Immunopathogenesis of Severe Malaria During Pregnancy

妊娠期严重疟疾的免疫发病机制

• 批准号: 8372558
• 负责人: JULIE M MOORE
• 金额: $ 30.81万
• 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/8372558
• 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. 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.

描述（申请人提供）：全世界每年有超过 2 亿人感染疟疾，导致近 100 万人死亡。妊娠期和幼儿期感染占疟疾发病率和死亡率的大部分。母亲恶性疟原虫感染引起的不良分娩结局包括早产、宫内生长受限、流产和死产等。这些不良的出生结局与许多疟疾引起的胎盘病理有关，包括母体炎症浸润和母体血液空间中过多的纤维蛋白沉积，但潜在的病因尚未得到描述。我们开发的小鼠模型利用 C57BL/6 和 A/J 小鼠中的 P. chabaudi 感染，在确定与疟疾相关的妊娠受损的机制基础方面显示出巨大的前景。模型系统来识别导致孕产妇疟疾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，全身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，具体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丧失中的作用。使用各种基因操纵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。蛋白酶激活受体的作用也将被评估，这些受体由凝血级联产物（包括组织因子）激活。在第二个目标中，将探讨感染疟疾的 B6 和 A/J 小鼠胎盘病理结果差异的分子基础。使用基因操纵的小鼠和氧化应激的药理学操作，将评估这些菌株中导致胎盘损伤的细胞、可溶性因子和过程，并提供代表胎盘损伤和胚胎损害的胎盘细胞凋亡的分子证据。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损害的机制基础，并可能为暴露于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寄生虫对一线抗疟疾药物的耐药性不断出现，这一方面的进展至关重要。妊娠期疟疾的新干预措施可能有助于显着降低与该疾病相关的发病率和胎儿危害。 公共卫生相关性：我们对疟疾发病机制的理解存在重大差距，特别是在孕妇中，更具体地说，在胎盘水平上。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，从而降低孕妇及其婴儿的发病率和死亡率。这项研究使用小鼠模型，将为解决这个问题提供相当多的线索。成功完成拟议的工作将确定胎盘疟疾止血失调的分子基础以及炎性胎盘疟疾诱导胎盘损伤和胎儿受损的关键机制。这项工作将有助于减轻发展中国家妇女因疟疾造成的疾病负担以及婴儿出生后几个月的死亡。