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

ABSTRACT Recent evidence suggests that pregnancy-associated malaria (PAM), associated with maternal anemia and low birth weight, results from preferential sequestration of parasitized red blood cells (pRBC) in the placenta via binding of variant surface antigens (VSA) expressed on the surface of pRBC to chondroitin sulfate A (CSA). The VSA mediating CSA binding (VSACSA) and thus sequestration of pRBC in the placenta are antigenically distinct from those that mediate pRBC sequestration elsewhere in the body, and it has been suggested that VSACSA are relatively conserved and may thus constitute an attractive target for vaccination against PAM. Using flow cytometry, levels of antibody to VSA and VSACSA expressed on the surface of red blood cells infected with Plasmodium falciparum isolates were measured during pregnancy and lactation in Ghanaian primigravid women enrolled in a trial of maternal vitamin A supplementation. Antibody responses to VSACSA were detected within the first trimester of pregnancy and increased with increasing duration of pregnancy, and they seemed to be isolate specific, indicating that different CSA-adherent parasite lines express antigenically distinct VSA and thus may not be as antigenically conserved as has been previously suggested. Levels of anti-VSACSA were not significantly associated with placental malarial infection determined by histology, indicating that primary immune responses to VSACSA may not be sufficient to eradicate placental parasitemia in primigravidae.

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Neonatal and Maternal Immunological Responses to Conserved Epitopes within the DBL-γ3 Chondroitin Sulfate A-Binding Domain of Plasmodium falciparum Erythrocyte Membrane Protein 1

Infection and Immunity ◽

10.1128/iai.73.12.7988-7995.2005 ◽

2005 ◽

Vol 73 (12) ◽

pp. 7988-7995 ◽

Cited By ~ 17

Author(s):

Kim Brustoski ◽

Martin Kramer ◽

Ulrike Möller ◽

Peter G. Kremsner ◽

Adrian J. F. Luty

Keyword(s):

T Cells ◽

Plasmodium Falciparum ◽

Membrane Protein ◽

Chondroitin Sulfate ◽

Erythrocyte Membrane ◽

Venous Blood ◽

Binding Domain ◽

Erythrocyte Membrane Protein ◽

Conserved Regions ◽

Chondroitin Sulfate A

ABSTRACT Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) mediates the adherence of P. falciparum-infected erythrocytes to placental syncytiotrophoblasts via interactions with chondroitin sulfate A (CSA), a characteristic of pregnancy-associated malaria. Pregnancy-associated malaria predicts increased susceptibility of newborns to malaria, and it is postulated that transplacental passage of parasite antigen induces immune regulatory activity in the neonate. We wished to examine the immune responsiveness to a CSA-binding domain of PfEMP1, the DBL-γ3 domain, in cord and maternal venous blood obtained from pregnancies with various histories of P. falciparum infection. We assessed in vitro T-cell cytokine and plasma immunoglobulin G (IgG) and IgM responses to four peptides corresponding to highly conserved regions of a DBL-γ3 domain common to central African parasite isolates. The presence of placental P. falciparum infection at delivery was associated with elevated frequencies of DBL-γ3 peptide-specific CD3+ interleukin-10-positive T cells in cord blood, while treatment and clearance of infection prior to delivery was associated with elevated frequencies of CD3+ gamma interferon-positive T cells. DBL-γ3 peptide-specific IgM antibodies were detected in 12 of 60 (20%) cord plasma samples from those born to mothers with P. falciparum infection during pregnancy. Consistent with polyclonal anti-PfEMP1 antibody responses that are associated with protection against pregnancy-associated malaria, the presence of maternal IgG antibodies with specificity for one of the DBL-γ3 peptides showed a parity-dependent profile. These data demonstrate that peptides corresponding to conserved regions of the DBL-γ3 domain of PfEMP1 are immunogenic in P. falciparum-infected mothers and their offspring.

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Plasmodium falciparum-infected Red Blood Cells Selected for Binding to Cultured Syncytiotrophoblast Bind to Chondroitin Sulfate A and Induce Tyrosine Phosphorylation in the Syncytiotrophoblast

Placenta ◽

10.1016/j.placenta.2005.04.009 ◽

2006 ◽

Vol 27 (4-5) ◽

pp. 384-394 ◽

Cited By ~ 29

Author(s):

N.W. Lucchi ◽

R. Koopman ◽

D.S. Peterson ◽

J.M. Moore

Keyword(s):

Plasmodium Falciparum ◽

Red Blood Cells ◽

Chondroitin Sulfate ◽

Tyrosine Phosphorylation ◽

Blood Cells ◽

Chondroitin Sulfate A

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Chondroitin Sulfate A is a Receptor for Plasmodium falciparum-Infected Erythrocyies

Trends in Glycoscience and Glycotechnology ◽

10.4052/tigg.9.299 ◽

1997 ◽

Vol 9 (47) ◽

pp. 299-300

Author(s):

M. Ishihara

Keyword(s):

Plasmodium Falciparum ◽

Chondroitin Sulfate ◽

Chondroitin Sulfate A

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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

Infection and Immunity ◽

10.1128/iai.00978-12 ◽

2013 ◽

Vol 81 (4) ◽

pp. 1031-1039 ◽

Cited By ~ 8

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.

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