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 Progress and Insights Toward an Effective Placental Malaria Vaccine

2021 ◽  
Vol 12 ◽  
Author(s):  
Benoît Gamain ◽  
Arnaud Chêne ◽  
Nicola K. Viebig ◽  
Nicaise Tuikue Ndam ◽  
Morten A. Nielsen
Keyword(s):  
Pregnant Women ◽  
Chondroitin Sulfate ◽  
Malaria Vaccine ◽  
Vaccine Development ◽  
Placental Malaria ◽  
Premature Delivery ◽  
Phase I Clinical Trials ◽  
Malaria Vaccines ◽  
Clinical Consequences ◽  
Chondroitin Sulfate A

In areas where Plasmodium falciparum transmission is endemic, clinical immunity against malaria is progressively acquired during childhood and adults are usually protected against the severe clinical consequences of the disease. Nevertheless, pregnant women, notably during their first pregnancies, are susceptible to placental malaria and the associated serious clinical outcomes. Placental malaria is characterized by the massive accumulation of P. falciparum infected erythrocytes and monocytes in the placental intervillous spaces leading to maternal anaemia, hypertension, stillbirth and low birth weight due to premature delivery, and foetal growth retardation. Remarkably, the prevalence of placental malaria sharply decreases with successive pregnancies. This protection is associated with the development of antibodies directed towards the surface of P. falciparum-infected erythrocytes from placental origin. Placental sequestration is mediated by the interaction between VAR2CSA, a member of the P. falciparum erythrocyte membrane protein 1 family expressed on the infected erythrocytes surface, and the placental receptor chondroitin sulfate A. VAR2CSA stands today as the leading candidate for a placental malaria vaccine. We recently reported the safety and immunogenicity of two VAR2CSA-derived placental malaria vaccines (PRIMVAC and PAMVAC), spanning the chondroitin sulfate A-binding region of VAR2CSA, in both malaria-naïve and P. falciparum-exposed non-pregnant women in two distinct Phase I clinical trials (ClinicalTrials.gov, NCT02658253 and NCT02647489). This review discusses recent advances in placental malaria vaccine development, with a focus on the recent clinical data, and discusses the next clinical steps to undertake in order to better comprehend vaccine-induced immunity and accelerate vaccine development.

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 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 Nonspecific Immunoglobulin M Binding and Chondroitin Sulfate A Binding Are Linked Phenotypes of Plasmodium falciparum Isolates Implicated in Malaria during Pregnancy

2003 ◽  
Vol 71 (8) ◽  
pp. 4767-4771 ◽  
Author(s):  
Alison M. Creasey ◽  
Trine Staalsoe ◽  
Ahmed Raza ◽  
David E. Arnot ◽  
J. Alexandra Rowe
Keyword(s):  
Plasmodium Falciparum ◽  
Chondroitin Sulfate ◽  
Blood Cells ◽  
Immunoglobulin M ◽  
Wide Range ◽  
Malaria During Pregnancy ◽  
Normal Human ◽  
Immunological Assays ◽  
Chondroitin Sulfate A ◽  
In Pregnancy

ABSTRACT Binding of immunoglobulin M (IgM) antibodies from normal human serum to the surface of Plasmodium falciparum-infected red blood cells (iRBC) has previously been demonstrated only in parasites that form rosettes with uninfected red cells. We show that natural, nonspecific IgM but not IgG, IgA, IgD, or IgE also binds to the surface of iRBC selected for adhesion to chondroitin sulfate A (CSA), a placental receptor for parasites associated with malaria in pregnancy. The protease sensitivity of IgM-binding appears to match that of CSA binding, suggesting that the two phenotypes may be mediated by the same parasite molecule. We also show that a wide range of mouse monoclonal antibodies of the IgM class bind nonspecifically to CSA-selected iRBC, an important consideration in the interpretation of immunological assays performed on these parasite lines.

