
pp. 15908-15917 ◽  
Author(s):  
Madeleine Dahlbäck ◽  
Lars M. Jørgensen ◽  
Morten A. Nielsen ◽  
Thomas M. Clausen ◽  
Sisse B. Ditlev ◽  
...  
Keyword(s):  
Chondroitin Sulfate ◽  
Binding Site ◽  
Placental Malaria ◽  
African Women ◽  
Major Health Problem ◽  
Major Health ◽  
Malaria During Pregnancy ◽  
High Parasite ◽  
Similar Affinity ◽  
Chondroitin Sulfate A

Malaria during pregnancy is a major health problem for African women. The disease is caused by Plasmodium falciparum malaria parasites, which accumulate in the placenta by adhering to chondroitin sulfate A (CSA). The interaction between infected erythrocytes and the placental receptor is mediated by a parasite expressed protein named VAR2CSA. A vaccine protecting pregnant women against placental malaria should induce antibodies inhibiting the interaction between VAR2CSA and CSA. Much effort has been put into defining the part of the 350 kDa VAR2CSA protein that is responsible for binding. It has been shown that full-length recombinant VAR2CSA binds specifically to CSA with high affinity, however to date no sub-fragment of VAR2CSA has been shown to interact with CSA with similar affinity or specificity. In this study, we used a biosensor technology to examine the binding properties of a panel of truncated VAR2CSA proteins. The experiments indicate that the core of the CSA-binding site is situated in three domains, DBL2X-CIDRPAM and a flanking domain, located in the N-terminal part of VAR2CSA. Furthermore, recombinant VAR2CSA subfragments containing this region elicit antibodies with high parasite adhesion blocking activity in animal immunization experiments.

scholarly journals Molecular characterization of Plasmodium falciparum PHISTb proteins as potential targets of naturally-acquired immunity against malaria

2020 ◽  
Vol 5 ◽  
pp. 136
Author(s):  
Tony I. Isebe ◽  
Joel L. Bargul ◽  
Bonface M. Gichuki ◽  
James M. Njunge ◽  
James Tuju ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Transmission ◽  
The Gambia ◽  
Antibody Responses ◽  
Transmission Intensity ◽  
Parasite Development ◽  
Natural Immunity ◽  
Malaria Transmission Intensity ◽  
Transmission Region ◽  
Antibody Levels

Background: Plasmodium falciparum causes the deadliest form of malaria in humans. Upon infection, the host’s infected red blood cells (iRBCs) are remodelled by exported parasite proteins in order to provide a niche for parasite development and maturation. Methods: Here we analysed the role of three PHISTb proteins Pf3D7_0532400, Pf3D7_1401600, and Pf3D7_1102500 by expressing recombinant proteins and evaluated antibody responses against these proteins using immune sera from malaria-exposed individuals from Kenya and The Gambia in Africa. Results: Our findings show that children and adults from malaria-endemic regions recognized the three PHISTb proteins. Responses against the PHISTb proteins varied with malaria transmission intensity in three different geographical sites in Kenya (Siaya and Takaungu) and The Gambia (Sukuta). Antibody responses against PHISTb antigens Pf3D7_1102500 and Pf3D7_1401600 were higher in Sukuta, a low transmission region in the Gambia, as compared to Siaya, a high transmission region in western Kenya, unlike Pf3D7_0532400. Anti-PHIST responses show a negative correlation between antibody levels and malaria transmission intensity for two PHIST antigens, Pf3D7_1102500 and Pf3D7_1401600. However, we report a correlation in antibody responses between schizont extract and Pf3D7_0532400 (p=0.00582). Acquisition of anti-PHIST antibodies was correlated with exposure to malaria for PHISTb protein Pf3D7_0532400 (p=0.009) but not the other PHIST antigens Pf3D7_1102500 and Pf3D7_1401600 (p=0.507 and p=0.15, respectively, CI=95%). Children aged below 2 years had the lowest antibody levels, but the responses do not correlate with age differences. Conclusions: Collectively, these findings provide evidence of natural immunity against PHISTb antigens that varies with level of malaria exposure and underscore potential for these parasite antigens as possible serological markers to P. falciparum infection aimed at contributing to malaria control through vaccine development.

scholarly journals Molecular basis for the dichotomy in Plasmodium falciparum adhesion to CD36 and chondroitin sulfate A

2002 ◽  
Vol 99 (15) ◽  
pp. 10020-10024 ◽  
Author(s):  
B. Gamain ◽  
S. Gratepanche ◽  
L. H. Miller ◽  
D. I. Baruch
Keyword(s):  
Plasmodium Falciparum ◽  
Chondroitin Sulfate ◽  
Molecular Basis ◽  
Chondroitin Sulfate A

Placenta cryosections for study of the adhesion of Plasmodium falciparum-infected erythrocytes to chondroitin sulfate A in flow conditions

2004 ◽  
Vol 6 (3) ◽  
pp. 249-255 ◽  
Author(s):  
Marion Avril ◽  
Boubacar Traoré ◽  
Fabio T.M. Costa ◽  
Catherine Lépolard ◽  
Jürg Gysin
Keyword(s):  
Plasmodium Falciparum ◽  
Chondroitin Sulfate ◽  
Flow Conditions ◽  
Chondroitin Sulfate A
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