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

点击翻译按钮获取中文摘要

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.