Research Groups

Mammalian Biology: Malaria

Research Interests and Description

Staff Research Scientist: Deepak Gaur, PhD

Research Interests

P. falciparum, P. vivax, basic parasite biology of erythrocyte invasion, receptor-ligand interactions, malaria vaccine development, molecular epidemiology.

Description of Research

Molecular basis of red cell invasion by the malaria parasites P. falciparum and P. vivax
Malaria is a major human disease that accounts for almost two million deaths annually. The causative agent of the most severe form of malaria is the apicomplexan parasite, Plasmodium falciparum, that has a complex life cycle involving two hosts, the Anopheles mosquito vector and the human host. Merozoites are extracellular invasive forms of the parasite that invade erythrocytes and mark the beginning of the asexual, blood stage of the life cycle, which is responsible for the clinical symptoms and pathology associated with malaria. Merozoites have an elongated and polarized structure with two specialized apical organelles, the rhoptries and micronemes that harbor invasion proteins.
Merozoites attach the erythrocyte surface, apically reorient, form a junction and then enter into a vacuole. This process is mediated by multiple ligand-receptor interactions (Figure 1), of which many remain unknown and the functional role of those that are known still remains to be defined. Among these are two families of proteins - the Duffy binding like (DBL) proteins and the Reticulocyte binding like homologue (PfRH) proteins (e.g. PfRH1, PfRH2a/2b, PfRH4 and PfRH5).
While P. vivax erythrocyte invasion is dependent on a single pathway mediated by the parasite Duffy binding protein and its receptor, the Duffy blood group antigen, P. falciparum exploits multiple parasite ligands to invade through a number of alternate pathways. These pathways are classified on the basis of the nature of the erythrocyte receptor, which is defined by enzymatic treatments such as neuraminidase or trypsin (Figure 2).Thus, the challenge in developing a malaria blood stage vaccine is the redundancy in invasion pathways. In order to block invasion a vaccine must counter all pathways, which is impossible with one antigen. Hence it is important to identify a combination of novel target antigens that block several pathways leading to a significant inhibition of erythrocyte invasion.
Research focuses on gaining a complete understanding of the molecular basis of erythrocyte invasion by P. falciparum and P. vivax. This involves a multidisciplinary approach involving molecular and cell biology, protein chemistry and genetics to address unknown aspects of red cell invasion. Current projects are aimed at identifying novel parasite molecules that mediate invasion through different alternate pathways.
Functional characterization of receptor-ligand interactions that mediate invasion
The focus is to study and functionally characterize the role of the PfRH proteins that have been shown to possess erythrocyte binding activity. However, their precise role in red cell invasion is not defined. In order to address these issues, a major research interest is to elucidate the functional properties of the PfRH proteins.
Malaria vaccine development
We are validating the vaccine potential of a number of P. falciparum merozoite proteins with the aim of translating the successful antigens into blood stage malaria vaccines. The approach is to test the ability of specific antibodies against the merozoite proteins to block erythrocyte invasion through in vitro invasion assays.

Recent Publications

Gaur, D., Chitnis C.E. 2011. Molecular Interactions and Signaling Mechanisms during Erythrocyte Invasion by Malaria Parasites. Curr Opin Microbiol 4, 422-8 PubMed link

Jiang, L., Gaur, D., Mu, J., Zhou, H., Long, C., Miller, L.H. 2011. Evidence for EBA-175 as a component of a ligand-blocking blood stage malaria vaccine. Proc Natl Acad Sci USA 108, 7553-8 PubMed link

Sahar, T., Reddy, K.S., Bharadwaj, M., Pandey, A.K., Singh, S., Chitnis, C.E., Gaur, D. 2011. Plasmodium falciparum Reticulocyte Binding-like Homologue Protein 2 (PfRH2) is a Key Adhesive Molecule Involved in Erythrocyte Invasion. PLoS One 6, e17102 PubMed link

Chauhan, V.S., Yazdani, S.S., Gaur, D. 2010. Malaria vaccine development based on merozoite surface proteins of Plasmodium falciparum. Hum Vaccin 6, 1-6 PubMed link

Hayton, K., Gaur, D., Liu, A., Takahashi, J., Henschen, B., Singh, S., Lambert, L., Furuya, T., Bouttenot, R., Doll, M., Nawaz, F., Mu, J., Jiang, L., Miller, L.H., Wellems, T.W. 2008. RH5 Binding Protein Mutations Specify Pathways of P. falciparum Invasion into Monkey and Human Erythrocytes. Cell Host Microbe 4, 1-12

Gaur, D., Singh, S., Singh, S., Jiang, L., Diouf, A., Miller, L.H. 2007. Recombinant Plasmodium falciparum reticulocyte homology protein 4 binds to erythrocytes and blocks invasion. Proc Natl Acad Sci USA 104, 17789-94 PubMed link