Immunopathogenesis of Severe Malaria During Pregnancy

描述(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。孕期和儿童早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导致的不良分娩结局包括早产、宫内发育受限、流产和死产。这些不良的出生结局与许多疟疾引起的胎盘病理有关，包括母体炎症渗入和母体血液中纤维蛋白沉积过多，但潜在的病因尚未描述。我们建立的小鼠模型，利用C57BL/6和A/J小鼠中的P.chabaudi感染，显示了识别疟疾相关妊娠损害的机制基础的巨大希望。本应用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，导致不良出生结局的分子机制。这项研究的中心假设是，全身性和胎盘性疟疾引起的炎症反应通过调节失调的凝血或胎盘细胞炎症渗入来调节妊娠丢失，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，将描述组织因子在疟疾引起的胚胎丢失中的作用。利用各种基因操作的小鼠和凝血的药理学操作，将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。还将评估由凝血级联反应产物(包括组织因子)激活的蛋白酶激活受体的作用。在第二个目标中，将探索感染疟疾的B6和A/J小鼠不同胎盘病理结果的分子基础。利用基因操作的小鼠和氧化应激的药物操作，将评估这些菌株中导致胎盘损伤的细胞、可溶性因素和过程，胎盘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以前所未有的程度揭示与疟疾相关的胎儿妥协的机制基础，并可能为接触疟疾的孕妇的新治疗方式铺平道路。鉴于缺乏保护性疟疾疫苗，以及对前线抗疟疾药物不断出现寄生虫抗药性，在这方面取得进展至关重要。孕期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。 与公共卫生相关：我们对疟疾发病机制的了解存在重大差距，特别是在孕妇身上，更具体地说，是在胎盘层面。提高对这一问题的认识对于改进疟疾的诊断和治疗至关重要，它可以减少孕妇及其婴儿的发病率和死亡率。使用小鼠模型，这项研究将对这个问题提供相当大的帮助。这项拟议工作的成功完成将确定胎盘性疟疾失控止血的分子基础，以及在炎症性胎盘疟疾中诱导胎盘损伤和胎儿损害的关键机制。这项工作将有助于减轻发展中世界妇女因疟疾造成的疾病负担，并有助于减少婴儿出生后最初几个月的死亡。

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. PUBLIC HEALTH RELEVANCE: There are major gaps in our understanding of the pathogenesis of malaria, particularly in pregnant women and, more specifically, at the placental level. Improved knowledge of this problem is critical to the development of improved diagnosis and treatment for malaria that can reduce morbidity and mortality for both pregnant women and their infants. Using a mouse model, this study will shed considerable light on this problem. Successful completion of the proposed work will identify the molecular basis for dysregulated hemostasis in placental malaria and key mechanisms in the induction of placental damage and fetal compromise in inflammatory placental malaria. This work will contribute to reduction of the disease burden of women due to malaria in the developing world and the loss of infants in their first few months of life.