The clinical symptoms of malaria occur upon host cell invasion by Plasmodium parasites, the causative agents of the disease. Therefore, recognition and invasion of host cells is an attractive target for therapeutics and an active area of research. Attachment of the parasite to a host cell during invasion requires specific receptor-ligand interactions. We aim to structurally and mechanistically define these interactions and attachment events. This knowledge is necessary to develop methods to inhibit invasion leading to therapeutic and vaccine design.
To complete their life cycle, malaria parasites must move through various cells in the human and mosquito. Parasites that lack a protein called CelTOS can enter these cells, but remain stuck inside. We solved the structure of CelTOS to decipher its function and found CelTOS resembles pore-forming proteins. We futher demonstrated CelTOS forms pores in plasma membranes from the cytosolic face out to aid in parasite exit from cells.
PfEBA-175 and Glycophorin A
The EBL family member erythrocyte binding antigen 175 (PfEBA-175) is a parasite surface protein and leading vaccine candidate for Plasmodium falciparum malaria. PfEBA-175 binds to the sugars of glycophorin A (GpA) on the red blood cell.
# co-first author
PvDBP and DARC
Plasmodium vivax is reliant on the Duffy Binding Protein (PvDBP) engagement of the Duffy Antigen/Receptor for Chemokines (DARC) on red blood cells for invasion. We have solved crystal structures of PvDBP in complex with DARC to identify the binding pockets. Our studies show that receptor binding drives dimerization of PvDBP, and PvDBP assembles around DARC for tight attachment.
PfEBA-140 and Glycophorin C
Erythrocyte binding antigen 140 (PfEBA-140, BAEBL, EBL-2) is an EBL ligand that recognizes glycophorin C (GpC) on the red blood cell. The crystal and solution structure of PfEBA-140 shows distinct differences to PfEBA-175 that account for receptor specificity. The structure of PfEBA-140 in complex with glycans from the receptor Glycophorin C reveal novel glycan binding pockets different from other EBL ligands and sialic acid binding proteins. Polymorphisms in one of the glycan binding pockets may explain receptor switching by PfEBA-140.
We are interested in understanding the molecular mechanisms of antibody-mediated neutralization. Several antibodies target the parasite 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.
Broadly neutralizing epitopes in PvDBP
Plasmodium vivax is reliant on the Duffy Binding Protein (PvDBP) engagement of the Duffy Antigen/Receptor for Chemokines (DARC) on red blood cells for invasion. We have identified inhibitory antibody epitopes that are conserved across global strains of PvDBP. These epitopes will inform future rounds of vaccine development.
Antibodies that target PfEBA-175
A strongly-neutralizing antibody R217 (red) binds to the glycan-binding sites and proposed dimer interface of PfEBA-175. In contrast, a weakly neutralizing antibody R218 (green) binds to residues far removed from receptor-binding regions. This work suggests neutralizing antibodies target functional regions of invasion proteins.
Antibody neutralization of PvDBP
Plasmodium vivax is reliant on the Duffy Binding Protein (PvDBP) engagement of the Duffy Antigen/Receptor for Chemokines (DARC) on red blood cells for invasion. Our studies show that receptor binding drives dimerization of PvDBP, and PvDBP assembles around DARC for tight attachment. This analysis also demonstrates that naturally acquired immunity targets the dimer interface and putative DARC binding site in PvDBP.
Producing antigens that focus the immune response to protective epitopes is critical for future vaccines. We aim to design and engineer novel antigens that will lead to protection.
Engineering PvDBP to focus the immune response
PvDBP is an excellent vaccine candidate for malaria. However, polymorphisms in PvDBP prevent strain specific responses reducing its efficacy as an antigen. Engineering PvDBP to eliminate strain-specific responses while boosting strain-transcengin protection is a major goal that will be achieved by structural vaccinology.
The emergence of drug resistance to currently available anti-malarial drugs is a major challenge in malaria control efforts. Therefore, defining the mechanisms that underlie drug resistance is of great importance. We will determine the molecular mechanisms that enable drug resistance to anti-malarial compounds through structural and mechanistic studies.
Acquired drug resistance to fosmidomycin
Defining the structural and mechanistic basis for acquired drug resistance to the anti-malarial drug fosmidomycin. The structure of PfHAD1, an enzyme that modulates resistance to fosmidomycin.
# co-first author, * co-senior author
Diverse substrate recognition by the drug resistance protein PfHAD1
PfHAD1 has a wide and diverse substrate specificity. We defined the structural basis for substrate ambiguity and specificity for this critical protein involved in drug resistance in malaria parasites.
# co-first author, * co-senior author