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 Immunogenicity of Duffy Binding-Like Domains That Bind Chondroitin Sulfate A and Protection against Pregnancy-Associated Malaria

2006 ◽  
Vol 74 (10) ◽  
pp. 5955-5963 ◽  
Author(s):  
Nivedita Bir ◽  
Syed Shams Yazdani ◽  
Marion Avril ◽  
Corinne Layez ◽  
Jürg Gysin ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Chondroitin Sulfate ◽  
Protective Immunity ◽  
Binding Domains ◽  
Malaria During Pregnancy ◽  
Protective Antibodies ◽  
Chondroitin Sulfate A

ABSTRACTSequestration ofPlasmodium falciparum-infected erythrocytes in the placenta is implicated in pathological outcomes of pregnancy-associated malaria (PAM).P. falciparumisolates that sequester in the placenta primarily bind chondroitin sulfate A (CSA). Following exposure to malaria during pregnancy, women in areas of endemicity develop immunity, and so multigravid women are less susceptible to PAM than primigravidae. Protective immunity to PAM is associated with the development of antibodies that recognize diverse CSA-binding, placentalP. falciparumisolates. The epitopes recognized by such protective antibodies have not been identified but are likely to lie in conserved Duffy binding-like (DBL) domains, encoded byvargenes, that bind CSA. Immunization of mice with the CSA-binding DBL3γ domain encoded byvar1CSAelicits cross-reactive antibodies that recognize diverse CSA-bindingP. falciparumisolates and block their binding to placental cryosections under flow. However, CSA-binding isolates primarily expressvar2CSA, which does not encode any DBLγ domains. Here, we demonstrate that antibodies raised against DBL3γ encoded byvar1CSAcross-react with one of the CSA-binding domains, DBL3X, encoded byvar2CSA. This explains the paradoxical observation made here and earlier that anti-rDBL3γ sera recognize CSA-binding isolates and provides evidence for the presence of conserved, cross-reactive epitopes in diverse CSA-binding DBL domains. Such cross-reactive epitopes within CSA-binding DBL domains can form the basis for a vaccine that provides protection against PAM.

scholarly journals Cryo-EM reveals the architecture of placental malaria VAR2CSA and provides molecular insight into chondroitin sulfate binding

2021 ◽  
Author(s):  
Kaituo Wang ◽  
Robert Dagil ◽  
Thomas Lavstsen ◽  
Sandeep Misra ◽  
Charlotte Spliid ◽  
...  
Keyword(s):  
Chondroitin Sulfate ◽  
Rational Design ◽  
Immune Escape ◽  
Binding Capacity ◽  
Placental Malaria ◽  
Structural Features ◽  
Cancer Therapies ◽  
Major Health Problem ◽  
Malaria Vaccines ◽  
Dynamics Simulations

Abstract Malaria during pregnancy remains a major health problem in Plasmodium falciparum endemic areas. Parasite-infected red blood cells sequester in the placenta through interaction between parasite-expressed protein VAR2CSA and the glycosaminoglycan chondroitin sulfate A (CS) abundantly present in the intervillous space. Placental malaria can have severe consequences for both mother and child by causing maternal anemia, low birth weight and stillbirth. Several VAR2CSA-based vaccines have been developed and clinically tested but they have failed to induce an antibody response that effectively inhibits placental adhesion of different genetic variants of VAR2CSA. The interaction between VAR2CSA and CS represents a unique case of an evolution-driven high-affinity interaction between a protein and an oncofetal carbohydrate. Here, we report cryo-EM structures of the VAR2CSA ectodomain up to 3.1 Å resolution revealing an overall V-shaped architecture and a complex domain organization. Notably, the surface displays a single significantly electropositive patch, compatible with binding of negatively charged CS. Using molecular docking and molecular dynamics simulations as well as comparative hydroxyl radical protein foot-printing of VAR2CSA in complex with placental CS, we identify the CS-binding groove, intersecting with the positively charged patch of the central VAR2CSA structure. We identify distinctive conserved structural features upholding the macro-molecular domain complex and CS binding capacity of VAR2CSA as well as divergent elements possibly allowing immune escape at or near the CS binding site. These observations enable rational design of second-generation placental malaria vaccines eliciting broadly VAR2CSA-reactive antibodies and novel cancer therapies.

scholarly journals Structural and Functional Insight into How thePlasmodium falciparumVAR2CSA Protein Mediates Binding to Chondroitin Sulfate A in Placental Malaria

2012 ◽  
Vol 287 (28) ◽  
pp. 23332-23345 ◽  
Author(s):  
Thomas M. Clausen ◽  
Stig Christoffersen ◽  
Madeleine Dahlbäck ◽  
Annette Eva Langkilde ◽  
Kamilla E. Jensen ◽  
...  
Keyword(s):  
Chondroitin Sulfate ◽  
Placental Malaria ◽  
Insight Into ◽  
Chondroitin Sulfate A

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.

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