Inflammation-associated anemia and the role of monocyte-derived inflammatory hemophagocytes in a model of blood-stage malaria

项目摘要/摘要 疟疾是由疟原虫物种的原生动物寄生虫引起的，是 疟疾流行地区。疾病症状从轻微到严重不等，严重的疟疾与 各种并发症，包括严重的疟疾贫血。疟疾贫血可能危及生命，尤其是 在最脆弱的群体中--幼儿和孕妇。疟疾的致病机制 尽管免疫反应失调与贫血有关，但人们对贫血的了解还不是很清楚。我们的团队 最近发现了一组独特的炎性噬血细胞，这些细胞是为了应对 约氏疟原虫17XNL感染，一种血液期疟疾的非致命性模型。这些技术的发展 炎性噬血细胞(IHPC)与贫血和血小板减少有关，尽管 导致这种新细胞类型发展的机制及其直接和间接的贡献 疟疾贫血还有待研究。本应用程序旨在调查iHPC在 疟原虫感染期间疟疾贫血的发展。这项研究提案的中心假设是 IHPC通过Toll样受体从单核细胞分化为细胞内信号 在感染过程中，这些细胞通过 吞噬血细胞。此应用程序旨在更好地理解以下所需的信号和信元类型 疟原虫感染期间IHPC的发育(目标1)，包括许可iHPC的信号和受体 在炎症条件下消耗红细胞和血小板(目标2)。此外，我们还将评估 疟疾流行地区的疟原虫感染者在发热性疾病期间是否会发展成iHPC；以及 这些细胞是否与贫血的发生有关(目标3)。拟议的研究将导致 更好地了解导致疟疾贫血的机制，并有可能阐明 可减少疟疾贫血期间疾病和死亡率的干预战略或治疗目标。 在Jessica Hamerman博士的指导下完成本申请中概述的实验，以及 通过支持文档中描述的培训计划，是我实现成为一名 独立科学家。在完成这一奖学金后，我将准备开始我自己的实验室，作为 独立的学术调查员。

Project Summary/Abstract Malaria is caused by protozoan parasites of the Plasmodium species and is a major health problem within malaria-endemic regions. Disease symptoms range from mild to severe, and severe malaria is associated with a variety of complications, including severe malarial anemia. Malarial anemia can be life-threatening, especially in the most vulnerable groups - young children and pregnant women. The mechanisms leading to malarial anemia are not well understood, although dysregulated immune responses have been implicated. Our group recently identified a unique population of inflammatory hemophagocytes that develop in response to Plasmodium yoelii 17XNL infection, a nonlethal model of blood stage malaria. The development of these inflammatory hemophagocytes (iHPCs) correlates with anemia and thrombocytopenia, although the mechanisms leading to the development of this novel cell type and its contributions, both direct and indirect, to malarial anemia have yet to be explored. This application aims to investigate the role of iHPCs in the development of malarial anemia during Plasmodium infection. The central hypothesis of this research proposal is that iHPCs differentiate from monocytes in response to cell-intrinsic signaling through Toll-like receptors during infection, and that these cells are responsible for the development of malarial anemia through hemophagocytosis. This application seeks to better understand the signaling and cell types necessary for iHPC development during Plasmodium infection (Aim 1), including the signals and receptors that license iHPCs to consume red blood cells and platelets under inflammatory conditions (Aim 2). Additionally, we will assess whether Plasmodium- infected individuals in malaria-endemic regions develop iHPCs during febrile illness, and whether these cells correlate with the development of anemia (Aim 3). The proposed research will result in a better understanding of the mechanisms leading to malarial anemia, and has the potential to elucidate possible intervention strategies or therapeutic targets that could reduce illness and mortality during malarial anemia. The completion of experiments outlined in this application under the guidance of Dr. Jessica Hamerman, along with the training plan described in the supporting documents, are key steps toward my goal of becoming an independent scientist. At the completion of this fellowship, I will be prepared to begin my own laboratory as an independent academic investigator.