Invasion of erythrocytes by the malaria parasite is a multi-step process involving several specific interactions between receptors on the red blood cells (RBCs) and specific parasite ligands. Inhibition of RBC invasion by the merozoites would prevent infection and consequently disease. Therefore, identification and characterization of the molecules involved in this process is critical for the develop of new drugs or characterization of the molecules involved in this process is critical for the development of new drugs or vaccines. P. vivax merozoites invade primarily the reticulocytes via a single pathway utilizing in part the Duffy antigen and the P. vivax into reticulocytes. Two other P. vivax reticulocyte-binding proteins were implicated in the specific recognition of the reticulocytes by P. vivax, however, the corresponding reticulocyte receptor(s) have not been identified. We will clone and characterize the reticulocyte receptor(s) and thus support the understanding of the functional relationship of this receptor(s) with the Duffy protein, ultimately helping to establish a transgenic mouse model for P. vivax. P. falciparum was three invasion options involving GPA, GPB and an unknown receptor 'X', of which only the interaction of GP with the parasite ligand EBA- 175 has been well characterized. The P. falciparum ligands that bind specifically to GPB or 'X' and the molecular basis for the alternative pathways of invasion are unknown. Thus, another aim of the proposed research is to identify the receptor(s) 'X' and to clone and characterize the parasite molecules involved in the two alternative pathways of invasion. We will identify receptor(s) 'X' and to clone and characterize the parasite molecules involved in the two alternative pathways of invasion. We will identify novel parasite ligand(s) by evaluating the binding specificity of three newly identified parasite genes containing binding motifs known to function in other BC/parasite interactions, and by isolating biochemically ligands that bind specifically to GPB and receptor(s) 'X'. Followed by cloning. The role of the putative ligands in invasion, and their functional binding domains will be characterized during parasite development in the RBC. To identify receptor 'X' we will use RBC mutants or transformed cells that express trypsin sensitive blood antigens in invasion and binding assays, respectively. The functional binding domains of GBP and receptor(s) 'X' with their corresponding parasite specific ligands will be defined using binding assays and inhibition of binding with specific antibodies or peptides.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
2P50HL054459-06
Application #
6448576
Study Section
Special Emphasis Panel (ZHL1)
Project Start
1996-02-01
Project End
2005-12-31
Budget Start
Budget End
Support Year
6
Fiscal Year
2001
Total Cost
Indirect Cost
Name
New York Blood Center
Department
Type
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10065
Migliaccio, Anna Rita (2018) A vicious interplay between genetic and environmental insults in the etiology of blood cancers. Exp Hematol 59:9-13
Ciaffoni, Fiorella; Cassella, Elena; Varricchio, Lilian et al. (2015) Activation of non-canonical TGF-?1 signaling indicates an autoimmune mechanism for bone marrow fibrosis in primary myelofibrosis. Blood Cells Mol Dis 54:234-41
Hricik, Todd; Federici, Giulia; Zeuner, Ann et al. (2013) Transcriptomic and phospho-proteomic analyzes of erythroblasts expanded in vitro from normal donors and from patients with polycythemia vera. Am J Hematol 88:723-9
Poletto, Valentina; Rosti, Vittorio; Villani, Laura et al. (2012) A3669G polymorphism of glucocorticoid receptor is a susceptibility allele for primary myelofibrosis and contributes to phenotypic diversity and blast transformation. Blood 120:3112-7
Huang, Cheng-Han; Ye, Mao (2010) The Rh protein family: gene evolution, membrane biology, and disease association. Cell Mol Life Sci 67:1203-18
Zhu, Xiang; Rivera, Alicia; Golub, Mari S et al. (2009) Changes in red cell ion transport, reduced intratumoral neovascularization, and some mild motor function abnormalities accompany targeted disruption of the Mouse Kell gene (Kel). Am J Hematol 84:492-8
Mutschler, Manuel; Magin, Angela S; Buerge, Martina et al. (2009) NF-E2 overexpression delays erythroid maturation and increases erythrocyte production. Br J Haematol 146:203-17
Ford, Louise; Lobo, Cheryl A; Rodriguez, Marilis et al. (2007) Differential antibody responses to Plasmodium falciparum invasion ligand proteins in individuals living in malaria-endemic areas in Brazil and Cameroon. Am J Trop Med Hyg 77:977-83
Peng, Jianbin; Redman, Colvin M; Wu, Xu et al. (2007) Insights into extensive deletions around the XK locus associated with McLeod phenotype and characterization of two novel cases. Gene 392:142-50
Hue-Roye, Kim; Lomas-Francis, Christine; Belaygorod, Larisa et al. (2007) Three new high-prevalence antigens in the Cromer blood group system. Transfusion 47:1621-9

Showing the most recent 10 out of 143 publications