DBL protein function in Plasmodium chabaudi invasion and cytoadhesion

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Plasmodium (P.) is a parasite that has evolved over millions of years and causes malaria in a range of animal hosts. There are six species that infect humans and over two hundred other species that infect animals, including rodents and monkeys, which are commonly used as models to study basic parasite biology and immunology. The effects of Plasmodium on these hosts vary from benign to lethal infections, depending on parasite genetics and the ability of the host to respond to infection. ******To be successful, parasites must invade host cells and avoid recognition by the host immune system. In Plasmodium, parasite invasion of red blood cells involves a complex process that begins with parasite binding to receptors on the host cells. Binding to different host receptors is also a mechanism that allows the parasite to hide in deep tissues, away from the immune system of the host. A family of binding proteins, called Duffy binding-like (DBL) proteins, is involved in both of these processes. DBL proteins are highly conserved across human, primate, and mouse Plasmodium species. ******We are interested in the role of DBL proteins in the invasion of red blood cells and binding to host receptors in order to better understand how these proteins contribute to parasite virulence, or how dangerous the parasite will be to the host. We have preliminary data that antibodies against DBL proteins from human species of malaria recognize related proteins from the mouse malaria, P. chabaudi. We also found that if we vaccinate mice with the DBL protein from human malaria, these animals are protected from infection with the mouse malaria. In these experiments, we observed that the parasites did not bind as well to the mouse cells in the liver and induced an immune response to help eliminate the parasites from the blood. ******My proposal is to use P. chabaudi as an animal model to study the diverse malaria DBL proteins involved in parasite binding and invasion. In one objective, we will characterize the DBL protein from P. chabaudi and determine whether it plays a role in these biological processes. We will also test whether the function of this DBL protein is conserved in other species of human and primate malaria. In the second objective, we will immunize mice with DBL proteins from different species and measure the effects on parasite binding and the immune response in the mouse. In parallel, we will test the function of these antibodies using laboratory assays for invasion, binding and immune responses with cultured parasites. ******Collectively, my research proposal will address the role of a protein family that evolved to make certain malaria parasites more dangerous. This fundamental knowledge will advance the field of malaria research and explore a new area of biology. It will reveal the importance of these proteins in some of the key mechanisms used by the parasite to survive. Ultimately, we can exploit this knowledge to develop vaccines or treatments for malaria.