Malaria remains a major global infectious disease, largely affecting people living in resource poor environments, and is one of the most important causes of childhood mortality. Drug-resistance is constantly undermining the usefulness of antimalarial regimens. There is an urgent need for the development of new therapeutic strategies. Plasmodium falciparum parasites utilize multiple ligand-receptor interactions for the invasion of human erythrocytes. Much work has focused on the characterization of parasite ligands, with the goal of developing them as vaccine candidates. Largely due to the genetic intractabiliy of enucleated human erythrocytes, the function of host human erythrocyte receptors in ligand-receptor interactions has not been comprehensively assessed. We have developed an approach combining an in vitro erythrocyte culture system, which supports P. falciparum invasion and growth, with lentiviral transduction to generate genetically modified erythrocytes. The best characterized ligand-receptor interaction in P. falciparum is that of the ligand EBA-175 and its receptor glycophorin A, with EBA-175 being developed as a vaccine candidate. Using this system, we have achieved knockdown in expression of glycophorin A, genetically demonstrating that it is required for efficient strain-specific parasite invasion. We hypothesize that targeting a limited number of erythrocyte receptors will be sufficient to abrogate P. falciparum invasion in all P. falciparum parasite lines. This project will functionally analyze erythrocyte determinants of the invasion process of P. falciparum. We will use 1) a loss-of- function approach to establish a hierarchy amongst putative erythrocyte receptors for invasion, 2) a combinatorial knockdown approach to identify minimal sets of erythrocyte surface determinants that are essential for invasion and 3) a genetic screen to identify human blood group antigens that are novel determinants of invasion. In the long-term we hope that our studies will provide a functional understanding of critical ligand-receptor interactions for P. falciparum invasion of erythrocytes to inform vaccine development and the design of host-targeted therapeutics.
Malaria parasites interact intimately with molecules on the red blood cell surface of the human host during invasion and growth. The identity of host molecules that are essential for malaria proliferation has remained elusive. We will use a novel approach of genetically manipulating stem cells to study the function of molecules in the host red blood cell. We hypothesize that the identification and analysis of essential host proteins will provide ideal candidates for the development of novel therapeutics and will greatly inform vaccine development.
|WAMIN Consortium Authors; Ahouidi, Ambroise D; Amambua-Ngwa, Alfred et al. (2016) Malaria Vaccine Development: Focusing Field Erythrocyte Invasion Studies on Phenotypic Diversity: The West African Merozoite Invasion Network (WAMIN). Trends Parasitol 32:274-83|
|Mantel, Pierre-Yves; Hjelmqvist, Daisy; Walch, Michael et al. (2016) Infected erythrocyte-derived extracellular vesicles alter vascular function via regulatory Ago2-miRNA complexes in malaria. Nat Commun 7:12727|
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|Paul, Aditya S; Egan, Elizabeth S; Duraisingh, Manoj T (2015) Host-parasite interactions that guide red blood cell invasion by malaria parasites. Curr Opin Hematol 22:220-6|
|Assefa, Samuel; Lim, Caeul; Preston, Mark D et al. (2015) Population genomic structure and adaptation in the zoonotic malaria parasite Plasmodium knowlesi. Proc Natl Acad Sci U S A 112:13027-32|
|Egan, Elizabeth S; Jiang, Rays H Y; Moechtar, Mischka A et al. (2015) Malaria. A forward genetic screen identifies erythrocyte CD55 as essential for Plasmodium falciparum invasion. Science 348:711-4|
|Tubman, VenÃ©e N; Mejia, Pedro; Shmukler, Boris E et al. (2015) The Clinically Tested Gardos Channel Inhibitor Senicapoc Exhibits Antimalarial Activity. Antimicrob Agents Chemother 60:613-6|
|Paul, Aditya S; Saha, Sudeshna; Engelberg, Klemens et al. (2015) Parasite Calcineurin Regulates Host Cell Recognition and Attachment by Apicomplexans. Cell Host Microbe 18:49-60|
|GrÃ¼ring, Christof; Moon, Robert W; Lim, Caeul et al. (2014) Human red blood cell-adapted Plasmodium knowlesi parasites: a new model system for malaria research. Cell Microbiol 16:612-20|
|Niang, Makhtar; Bei, Amy Kristine; Madnani, Kripa Gopal et al. (2014) STEVOR is a Plasmodium falciparum erythrocyte binding protein that mediates merozoite invasion and rosetting. Cell Host Microbe 16:81-93|
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