Molecular Pathogenesis of Malaria and Sickle Cell Disease
Malaria is a parasitic disease with enormous public health significance. According to current estimates, a child in Africa is killed by malaria each minute. With over 200 million infections, and ~700,000 deaths each year, there is an urgent need for new antimalarial therapies. The development of drug resistant strains, particularly those resistant to the most effective antimalarial treatment - artemisinin combination therapy (ACT) - has served as a wake-up call to the world to discover novel antimalarial treatments.
Working in the Chishti lab, CMP PhD student Michael Baldwin is focusing on malaria research. One major research interest is to understand the mechanism of malaria parasite invasion of human red blood cells (RBCs). The identification of parasite invasion proteins (termed ligands) and their cognate RBC receptors is essential for the development of new vaccines against malaria. In the human malaria parasite, Plasmodium falciparum, RBC invasion takes place via two distinct molecular pathways involving either a sialic acid-dependent or independent mechanism. Previously, we identified a novel sialic acid-independent pathway for parasite invasion in RBCs. Two specific regions of the human anion exchanger protein known as Band 3 were identified as crucial host receptor sites for malaria parasite surface ligands termed MSP1 and MSP9. Currently, we are identifying additional components of the malaria parasite invasion complex in RBCs using phage display technology. New ligands on the surface of infective malaria parasites (merozoites), identified by these screens, are expected to form the foundation of a future multi-subunit malaria vaccine as well as enhance our understanding of the complex molecular mechanisms of the malaria invasion pathway.
A second malaria project is focused on the parasite-derived signal peptide peptidase. This highly conserved protease, termed PfSPP, plays a key role in the endoplasmic reticulum during protein processing and export in infected RBCs. PfSPP is a presenilin-like aspartate protease, and its absence is lethal to the parasite. Previous studies have identified pharmacological inhibitors effective against this class of proteases, establishing a drug discovery platform targeting PfSPP in malaria. The current challenge is to identify the physiological substrates of PfSPP, which could be targeted in combination with anti-PfSPP inhibitors, to develop more effective anti-malaria therapies. Using novel transfection-based assays and bioinformatics strategies, we are currently screening the malaria genome to identify natural substrates of PfSPP for development as new therapeutic targets.
Finally, we are investigating the role of cysteine proteases in sickle cell disease. The sickle cell trait provides protection against malaria, and a detailed understanding of both host and parasite cysteine proteases (calpains) may unveil novel targets for therapeutic intervention against sickle cell disease and malaria.