Xuerong Li, PhD
Research Assistant Professor
909 S. Wolcott Ave.
Malaria is one of the most common infectious diseases, and has enormous public health significance. An estimated 300-660 million cases of malaria infections occur worldwide annually, and ~1-2 million people die due to complications of malaria each year. Because of emerging drug resistance and lack of an effective vaccine, there is an urgent need to identify new drug and vaccine targets against malaria.
Our major research challenge is to understand how the malaria parasite invades human red blood cells. This step is important for finding novel malaria proteins involved in the host invasion process. The identification of parasite invasion proteins and their cognate host receptors is considered essential for the development of new drugs and vaccines against malaria. In human malaria parasite, Plasmodium falciparum, erythrocyte invasion takes place via two distinct molecular pathways involving either a sialic acid-dependent or sialic acid-independent mechanism. Recently, we identified a novel sialic acid-independent pathway for P. falciparum invasion in human erythrocytes. We showed that two non-glycosylated extracellular regions of human band 3 anion exchanger function as a crucial host receptor for malaria parasite surface proteins termed MSP1 and MSP9. Currently, we are identifying additional components of the parasite invasion complex to develop effective therapeutic strategies and vaccine against malaria.
Malaria parasite proteases have long been considered potential therapeutic targets. A variety of proteases, such as aspartic, cysteine, and serine proteases have been evaluated as potential drug candidates. Some of these proteases are important for host hemoglobin degradation, while other enzymes are necessary for parasite invasion and egress from erythrocytes. Recently, we identified a highly conserved single signal peptide peptidase (SPP) gene in the malaria parasite genome, which plays an essential role in parasite invasion and growth in human erythrocytes. Plasmodium falciparum SPP (PfSPP) is a presenilin-like aspartic protease associated with parasite micronemes and other organelles. Gene disruption of PfSPP indicates that its absence is lethal for the blood stage of parasite development. Importantly, selective SPP inhibitors completely blocked malaria parasite invasion and growth in human erythrocytes. These results suggest a critical role of PfSPP in malaria parasite life cycle, and identify the intramembrane aspartyl protease as a potential drug target against malaria across species. Currently, we are searching for the natural substrates of PfSPP in the parasite genome with the goal of developing new drugs and vaccine against malaria.
- Li X, Chen H, Bahamontes-Rosa N, Kun JF, Traore B, Crompton PD, Chishti AH: Plasmodium falciparum signal peptide peptidase is a promising drug target against blood stage malaria. Biochem Biophys Res Commun 2009, 380(3):454-459.
- Li X, Chen H, Oh SS, Chishti AH: A Presenilin-like protease associated with Plasmodium falciparum micronemes is involved in erythrocyte invasion. Mol Biochem Parasitol 2008, 158(1):22-31.
- Li X, Chen H, Khan AA, Lauterbach SB, Lanzillotti R, Rai PR, Kane RS, Coetzer TL, Chishti AH: Receptor-based identification of an inhibitory peptide against blood stage malaria. Biochem Biophys Res Commun 2008, 376(3):489-493.
- Li X, Chen H, Jeong JJ, Chishti AH: BDA-410: a novel synthetic calpain inhibitor active against blood stage malaria. Mol Biochem Parasitol 2007, 155(1):26-32.
- Chen H, Khan AA, Liu F, Gilligan DM, Peters LL, Messick J, Haschek-Hock WM, Li X, Ostafin AE, Chishti AH: Combined deletion of mouse dematin-headpiece and beta-adducin exerts a novel effect on the spectrin-actin junctions leading to erythrocyte fragility and hemolytic anemia. J Biol Chem 2007, 282(6):4124-4135.
- Jeong JJ, Kumar A, Hanada T, Seo PS, Li X, Hanspal M, Chishti AH: Cloning and characterization of Plasmodium falciparum cysteine protease, falcipain-2B. Blood Cells Mol Dis 2006, 36(3):429-435.
- Kariuki MM*, Li X*, Yamodo I, Chishti AH, Oh SS: Two Plasmodium falciparum merozoite proteins binding to erythrocyte band 3 form a direct complex. Biochem Biophys Res Commun 2005, 338(4):1690-1695. (*equal contribution)
- Li X, Chen H, Oo TH, Daly TM, Bergman LW, Liu SC, Chishti AH, Oh SS: A co-ligand complex anchors Plasmodium falciparum merozoites to the erythrocyte invasion receptor band 3. J Biol Chem 2004, 279(7):5765-5771.
- Goel VK*, Li X*, Chen H, Liu SC, Chishti AH, Oh SS: Band 3 is a host receptor binding merozoite surface protein 1 during the Plasmodium falciparum invasion of erythrocytes. Proc Natl Acad Sci U S A 2003, 100(9):5164-5169. (*equal contribution)