Erythrocytes in human blood are infected by malaria parasite Plasmodium falciparum, resulting in all the symptoms and pathologies of the disease. Conservative estimates predict 2-300 million people are afflicted with malaria and over a million children die from the infection each year. The growing threat of drug resistant forms of malaria has created an urgent requirement for new drugs. Targeting unique features of host and parasite interactions provides one approach to new drug and vaccine development. Plasmodium falciparum causes the most virulent form of human malaria. A striking feature of P.falciparum is its development in a vacuole when it infects the erythrocyte. This host cell is non-endocytic and does not invaginate its plasma membrane. Yet P. falciparum induces both membrane invagination and vacuole formation in these cells. Thus it must induce endocytic mechanisms to take up solutes and macromolecules. The long term aim of this proposal is to identify and characterize the mechanisms by which endocytic vacuoles in erythrocytes can be induced by malaria parasites. The studies will contribute to our understanding of the basic biology of the erythrocyte and parasite, and thereby contribute to human health. Molecular, genetic tools using transfection, genomics combined with high resolution imaging techniques and biochemical subcellular fractionation assays will be used to identify and purify erythrocyte membrane components that are recruited into the vacuole and evauate their interactions with specific lipids and protein components of both host and parasite origin. The consequence of ablation parasite gene products or expression of transdominant forms of mutant parasite genes on erythrocyte vacuole formation, expression of antigens on the erythrocyte surface, drug and toxin uptake and parasite growth will be evaluated in vitro cultures. These studies maybe important for understanding mechanisms of chemo and immunprophylaxis directed against erythrocyte membrane defects as well infection by a major human pathogen. The maintenance of human erythrocyte function in circulation, clearance of older red cells and the production of new ones must all be carefully coordinated to optimize tissue oxygen delivery. This requires understanding of erythrocyte membrane function. We utilize malaria parasites as a probe to study erythrocyte membrane function and their modulation by parasite pathogenic processes. Our studies are aimed at understanding how to better target drugs and other therapies to erythrocyte membrane defects as well as infection of these cells by a major human pathogen.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI039071-16
Application #
8306170
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Rogers, Martin J
Project Start
1996-07-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
16
Fiscal Year
2012
Total Cost
$367,538
Indirect Cost
$122,513
Name
University of Notre Dame
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
824910376
City
Notre Dame
State
IN
Country
United States
Zip Code
46556
Mbengue, Alassane; Bhattacharjee, Souvik; Pandharkar, Trupti et al. (2015) A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria. Nature 520:683-7
Safeukui, Innocent; Gomez, Noé D; Adelani, Aanuoluwa A et al. (2015) Malaria induces anemia through CD8+ T cell-dependent parasite clearance and erythrocyte removal in the spleen. MBio 6:
Abdul-Wahid, Badi'; Feng, Haoyun; Rajan, Dinesh et al. (2014) AWE-WQ: fast-forwarding molecular dynamics using the accelerated weighted ensemble. J Chem Inf Model 54:3033-43
Fru-Cho, Jerome; Bumah, Violet V; Safeukui, Innocent et al. (2014) Molecular typing reveals substantial Plasmodium vivax infection in asymptomatic adults in a rural area of Cameroon. Malar J 13:170
Jiang, Rays H Y; Stahelin, Robert V; Bhattacharjee, Souvik et al. (2013) Eukaryotic virulence determinants utilize phosphoinositides at the ER and host cell surface. Trends Microbiol 21:145-56
Fernandez-Pol, Sebastian; Slouka, Zdenek; Bhattacharjee, Souvik et al. (2013) A bacterial phosphatase-like enzyme of the malaria parasite Plasmodium falciparum possesses tyrosine phosphatase activity and is implicated in the regulation of band 3 dynamics during parasite invasion. Eukaryot Cell 12:1179-91
Bhattacharjee, Souvik; Stahelin, Robert V; Haldar, Kasturi (2012) Host targeting of virulence determinants and phosphoinositides in blood stage malaria parasites. Trends Parasitol 28:555-62
Abdul-Wahid, Badi'; Yu, Li; Rajan, Dinesh et al. (2012) Folding Proteins at 500 ns/hour with Work Queue. Proc IEEE Int Conf Escience 2012:1-8
Bhattacharjee, Souvik; Stahelin, Robert V; Speicher, Kaye D et al. (2012) Endoplasmic reticulum PI(3)P lipid binding targets malaria proteins to the host cell. Cell 148:201-12
Bhattacharjee, Souvik; Speicher, Kaye D; Stahelin, Robert V et al. (2012) PI(3)P-independent and -dependent pathways function together in a vacuolar translocation sequence to target malarial proteins to the host erythrocyte. Mol Biochem Parasitol 185:106-13

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