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

项目概要/摘要 疟疾是由疟原虫属的原生动物寄生虫引起的， 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性贫血疟疾性贫血可危及生命，特别是 在最脆弱的群体-幼儿和孕妇中。导致疟疾的机制 贫血症还没有得到很好的理解，虽然失调的免疫反应已经牵连。我们集团 最近发现了一个独特的炎症性噬血细胞群体， 约氏疟原虫17 XNL感染，血液期疟疾的非致死模型。发展这些 炎性噬血细胞（iHPC）与贫血和血小板减少症相关，尽管 导致这种新型细胞类型发展的机制及其直接和间接的贡献， 疟疾性贫血还有待探索。本申请的目的是研究iHPC在细胞凋亡中的作用。 疟原虫感染期间发生疟疾性贫血。这项研究的核心假设是 iHPC通过Toll样受体响应细胞内在信号传导而从单核细胞分化 在感染过程中，这些细胞负责疟疾贫血的发展， 噬血作用本申请旨在更好地理解细胞内信号传导和细胞类型， 疟原虫感染期间的iHPC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，我们将评估 疟疾流行地区的疟原虫感染个体是否在发热性疾病期间发展iHPC，以及 这些细胞是否与贫血的发展相关（目的3）。这项研究将产生一个 更好地了解导致疟疾贫血的机制，并有可能阐明可能的 干预策略或治疗目标，可以减少疟疾贫血期间的疾病和死亡率。 在Jessica Hamerman博士的指导下完成本申请中概述的实验，沿着 与支持文件中描述的培训计划，是实现我成为一名 独立科学家在这个奖学金结束后，我将准备开始我自己的实验室， 独立的学术研究者。

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.