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，是一个主要的健康问题 疟疾流行地区。疾病症状从轻微到严重不等，严重的疟疾与 多种并发症，包括严重的疟疾贫血。疟疾性贫血可能危及生命，特别是 最弱势群体——幼儿和孕妇。导致疟疾的机制 尽管免疫反应失调与贫血有关，但人们对贫血的了解还不太清楚。我们组 最近发现了一个独特的炎症噬血细胞群，它们响应于 约氏疟原虫 17XNL 感染，血期疟疾的非致死模型。这些的发展 炎症噬血细胞（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 疟疾性贫血尚待探索。该应用旨在研究 iHPC 在 疟原虫感染期间发生疟疾性贫血。本研究提案的中心假设 是 iHPC 通过 Toll 样受体响应细胞内在信号而与单核细胞分化 在感染期间，这些细胞通过以下途径导致疟疾贫血的发生： 噬血作用。该应用旨在更好地了解信号传导和细胞类型所需的 疟原虫感染期间的 iHPC 开发（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者是否在发热性疾病期间产生 iHPC，以及 这些细胞是否与贫血的发生相关（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，并有可能阐明可能的情况 可以减少疟疾贫血期间疾病和死亡率的干预策略或治疗目标。 在 Jessica Hamerman 博士的指导下完成了本申请中概述的实验， 以及支持文件中描述的培训计划，是我实现成为一名 独立科学家。完成本次研究金后，我将准备开始我自己的实验室 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.