Research Abstract:
We are interested in the molecular events that occur during erythrocyte invasion by Plasmodium parasites, the etiological agents of malaria. We use the tools of structural biology, biochemistry, cell biology and parasitology to examine proteins and protein complexes associated with these events.
Malaria causes an estimated 300-500 million cases and 1-3 million deaths annually, 80% of which are in children under the age of five. The clinical symptoms of malaria culminate upon red blood cell invasion by Plasmodium parasites, the etiological agents of Malaria. Therefore, preventing binding and invasion of red blood cells is an attractive target for therapeutics (drugs and vaccines).
Attachment of the parasite to a red blood cell requires several interactions mediated by the Erythrocyte-binding like family (EBL). One such interaction occurs between erythrocyte binding antigen 175 (PfEBA-175), a parasite surface protein, and the sugars of glycophorin A (GpA) on the red blood cell. Previously, we have solved the crystal structure of the binding domain of EBA-175 in complex with glycans that contains the essential components of GpA. We are in the process of expanding this work to other interactions and events during erythrocyte invasion. A detailed understanding of the interactions is necessary to develop methods to inhibit invasion.
Towards vaccine design, we are interested in understanding the molecular mechanisms of antibody-mediated neutralization. Several antibodies target the parasite EBL-proteins, but only a subset of the antibodies are neutralizing and can block invasion. Our work will determine the epitopes recognized by neutralizing antibodies, and characterize the mechanism of inhibition.
Postdoctoral positions are now available. Go to our website for more information. |
Selected Publications:
Tolia NH, Enemark EJ, Sim BKL, Joshua-Tor L. Structural basis for the EBA-175 erythrocyte invasion pathway of the malaria parasite P. falciparum. Cell 2005 122: 183-193.
Irvine DV*, Zaratiegui M*, Tolia NH*, Goto DB, Chitwood DH, Vaughn MW, Joshua-Tor L, Martienssen RA. Argonaute slicing is required for heterochromatic silencing and spreading. Science 2006 313: 1134-1137. co-first authors
Tolia NH§, Joshua-Tor L. Strategies for protein coexpression in Escherichia coli. Nature Methods 2006 3: 55-64. §corresponding author
Yigit E, Batista PJ, Bei Y, Pang KM, Chen CG, Tolia NH, Joshua-Tor L, Mitani S, Simard MJ, Mello CC. Analysis of the C. elegans Argonaute family reveals that distinct Argonautes act sequentially during RNAi. Cell 2006 127: 747-757.
Rivas FV*, Tolia NH*, Song JJ*, Aragon JP, Liu J, Hannon GJ, Joshua-Tor L. Purified Argonaute2 and an siRNA form recombinant human RISC. Nature Struc & Mole Bio 2005 12: 340-349. Epub Mar 30. *co-first authors. |