DBL protein function in Plasmodium chabaudi invasion and cytoadhesion

疟原虫 (P.) 是一种经过数百万年进化的寄生虫，可在多种动物宿主中引起疟疾。有六种感染人类的​​物种和超过两百种其他感染动物的物种，包括啮齿类动物和猴子，这些动物通常用作研究基本寄生虫生物学和免疫学的模型。疟原虫对这些宿主的影响从良性感染到致命感染不等，具体取决于寄生虫遗传学和宿主对感染的反应能力。 为了获得成功，寄生虫必须侵入宿主细胞并避免被宿主免疫系统识别。在疟原虫中，寄生虫入侵红细胞涉及一个复杂的过程，该过程从寄生虫与宿主细胞上的受体结合开始。与不同宿主受体的结合也是一种机制，使寄生虫能够隐藏在深层组织中，远离宿主的免疫系统。称为达菲结合样 (DBL) 蛋白的结合蛋白家族参与了这两个过程。 DBL 蛋白在人类、灵长类动物和小鼠疟原虫物种中高度保守。 我们对 DBL 蛋白在红细胞入侵和与宿主受体结合中的作用感兴趣，以便更好地了解这些蛋白如何影响寄生虫的毒力，或者寄生虫对宿主的危险程度。我们有初步数据表明，针对人类疟疾 DBL 蛋白的抗体可识别小鼠疟疾 P. chabaudi 的相关蛋白。我们还发现，如果给小鼠接种来自人类疟疾的 DBL 蛋白，这些动物就可以免受小鼠疟疾的感染。在这些实验中，我们观察到寄生虫与肝脏中的小鼠细胞结合不佳，并诱导免疫反应以帮助消除血液中的寄生虫。 我的建议是使用 P. chabaudi 作为动物模型来研究参与寄生虫结合和入侵的多种疟疾 DBL 蛋白。出于一个目标，我们将表征 P. chabaudi 的 DBL 蛋白，并确定它是否在这些生物过程中发挥作用。我们还将测试这种 DBL 蛋白的功能在其他物种的人类和灵长类疟疾中是否保守。在第二个目标中，我们将使用来自不同物种的 DBL 蛋白对小鼠进行免疫，并测量其对寄生虫结合和小鼠免疫反应的影响。与此同时，我们将使用实验室检测方法来测试这些抗体的功能，以检测培养寄生虫的入侵、结合和免疫反应。 总的来说，我的研究计划将探讨蛋白质家族的作用，该蛋白质家族的进化使某些疟疾寄生虫变得更加危险。这些基础知识将推动疟疾研究领域的发展，并探索生物学的新领域。它将揭示这些蛋白质在寄生虫生存的一些关键机制中的重要性。最终，我们可以利用这些知识来开发疟疾疫苗或治疗方法。

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.