P. falciparum is the main cause of disease and death from malaria. An important difference between P. falciparum and other human malaria parasites is the way in which P. falciparum modifies the surface of the erythrocyte so that PEs can adhere to host cells. Adherence protects the parasite from destruction, as non-adherent mature PEs are cleared rapidly in the spleen. Parasites sequester in various organs including heart, lung, brain, liver, kidney, subcutaneous tissues and placenta.
The various endothelial cells in these organs and syncytiotrophoblasts in placenta express different and variable amounts of host receptors. To successfully adhere to these cells, parasites express diverse members of the variant PfEMP1 family that mediate binding to the various receptors present on those cells. The overall objective of our project is to comprehend the functional and immunological characteristics of PfEMP1 variants expressed by placental parasites and parasites associated with major clinical outcomes in children including cerebral malaria. Such knowledge is essential for providing a rational basis for accelerating vaccine and therapeutic developments to combat severe forms of malaria.
Adhesive and post-adhesive mechanisms associated to pregnancy associated malaria
Over 50 million women are exposed to the risk of malaria in pregnancy every year. Pregnancy associated malaria (PAM) results in substantial maternal and especially fetal and infant morbidity, causing up to 200 000 infant deaths every year. P. falciparum infection causes adverse pregnancy outcomes, including anaemia and the risk of hypertension in first-time pregnant mothers, but also low birthweight due to preterm delivery and fetal growth restriction. PAM is coupled with massive accumulation of PEs and monocytes in the placental intervillous blood spaces. Adhesion of PEs to placental chondroitin-4-sulfate (CSA) has been linked to the severe disease outcome of PAM. A large body of evidence strongly suggests that var2CSA, a member of the P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1) family, has an important role in PAM disease and immunity. Although var2CSA is the main candidate for a pregnancy malaria vaccine, experimental evidence suggests that antigenic polymorphism, the lack of structural information and gaps in our understanding of placental sequestration as well as gaps in our understanding of placental immunopathology may pose a challenge for vaccine and therapeutic development. Accordingly, we will focus our research activities on the identification and the deciphering of the interactions involved during pregnancy associated malaria.
Adhesive mechanisms associated to severe malaria in children
The World Health Organization reported an estimated 216 million cases of malaria worldwide in 2010 and 655,000 subsequent deaths from the disease, mostly among children below five years of age and pregnant woman. Recent works have demonstrated that some var genes belonging to the group A and B such as ITvar19 are particularly relevant in the context of the severe malaria pathogenesis as their expression is associated with major clinical outcomes in children including cerebral malaria. These studies have also highlighted the existence of a novel and still unidentified endothelial receptor likely implicated in a new parasite sequestration mechanism. The aim of the current study is to decipher the detailed molecular mechanisms involved in the binding of the var group B/A encoded PfEMP1-ITvar19 to the brain endothelium.
The results generated during our project will have direct implications for the development of a malaria vaccine that would ease this burden of death and debilitation in sub-Saharan Africa and Asia.
- In the case of PAM, the results that we obtained during the last two years have been the basis to initiate a vaccine development program (PRIMALVAC project) with the European Vaccine Initiative (EVI). The PRIMALVAC project’s main objective is to obtain proof of concept that a var2CSA based vaccine inducing long lasting or rapidly boosted cross reactive and inhibitory antibodies can be designed. Multiple forms of the var2CSA protein are being generated and their activity as immunogens that elicit functional and cross-reactive antibodies against placental parasite forms will be assessed. The best candidate will then be transitioned to preclinical and clinical development. The development of new projects arising from the Labex GR-Ex notably on malaria and red cell diseases such as sickle cell will be initiated during the next years
- Strong expertise in malaria parasite cytoadhesion mechanisms
- Collaborative projects with European and American academic partners and with Biophysicians (Xray crystallography and Cryo electron microscopy)
- Access to a flow cyto-adhesion platform to screen inhibitory activities of drugs and vaccine candidates
- Strong internal and external collaborations for developing camelidae nanobodies (VHH)
- Srivastava, A., Gangnard, S., Dechavanne, S., Amirat, F., Lewit Bentley, A., Bentley, G. A., and Gamain, B. (2011) Var2CSA minimal CSA binding region is located within the N-terminal region, PLoS One 6, e20270.
- Avril, M., Hathaway, M. J., Srivastava, A., Dechavanne, S., Hommel, M., Beeson, J. G., Smith, J. D., and Gamain, B. (2011) Antibodies to a full-length VAR2CSA immunogen are broadly strain-transcendent but do not cross-inhibit different placental-type parasite isolates, PLoS One 6, e16622.
- Srivastava, A., Gangnard, S., Round, A., Dechavanne, S., Juillerat, A., Raynal, B., Faure, G., Baron, B., Ramboarina, S., Singh, S. K., Belrhali, H., England, P., Lewit-Bentley, A., Scherf, A., Bentley, G. A., and Gamain, B. (2010) Full-length extracellular region of the var2CSA variant of PfEMP1 is required for specific, high-affinity binding to CSA, Proceedings of the National Academy of Sciences of the United States of America 107, 4884-4889.
- Bentley, G. A., and Gamain, B. (2008) How does Plasmodium falciparum stick to CSA? Let’s see in the crystal, Nat Struct Mol Biol 15, 895-897.
- Viebig, N. K., Levin, E., Dechavanne, S., Rogerson, S. J., Gysin, J., Smith, J. D., Scherf, A., and Gamain, B. (2007) Disruption of var2csa gene impairs placental malaria associated adhesion phenotype, PLoS ONE 2, e910.
- Gamain, B., Smith, J. D., Viebig, N. K., Gysin, J., and Scherf, A. (2007) Pregnancy-associated malaria: parasite binding, natural immunity and vaccine development, Int J Parasitol 37, 273-283.
- Viebig, N. K., Gamain, B., Scheidig, C., Lepolard, C., Przyborski, J., Lanzer, M., Gysin, J., and Scherf, A. (2005) A single member of the Plasmodium falciparum var multigene family determines cytoadhesion to the placental receptor chondroitin sulphate A, EMBO Rep 6, 775-781.
- Gamain, B., Trimnell, A. R., Scheidig, C., Scherf, A., Miller, L. H., and Smith, J. D. (2005) Identification of multiple chondroitin sulfate A (CSA)-binding domains in the var2CSA gene transcribed in CSA-binding parasites, J Infect Dis 191, 1010-1013.
- Gamain, B., Smith, J. D., Avril, M., Baruch, D. I., Scherf, A., Gysin, J., and Miller, L. H. (2004) Identification of a 67-amino-acid region of the Plasmodium falciparum variant surface antigen that binds chondroitin sulphate A and elicits antibodies reactive with the surface of placental isolates, Mol Microbiol 53, 445-455.
- Gamain, B., Gratepanche, S., Miller, L. H., and Baruch, D. I. (2002) Molecular basis for the dichotomy in Plasmodium falciparum adhesion to CD36 and chondroitin sulfate A, Proc Natl Acad Sci U S A 99, 10020-10024.