Malaria proteins localized on the surface of the merozoite has been a major target for developing a much needed multi-subunit vaccine for Plasmodium falciparum malaria, which claims over one million lives each year. The immune response to these merozoite proteins is expected to block parasite invasion into host red blood cells (RBCs). A sialic acid-dependent invasion pathway largely influenced by the interaction of parasite EBA-175 (175 kDa erythrocyte-binding antigen) with sialic acid residues of RBC glycophorin A has been well characterized. However, lines of evidence indicate that this invasion pathway is non-essential for parasite survival. Recently, we identified a sialic acid-independent invasion pathway that relies on the binding of P. falciparum merozoite surface protein-1 (MSP1) to RBC band 3. Here, we propose to extend our findings under the following specific aims. (1) Specificity of the MSPl-band 3 interaction. We propose to map the band 3-binding sites within MSP1, determine binding affinity, and examine the effect of MSP1 domains containing the band 3-binding site on P. falciparum invasion into RBCs. (2) Participation of EBA-175 in the sialic acid-independent invasion pathway. Our preliminary evidence indicates that EBA-175 interacts directly with the band 3 receptor and MSP1, presumably by forming a ternary complex, band 3/MSP1/EBA-175. We propose to investigate a potential role of EBA-175 in the band 3-dependent invasion pathway by characterizing the binding interface of the ternary protein complex. Major methods used will include yeast two-hybrid assay, solution-binding assay using BIACORE biosensor, and site-directed mutagenesis. (3) Role of the band 3 receptor in sialic acid-dependent pathway. We propose to examine the invasion inhibition potential of band 3 in the sialic acid-dependent P. falciparum line maintained in vitro. This study will provide the first evidence on whether the band 3 provides a pathway alternative to the sialic acid-dependent pathway or functions as a primary invasion receptor across P. falciparum lines. Together, a clear understanding of the sialic acid-independent invasion mechanism will provide valuable insights into the development of an effective subunit malaria vaccine.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL060961-05
Application #
6630767
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Qasba, Pankaj
Project Start
1998-07-10
Project End
2008-06-30
Budget Start
2003-09-20
Budget End
2004-06-30
Support Year
5
Fiscal Year
2003
Total Cost
$311,740
Indirect Cost
Name
University of Illinois at Chicago
Department
Pharmacology
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Nwankwo, Jennifer O; Gremmel, Thomas; Gerrits, Anja J et al. (2017) Calpain-1 regulates platelet function in a humanized mouse model of sickle cell disease. Thromb Res 160:58-65
Ranjan, Ravi; Karpurapu, Manjula; Rani, Asha et al. (2016) Hemozoin Regulates iNOS Expression by Modulating the Transcription Factor NF-?B in Macrophages. Biochem Mol Biol J 2:
Lu, Yunzhe; Hanada, Toshihiko; Fujiwara, Yuko et al. (2016) Gene disruption of dematin causes precipitous loss of erythrocyte membrane stability and severe hemolytic anemia. Blood 128:93-103
Nwankwo, Jennifer O; Lei, Jianxun; Xu, Jian et al. (2016) Genetic inactivation of calpain-1 attenuates pain sensitivity in a humanized mouse model of sickle cell disease. Haematologica 101:e397-e400
Schiemer, James; Bohm, Andrew; Lin, Li et al. (2016) G?13 Switch Region 2 Relieves Talin Autoinhibition to Activate ?IIb?3 Integrin. J Biol Chem 291:26598-26612
Baldwin, Michael R; Li, Xuerong; Hanada, Toshihiko et al. (2015) Merozoite surface protein 1 recognition of host glycophorin A mediates malaria parasite invasion of red blood cells. Blood 125:2704-11
Baldwin, Michael; Russo, Crystal; Li, Xuerong et al. (2014) Plasmodium falciparum signal peptide peptidase cleaves malaria heat shock protein 101 (HSP101). Implications for gametocytogenesis. Biochem Biophys Res Commun 450:1427-32
Baldwin, Michael; Yamodo, Innocent; Ranjan, Ravi et al. (2014) Human erythrocyte band 3 functions as a receptor for the sialic acid-independent invasion of Plasmodium falciparum. Role of the RhopH3-MSP1 complex. Biochim Biophys Acta 1843:2855-70
Li, Xuerong; Marinkovic, Marina; Russo, Crystal et al. (2012) Identification of a specific region of Plasmodium falciparum EBL-1 that binds to host receptor glycophorin B and inhibits merozoite invasion in human red blood cells. Mol Biochem Parasitol 183:23-31
Li, Xuerong; Chen, Huiqing; Bahamontes-Rosa, Noemi et al. (2009) Plasmodium falciparum signal peptide peptidase is a promising drug target against blood stage malaria. Biochem Biophys Res Commun 380:454-9

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