An estimated 3.2 billion people in the world are at risk for malaria while vaccine development efforts have yet to be successful. The malaria species Plasmodium vivax and Plasmodium knowlesi together account for 70-80 million human malaria infections and represent the key target species for an effective malaria vaccine. Additionally, P. vivax infection causes debilitating symptoms in patients who have previously been unexposed to the parasite. This characteristic of the disease is of particular interest to the U.S. Armed Forces who are stationed in P. vivax endemic areas such as Afghanistan and Iraq. The closely related species P. knowlesi, a newly emerging pathogen, accounts for up to 20% of all malaria infections in some regions of Southeast Asia. It has been observed that only people that express the Duffy blood group antigen on the surface of their erythrocytes become infected with blood-stage P. knowlesi or P. vivax. Several current vaccine strategies are focused on interruption of the interaction of the Duffy antigen and the parasite Duffy binding protein (DBP). While this strategy is promising, little is known about the expression of the Duffy receptor and whether such a vaccine strategy would be effective. Previous studies have suggested that Duffy antigen expression may vary across Duffy positive populations. In this proposal we will address the following questions: a) do phenotypes of Duffy positive individuals (Fya+/Fya+, Fya+/Fyb+, and Fyb+,Fyb+) differ in the distribution of Duffy receptors or binding affinity to DBP, b) does the sex of the donor influence the binding of DBP, c) does erythrocyte surface topology influence DBP binding, and d) does greater DBP binding affinity lead to increased levels of parasite infections? To address these questions we will identify the level and location of Duffy receptor expression on the surface of erythrocytes, determine binding affinity of recombinant DBP variants, and measure parasite invasion efficiency using high throughput flow cytometry. We will study these parameters across three sample groupings;males expressing Fya, Fyb, or Fya/Fyb Duffy receptors, males and females homozygous positive for Fya or Fyb to identify if the sex of the donor effects Duffy receptor distribution, and: samples from patients with hemoglobin or erythrocyte surface proteins variants. We believe that these studies will yield important information about parasites invasion which will guide vaccine development and implementation.
The relevance of this study is that it helps understand how malaria parasites invade red blood cells and how humans have changed to avoid this infection. Based on this knowledge we can design an effective vaccine against 2 of the 5 types of malaria. The vaccine we design will be tested in Papua New Guinea starting in 2011.
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