Exploring the etiology of oxidative damage and cell death in placental malaria

摘要 疟疾是世界许多地区的一个主要公共卫生问题，主要影响孕妇和 年幼的孩子。孕期感染恶性疟原虫可导致显著的胎儿损害和 每年导致数十万名婴儿死亡。这些结果与 疟疾引起的胎盘病变的数量，包括母体炎症细胞渗入胎盘 胎盘对感染的反应。反过来，这又与绒毛胎盘的严重损害有关， 包括合体滋养层细胞坏死性死亡。完全理解关键的细胞和分子 然而，在胎盘性疟疾中，驱动胎盘损伤和功能障碍的机制仍然不清楚。 有证据表明，中性粒细胞和单核细胞在炎症性胎盘疟疾中积聚，并且 尤其是中性粒细胞也与非妊娠患者的严重疟疾有关。然而，几乎没有什么细节 这些细胞在胎盘疟疾发病机制中的作用是可用的。受激动人心的初步数据激励 这表明胎盘疟疾中存在严重的脂质过氧化，我们假设激活了先天免疫细胞， 通过氧化机制，直接导致胎盘疟疾合体滋养层细胞的应激和死亡， 从而通过胎盘功能障碍导致不良的出生结局。此应用程序的目标是 使用疟疾流行人群的胎盘组织、绒毛外植体和一只小鼠来解决这一假设 该模型概括了胎盘性疟疾的关键方面。 研究目标将通过三个具体目标来实现。第一，保存的胎盘组织 接触疟疾的肯尼亚妇女将通过空间转录组学进行评估，以确定在多大程度上 自然感染时滋养层细胞氧化应激和坏死性下垂是一致的。第二，中国经济的影响 滋养层细胞暴露于激活的中性粒细胞和单核细胞将在体外模拟 胎盘性疟疾。氧化损伤、坏死性下垂等细胞死亡机制与合体滋养层细胞 暴露于中性粒细胞和单核细胞的绒毛外植体的破坏情况将受到监测。 爆裂。第三，中性粒细胞和单核细胞氧化爆发的作用，以及致氧化剂疟疾的相对作用 血球蛋白在驱动胎盘氧化应激和损伤中的作用将在近交系小鼠模型中进行研究 胎盘性疟疾。这项研究的成功完成将扩大对心力衰竭的机制基础的理解。 疟疾引起的胎盘损害和胎儿损害，导致确定新的辅助药物靶点 孕期疟疾的治疗。通过促进调解人的基本知识 合体滋养层细胞的破坏和死亡，这项工作将对其他妊娠条件产生影响 与母体单核细胞和中性粒细胞活性、胎盘氧化损伤和细胞死亡相关 胎盘功能障碍。

Abstract Malaria is a major public health problem for many regions of the world, affecting mainly pregnant women and young children. Plasmodium falciparum infection during pregnancy results in significant fetal compromise and contributes to hundreds of thousands of infant deaths each year. These outcomes are associated with a number of malaria-induced placental pathologies, including infiltration of maternal inflammatory cells into the placenta in response to the infection. This, in turn, is linked to significant damage to the villous placenta, including necrotic death of syncytiotrophoblast. Complete understanding of the critical cellular and molecular mechanisms that drive placental damage and dysfunction in placental malaria, however, remains elusive. Evidence suggests that neutrophils and monocytes accumulate in inflammatory placental malaria, and neutrophils in particular are also implicated in severe malaria in non-pregnant patients. However, few details of the roles of these cells in placental malaria pathogenesis are available. Motivated by exciting preliminary data that show profound lipid peroxidation in placental malaria, we hypothesize that activated innate immune cells, through oxidative mechanisms, directly contribute to syncytiotrophoblast stress and death in placental malaria, thereby precipitating poor birth outcomes via placental dysfunction. The objective of this application is to address this hypothesis using placenta tissue from a malaria endemic population, villous explants and a mouse model that recapitulates key aspects of placental malaria. The study objectives will be achieved through three Specific Aims. First, preserved placental tissues from Kenyan women exposed to malaria will be assessed by spatial transcriptomics to establish the extent to which trophoblast oxidative stress and necroptosis are coincident in natural infection. Second, the impact of trophoblast exposure to activated neutrophils and monocytes will be characterized in an in vitro simulation of placental malaria. Oxidative damage, necroptosis and other cell death mechanisms, and syncytiotrophoblast destruction will be monitored in villous explants exposed to neutrophils and monocytes undergoing respiratory burst. Third the role of neutrophil and monocyte oxidative burst, and the relative role of pro-oxidant malarial hemozoin, in driving placental oxidative stress and damage will be investigated in an outbred mouse model for placental malaria. Successful completion of this research will expand understanding of the mechanistic basis of malaria-induced placental damage and fetal compromise, leading to identification of new targets for adjunctive therapies in malaria during pregnancy. By advancing fundamental knowledge of mediators of syncytiotrophoblast compromise and death, this work will have implications for other pregnancy conditions associated with maternal monocyte and neutrophil activity, placental oxidative damage, and cell death-related placental dysfunction.