By managing to express the protein that enables red blood cells infected with the malaria agent Plasmodium falciparum to bind to the placenta and by deciphering its molecular mechanisms, a team of researchers from CNRS and the Institut Pasteur has taken an important first step in the development of a vaccine against pregnancy-associated malaria. Their work was published in the journal PNAS.
In endemic areas where malaria is rife, the main victims are children less than three years old. This is because adults acquire, in the course of their lives, an immunity that protects them against the parasite. However, pregnant women, especially during a first pregnancy, have potentially fatal reactions to P. falciparum. The parasites also prevent exchanges of gases and nutrients through the placenta, thereby leading to spontaneous abortions, premature deliveries and newborn babies with too low birth weight, which are serious conditions in countries where infantile mortality is very high in the first year.
Following a bite by an infectious mosquito, the parasite first multiplies in the liver, before entering the bloodstream where it invades the erythrocytes (or red blood cells). The parasite then rapidly modifies the surface of its host erythrocyte with one of the sixty variable proteins of the PfEMP1 (Plasmodium falciparum Erythrocyte Membrane Protein 1) family. These proteins protect the parasite from the host's immune response and enable it to adhere to the host's cells. The severity of pregnancy-associated malaria (PAM) has been associated with the ability of parasitized erythrocytes to bind to a sugar present in the placenta, chondroitin sulfate A (CSA). After several pregnancies, women acquire protective antibodies that block CSA-binding.
One of the potential vaccination strategies for PAM is to recreate this protective immunity, by blocking the binding of parasitized erythrocytes to the placenta. Previous work carried out by the team headed by Benoît Gamain, CNRS researcher at the Unité Bases Génétiques et Moléculaires des Interactions de la Cellule Eucaryote (Institut Pasteur), has shown that one of the proteins of the PfEMP1 family, known as var2CSA, plays an important role in PAM. It is thus the prime target for a vaccine. However, the var2CSA protein shows considerable polymorphism, is very large and has a very complex structure. These characteristics have, until now, prevented researchers from reproducing it in the laboratory and studying it to elucidate its structure and its action mechanisms. Only selected "chunks" of proteins involved in these binding areas, known as domains, have been synthesized.
Gamain and his colleagues have, for the first time, succeeded in producing the entire var2CSA protein for the purpose of studying it. This protein has shown specific, high-affinity binding to CSA, more than a thousand times greater than that of the simple domains synthesized previously. Therefore it is indeed a functional protein, with all the characteristics and functions of the var2CSA protein expressed at the surface of parasitized erythrocytes.
Structural studies conducted in collaboration with researchers at EMBL (European Molecular Biology Laboratory) in Grenoble then made it possible to observe the structure of this protein. Var2CSA has a compact rather than a lengthened shape, as was assumed previously, and has a CSA-binding pocket that is most probably created when the protein folds upon itself.
For the researchers, these results constitute a first step in the race to develop vaccinal or therapeutic approaches aimed at protecting women during their first pregnancies as well as their unborn fetuses. Their work, conducted within the European "Premalstruct" (1) consortium headed by Gamain, is now going to focus on the CSA-binding pocket, responsible for the adhesion of parasitized erythrocytes to the cells of the placenta.
Artemisinin resistance detected in children with severe malaria in Uganda