There is a fundamental gap in understanding of interactions required for erythrocyte invasion by Plasmodium parasites. Our long-term goal is to determine how receptor-ligand interactions during erythrocyte invasion are mediated at the molecular level and how they can be exploited for preventative, therapeutic and diagnostic purposes. The objectives of this application are to understand the molecular basis of receptor recognition by the Erythrocyte-binding like (EBL) family and to establish the mode of inhibition of neutralizing monoclonal antibodies that target this family. The central hypothesis of the application is that the binding domains (DBL domains) of EBL family members possess a conserved fold that dimerizes, creating receptor-binding pockets and channels that are used to recognize a variety of receptors, and that inhibitory antibodies target binding pockets and channels either by preventing their formation or their accessibility The rationale for the proposed research is that once the functional regions of the EBL family members have been determined these can be exploited for vaccine design, novel protein-based therapeutics and/or diagnostics. Thus, the proposed research is relevant to that part of the NIH's mission of developing fundamental knowledge that may reduce the burden of human disease. In addition, the proposed research will advance our understanding of receptor- ligand interactions, ligand-antibody interactions and microbial pathogenesis. Supported by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Identify the receptor binding pockets of the EBL family members;and 2) Determine how neutralizing antibodies bind to DBL domains and inhibit invasion. Under the first aim, structural, in vitro and in vivo studies will be used to comprehensively determine the molecular details of interactions mediated by the EBL family. Under the second aim, structural and interaction mapping studies will reveal epitopes of the EBL family targeted by neutralizing antibodies towards identifying epitopes that have the greatest neutralizing potential. The proposed research is significant because it is expected to advance and expand our understanding of receptor-ligand and ligand-antibody interactions and to provide the knowledge required to develop diagnostics, preventative and therapeutic interventions for malaria.

Public Health Relevance

The proposed studies address an important and under-investigated area of malaria host-pathogen interactions that has applicability to preventing red blood cell invasion by Plasmodium parasites. The proposed research has relevance to public health, because red blood cell invasion is a critical step in the progression of the disease, Malaria. Thus, the findings are expected to be applicable to the health of human beings as they could be exploited for novel treatments and diagnostics for Malaria.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI080792-04
Application #
8305771
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Wali, Tonu M
Project Start
2009-08-15
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$372,438
Indirect Cost
$127,413
Name
Washington University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Malpede, Brian M; Tolia, Niraj H (2014) Malaria adhesins: structure and function. Cell Microbiol 16:621-31
Salinas, Nichole D; Tolia, Niraj H (2014) A quantitative assay for binding and inhibition of Plasmodium falciparum Erythrocyte Binding Antigen 175 reveals high affinity binding depends on both DBL domains. Protein Expr Purif 95:188-94
Salinas, Nichole D; Paing, May M; Tolia, Niraj H (2014) Critical glycosylated residues in exon three of erythrocyte glycophorin A engage Plasmodium falciparum EBA-175 and define receptor specificity. MBio 5:e01606-14
Batchelor, Joseph D; Malpede, Brian M; Omattage, Natalie S et al. (2014) Red blood cell invasion by Plasmodium vivax: structural basis for DBP engagement of DARC. PLoS Pathog 10:e1003869
Chen, Edwin; Paing, May M; Salinas, Nichole et al. (2013) Structural and functional basis for inhibition of erythrocyte invasion by antibodies that target Plasmodium falciparum EBA-175. PLoS Pathog 9:e1003390
Malpede, Brian M; Lin, Daniel H; Tolia, Niraj H (2013) Molecular basis for sialic acid-dependent receptor recognition by the Plasmodium falciparum invasion protein erythrocyte-binding antigen-140/BAEBL. J Biol Chem 288:12406-15
Badiane, Aida S; Bei, Amy K; Ahouidi, Ambroise D et al. (2013) Inhibitory humoral responses to the Plasmodium falciparum vaccine candidate EBA-175 are independent of the erythrocyte invasion pathway. Clin Vaccine Immunol 20:1238-45
Batchelor, Joseph D; Zahm, Jacob A; Tolia, Niraj H (2011) Dimerization of Plasmodium vivax DBP is induced upon receptor binding and drives recognition of DARC. Nat Struct Mol Biol 18:908-14