Immunopathogenesis of Severe Malaria During Pregnancy

妊娠期严重疟疾的免疫发病机制

• 批准号: 8676820
• 负责人: JULIE M MOORE
• 金额: $ 29.95万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-05 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8676820
• 关键词: A/J Mouse; Ablation; Accounting; Antimalarials; Apoptosis; Area; Automobile Driving; Biological Models; Birth; Blood; Blood Platelets; C57BL/6 Mouse; Cells; Cessation of life; Clinical; Coagulation Process; Deposition; Development; Diagnosis; Disease; Embryo; Embryo Loss; Etiology; Fetal Growth Retardation; Fibrin; Fibrin split products; Goals; Hemostatic function; Histopathology; Human; Hypoxia; Immune response; Immunology; Infant; Infection; Infection Control; Infiltration; Inflammation; Inflammatory; Inflammatory Infiltrate; Inflammatory Response; Intervention; Knowledge; Laboratories; Lead; Life; Light; Link; Low-Molecular-Weight Heparin; Malaria; Malaria Vaccines; Mediating; Modality; Modeling; Molecular; Morbidity - disease rate; Mus; Outcome; Oxidative Stress; Parasite resistance; Pathogenesis; Pathologic Processes; Pathology; Pharmaceutical Preparations; Pharmacotherapy; Plasmodium falciparum; Pregnancy; Pregnancy loss; Pregnant Women; Prevention; Process; Production; Prophylactic treatment; Proteinase-Activated Receptors; Reproductive Biology; Research; Resources; Risk; Role; Signal Transduction; TNF gene; Testing; Therapeutic Intervention; Thromboplastin; Thrombosis; Tumor Necrosis Factor-alpha; Vaccination; Woman; Work; abortion; animal facility; base; burden of illness; cytokine; early childhood; fetal; improved; laboratory facility; mortality; mouse model; prevent; stillbirth; tool; trophoblast

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.

描述（由申请人提供）：每年，全世界有超过2亿人患有疟疾感染，导致近100万人死亡。怀孕期间的感染和幼儿期间，大部分疟疾发病率和死亡率。女性恶性疟原虫感染引起的出生结果差，范围从术前分娩和宫内生长限制到流产和死产。这些较差的出生结果与许多疟疾诱导的胎盘病理学有关，包括母体炎症性浸润和孕妇血液空间中过度的纤维蛋白沉积，但尚未描述潜在的病因。我们开发的鼠模型利用了C57BL/6和A/J小鼠的P. chabaudi感染，在​​识别与疟疾相关的妊娠妥协的机械基础上显示出巨大的希望。该应用的目的是使用该模型系统来识别驱动炎症和超含量的分子机制，以促进炎症和超含量的型生产。拟议研究的中心假设是，根据母体和胎儿的贡献，全身性和胎盘疟疾诱导的炎症反应通过失调的凝血或胎盘细胞炎性浸润介导了妊娠丧失。该提案的目标将通过两个特定的目标来实现。在第一个目的中，将表征O组织在疟疾引起的胚胎损失中的作用。使用多种遗传操纵小鼠和对凝血的药理操纵，将评估组织因子在驱动凝结，炎症反应，胎盘损伤和胚胎损失方面的重要性。还将评估蛋白酶活化受体的作用，这些受体被包括组织因子在内的凝血级联产物激活。在第二个目标中，将探索疟疾感染的B6和A/J小鼠的差异胎盘病理结局的分子基础。使用遗传操纵的小鼠和对氧化应激的药理操纵，将评估细胞，可溶性因子和过程中负责这些菌株中胎盘损伤的过程，并有分子证据表明胎盘凋亡代表胎盘损伤和胚胎损害。成功完成这项工作有望在前所未有的程度上揭示与疟疾相关的胎儿妥协的机理基础，并为疟疾暴露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的抗寄生虫性的永久出现，这方面的进展至关重要。怀孕期间疟疾的新干预措施可能会大大降低与该疾病有关的发病率和胎儿妥协。