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PreMalStruct


Structural analysis of the CSA binding interactions involved during pregnancy associated malaria
 
 
Framework programme:
7
Contract/Grant agreement number:
201222
EC contribution:
2,300,000 €
Duration:
36 months
Funding scheme:
Collaborative project Small or medium-scale focused research project
Starting date:
01/02/2008
Project Web site:
http://www.premalstruct.org
 

Keywords: Pregnancy; Malaria; vaccine; structure; drug

Background

Women become more susceptible to severe Plasmodium falciparum infections during their first pregnancy. Pregnancy-associated malaria (PAM) is coupled with massive accumulation of parasitised erythrocytes in the placental intervillous blood spaces, contributing to disease and death in pregnant women and developing infants. Prevention may be possible by vaccinating women before their first pregnancy. Adhesion of P. falciparum-infected erythrocytes (PE) to placental chondroitin-4-sulfate (CSA) has been linked to the severe disease outcome of PAM.

After one or two pregnancies, transcendent antibodies that recognise placental PEs from different geographic regions develop and correlate with protection from malaria. Antibodies against CSA-binding parasites are associated with maternal malaria resistance after multiple pregnancies and also block CSA-binding of placental isolates from different parts of the world, demonstrating the concept of a transcending immune response to the P. falciparum ligands that mediate adhesion to CSA.

These findings suggest that the surface molecule(s) expressed by placental variants have conserved antigenic determinants, thus spurring efforts to characterise them in order to induce protective antibodies by vaccination.

Recent evidence strongly suggests that var2CSA, a member of the P. falciparum Erythrocyte Membrane protein 1 (PfEMP1) family, may play an important role in PAM and immunity. Although var2CSA is the main candidate for a pregnancy malaria vaccine, experimental evidence implies that antigenic polymorphism and the lack of a small animal in vivo experimental model may pose a challenge for vaccine development.

It is vital that research deciphers the molecular basis for the CSA binding to the parasite ligands in order to define the common features within the different CSA-binding domains and the cross-reactive epitopes that are likely to be the targets of natural protective antibodies. This knowledge will be helpful in the design of novel PfEMP1-CSA-based antigens capable of inducing broad and potent neutralising antibodies to a wide variety of strains, and in identifying molecules with inhibitory capacity that could be considered for therapeutic strategies as anti-adhesive drugs.

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