Research Groups

Mammalian Biology: Malaria

Research Interests and Description

Staff Research Scientist: Chetan Chitnis

Research Interests

Characterization of P. falciparum proteins as novel drug targets and vaccine candidates; understanding the basic biology of red cell invasion and cytoadherence by malaria parasites and development of malaria vaccine candidate antigens for clinical trials.

Description of Research

Receptor-ligand interactions involved in erythrocyte invasion
Work is focused on understanding the interaction of a family of erythrocyte binding proteins, which includes Duffy binding proteins from P. vivax and P. knowlesi as well as P. falciparum EBA175, with host receptors during invasion. The receptor-binding domains of these proteins lie in conserved cysteine-rich regions that are referred to as region II. We have mapped the receptor-binding residues within P. vivax region II (PvRII) and have demonstrated that a sulfated tyrosine (Tyr 41) in the extracellular region of the Duffy antigen is critical for recognition. Determination of the three-dimensional structure reveals that the Duffy recognition site within PvRII, which includes positively charged as well as hydrophobic residues that are predicted to interact with sulfated Tyr41 on the Duffy antigen, is fully exposed and conserved. Two polymorphic clusters reported within PvRII lie distal to the binding residues. A field study carried out in children residing in an endemic area of Papua New Guinea demonstrated that acquisition of high titre binding inhibitory antibodies directed against PvRII is associated with protection against P. vivax infection. Importantly, anti-PvRII binding inhibitory antibodies were cross-reactive and blocked binding of 5 polymorphic PvRII domains. These observations provide support for the development of a vaccine based on PvRII.
Receptor ligand interactions involved in cytoadherence
Adhesion of P. falciparum-infected erythrocytes (IEs) to host endothelial cells, uninfected erythrocytes and platelets are important pathogenic mechanisms in malaria. We have recently identified a novel cytoadherence receptor, gC1qR, which binds complement component C1q and is expressed both on endothelial cells as well as platelets. We have demonstrated that P. falciparum isolates use gC1qR as a receptor to bind endothelial cells as well as for platelet-mediated clumping. We have now completed a field study in children residing in a malaria-endemic area of Mozambique and have demonstrated that platelet-mediate clumping and binding to gC1qR are associated with severe malaria. We are also studying interactions that mediate rosetting and sequestration of P. falciparum-infected erythrocytes in the placenta.
Malaria vaccine development
We are developing a vaccine for P. vivax malaria based on PvRII. Methods to produce recombinant PvRII have been developed and efforts to identify an optimal adjuvant formulation are underway. Our P. falciparum vaccine candidate, JAIVAC-1, comprises of a physical mixture of the receptor-binding domain, PfF2, of EBA-175 and the conserved C-terminal 19kD region of merozoite surface protein 1 (PfMSP1₁₉) formulated with adjuvant Montanide ISA720. Clinical grade JAIVAC-1 has been manufactured under cGMP by an Indian biotechnology company, Bharat Biotech, Hyderabad. Toxicology studies with JAIVAC-1 have been completed and an application to conduct a Phase I human trial to evaluate safety and immunogenicity is currently under review by Indian regulatory authorities.

Recent Publications

Gill, J., Chitnis, C.E., Sharma, A. 2009. Structural insights into chondroitin sulphate A binding Duffy-binding-like domains from Plasmodium falciparum: implications for intervention strategies against placental malaria. Malar J. 8, 67

Mayor, A., Rovira-Vallbona, E., Srivastava, A., Sharma, S.K., Pati, S.S., Puyol, L., Quinto, L., Bassat, Q., Machevo, S., Mandomando, I., Chauhan, V.S., Alonso, P.L., Chitnis, C.E. 2009. Functional and immunological characterization of a Duffy binding-like alpha domain from Plasmodium falciparum erythrocyte membrane protein 1 that mediates rosetting. Infect Immun. 77, 3857-3863

Biswas, A.K., Hafiz, A., Banerjee, B., Kim, K.S., Datta, K., Chitnis, C.E. 2008. Plasmodium falciparum uses gC1qR/HABP1/p32 as a receptor to bind to vascular endothelium and for platelet-mediated clumping. PLoS Pathogens. 3, e130

Chitnis, C.E., Sharma, A. 2008. Targeting the Plasmodium vivax Duffy-binding protein. Trends Parasitol. 24, 29-34

King, C.L., Michon, P., Shakri A.R., Marcotty, A., Stanisic, D., Zimmerman, P.A., Cole-Tobian, J.L., Mueller, I., C.E. Chitnis. 2008. Naturally acquired Duffy-binding protein-specific binding inhibitory antibodies confer protection from blood-stage Plasmodium vivax infection. Proc Natl Acad Sci USA. 105, 8363-8368

Moreno, A., Caro-Aguilar, I., Yazdani, S.S., Shakri, A.R., Lapp, S., Strobert, E., McClure, H., Chitnis, C.E., Galinski, M.R. 2008. Preclinical assessment of the receptor-binding domain of Plasmodium vivax Duffy-binding protein as a vaccine candidate in rhesus macaques. Vaccine 26, 4338-4344