Immunopathogenesis of Severe Malaria During Pregnancy

描述（由申请人提供）：全球每年有超过2亿人感染疟疾，导致近100万人死亡。妊娠期和幼儿期感染是疟疾发病率和死亡率的主要原因。母体恶性疟原虫感染引起的不良分娩结果包括早产、宫内生长受限、流产和死产。这些不良的分娩结果与许多疟疾引起的胎盘病理有关，包括母体炎症浸润和母体血腔中纤维蛋白过量沉积，但其潜在的病因尚未描述。我们在C57BL/6和A/J小鼠中利用恰波迪疟原虫感染建立的小鼠模型，在确定疟疾相关妊娠损害的机制基础方面显示出很大的希望。本应用程序的目的是使用该模型系统来确定导致孕产妇疟疾炎症和高凝的分子机制，从而导致不良的分娩结果。该研究的中心假设是，系统性和胎盘疟疾引起的炎症反应通过凝血失调或胎盘细胞炎症浸润介导妊娠丢失，这取决于母体和胎儿的贡献。建议的目标将通过两个具体目标来实现。在第一个目标中，组织因子在疟疾诱导的胚胎丢失中的作用将被描述。使用多种基因操纵小鼠和药物操纵凝血，组织因子在驱动凝血，炎症反应，胎盘损伤和胚胎丢失中的重要性将被评估。蛋白酶激活受体的作用，它是由凝血级联的产物，包括组织因子激活，也将被评估。在第二个目标中，将探讨疟疾感染的B6和A/J小鼠胎盘病理结果差异的分子基础。利用转基因小鼠和氧化应激的药理学操作，这些品系中负责胎盘损伤的细胞、可溶性因子和过程将被评估，并提供胎盘凋亡代表胎盘损伤和胚胎损害的分子证据。这项工作的成功完成有望在前所未有的程度上揭示疟疾相关胎儿损害的机制基础，并可能为疟疾暴露孕妇的新治疗方式铺平道路。鉴于缺乏保护性疟疾疫苗以及寄生虫不断出现对一线抗疟疾药物的耐药性，这方面的进展至关重要。针对怀孕期间疟疾的新干预措施可能有助于显著降低与该疾病相关的发病率和胎儿损害。

DESCRIPTION (provided by applicant): Every year, more than 200 million people suffer from malarial infection worldwide, leading to nearly 1 million deaths. Infection during pregnancy and early childhood accounts for the majority of malarial morbidity and mortality. Poor birth outcomes induced by maternal Plasmodium falciparum infection range from pre-term delivery and intrauterine growth restriction to abortion and stillbirth. These poor birth outcomes have been linked to a number of malaria-induced placental pathologies, including maternal inflammatory infiltrate and excessive fibrin deposition in the maternal blood space, but the underlying etiology has not been described. The murine model that we have developed, which utilizes P. chabaudi infection in C57BL/6 and A/J mice, shows great promise for identifying the mechanistic basis for malaria-associated compromise of pregnancy., The objective of this application is to use this model system to identify the molecular mechanisms that drive inflammation and hypercoagulation in maternal malaria, leading to poor birth outcomes. The central hypothesis for the proposed research is that systemic and placental malaria-induced inflammatory responses mediate pregnancy loss via dysregulated coagulation or placental cellular inflammatory infiltrate, depending on both maternal and fetal contributions. The objectives of the proposal will be achieved through two Specific Aims. In the first Aim, the role o Tissue Factor in malaria-induced embryonic loss will be characterized. Using a variety of genetically manipulated mice and pharmacological manipulation of coagulation, the importance of Tissue Factor in driving coagulation, inflammatory responses, placental damage and embryo loss will be assessed. The role of Protease Activated Receptors, which are activated by products of the coagulation cascade, including Tissue Factor, will also be evaluated. In the second Aim, the molecular basis for differential placental pathological outcomes of malaria-infected B6 and A/J mice will be explored. Using genetically manipulated mice and pharmacological manipulation of oxidative stress, the cells, soluble factors and processes responsible for placental damage in these strains will be evaluated, with molecular evidence of placental apoptosis representing placental damage and embryo compromise. Successful completion of this work promises to reveal to an unprecedented extent the mechanistic basis for malaria-associated fetal compromise and could pave the way for new treatment modalities for malaria-exposed pregnant women. Progress on this front is critical given the lack of a protective malaria vaccine and the perpetual emergence of parasite resistance to frontline anti-malarial drugs. New interventions for malaria during pregnancy could contribute to significant reduction in the morbidity and fetal compromise associated with this disease.