Immunopathogenesis of Severe Malaria During Pregnancy

描述（由申请人提供）：每年，全世界有2亿多人感染疟疾，导致近100万人死亡。妊娠和幼儿期感染占疟疾发病率和死亡率的大部分。由母体恶性疟原虫感染引起的不良出生结局包括早产和宫内生长受限到流产和死产。这些不良的出生结局与许多疟疾诱导的胎盘病理学有关，包括母体炎症浸润和母体血液空间中过度的纤维蛋白沉积，但尚未描述潜在的病因。我们开发的小鼠模型，利用C57 BL/6和A/J小鼠中的夏氏疟原虫感染，显示出很大的希望，以确定疟疾相关的妊娠损害的机制基础。本申请的目的是使用该模型系统来识别在母体疟疾中驱动炎症和高凝状态的分子机制，从而导致不良的出生结果。拟议研究的中心假设是，系统性和胎盘疟疾诱导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。该提案的目标将通过两个具体目标来实现。在第一个目标中，组织因子在疟疾引起的胚胎损失中的作用将被表征。将使用各种遗传操作小鼠和凝血药理学操作，评估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。还将评价蛋白酶激活受体的作用，蛋白酶激活受体由凝血级联反应的产物（包括组织因子）激活。在第二个目标中，将探讨疟疾感染的B6和A/J小鼠的不同胎盘病理结果的分子基础。使用遗传操作的小鼠和氧化应激的药理学操作，将评价这些品系中负责胎盘损伤的细胞、可溶性因子和过程，胎盘细胞凋亡的分子证据代表胎盘损伤和胚胎损害。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对一线抗疟疾药物的抗药性不断出现，这方面的进展至关重要。对妊娠期疟疾采取新的干预措施可能有助于显著降低与这种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.