SUMMER RESEARCH on the ROLE of the Pfemp1 PROTEIN and ICAM-1 PROTEIN in MALARIA

Victoire Ndong [email protected] Faculty mentor: Amy L Springer

SUMMER RESEARCH ON THE ROLE OF THE PfEMP1 PROTEIN AND ICAM-1 PROTEIN IN MALARIA

Malaria is one of the most common infectious diseases in tropical countries particularly those in sub-Saharan Africa. Malaria is caused by the protozoan parasites of the Plasmodium genus. The parasites are transmitted by the female Anopheles mosquito and in the human host; they multiply in the red blood cells. There are many types of malaria caused by different types of

Plasmodia. The most common symptoms are fever, anemia, flu like symptoms and in the most severe cases coma and death. Malaria has developed into a real problem in certain countries, it kills thousands of people and a vaccine hasn’t been yet discovered due to the variations of the antigen. Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is an important virulence factor encoded by a family of roughly 60 variant genes and is used by the parasite to interact with the human host (3). It is also an adhesive molecule that binds to certain human receptors. We propose to study mutations in a PfEMP1 protein that binds to host ICAM-1 protein, in order to further define the residues involved in binding.

The invasion of the erythrocyte and the cytoadhesion of the infected erythrocyte require the binding function of common adhesion molecules found in two families of parasite ligands:

The erythrocyte Binding Ligand (EBL) family of erythrocyte invasion ligands and the

P.falciparum Erythrocyte membrane protein 1(PfEMP1) family of cytoadherence ligands found on the surface of infected cells (1). Also Duffy-binding like (DBL) domains are involved in parasite invasion of erythrocytes or cytoadherence of infected erythrocytes and they are common to two different families of Malaria protein (1). Victoire Ndong [email protected] Faculty mentor: Amy L Springer Severe malaria is associated with cytoadherance of Plasmodium falciparum infected erythrocytes. That is caused by the binding of PfEMP1 to specific host ligands. Cerebral malaria is a major cause of death and it has been associated with infected erythrocyte binding to

Intercellular Adhesion Molecule 1 (ICAM-1). Two exons encode for the PfEMP1; one encodes for the conserved cytoplasmic tale and the other encodes for the variable extracellular region.

The binding region for ICAM-1 has been identified from three different PfEMP1 proteins and shown to reside within two contiguous domains, or regions: DBL2β and the c2 (2). In fact there is interdependence between the two domains so that both are required for ICAM-1 binding. In our research, we want to extend our understanding of the critical binding region for ICAM in a

PfEMP1 named A4tres. For that we will use the IT P. falciparum strain which displays cytoadherent phenotypes in the laboratory. Our research will help us determine the functional evolution of the ways ICAM-1 binds within the PfEMP1 family and see if our findings can help in discovering vaccine targets.

To carry out our research we will use recombinant ICAM-1 and we will monitor the way it binds to PfEMP1 domains expressed in an in vitro system. We will make ICAM-1 recombinants and we will label them with magnetic beads that can be detected easily with the microscope. We will also use immunofluorescence techniques to get qualitative scoring. That study will permit us to compare the binding of different proteins.

Coming from a country (Senegal) where malaria is among the deadliest diseases, I consider doing this research a way to help me understand better the disease and the ways it functions. Malaria like HIV is a disease for which a vaccine wasn’t found yet and both have a big impact on African populations. I am planning to write a thesis about Malaria and this Victoire Ndong [email protected] Faculty mentor: Amy L Springer research can help me in my future plans to do extended studies of the P. falciparum parasites.

That will be my contribution to scientific research towards finding a vaccine against Malaria.

Literature cited

1- D.P.-G. Howell et al. / Molecular & Biochemical Parasitology 148 (2006) 1–9: Disguising itself—insights into Plasmodium falciparum binding and immune evasion from the DBL crystal structure

2- A.L. Springer et al. / Molecular & Biochemical Parasitology 137 (2004) 55–64 Functional interdependence of the DBL_ domain and c2 region for binding of the Plasmodium falciparum variant antigen to ICAM-1_

3- K. Flick et al. / Molecular & Biochemical Parasitology 134 (2004) 3-9 Var genes, PfEMP1 and the human host