Immunopathogenesis of Severe Malaria During Pregnancy

妊娠期严重疟疾的免疫发病机制

基本信息

批准号：
7806654
负责人：
JULIE M MOORE
金额：
$ 30.35万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-05 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7806654
关键词：
Ablation Aborted Fetus Acute Address Affect Anemia Anti-Inflammatory Agents Anti-inflammatory Antimalarials Area Arts Blood Blood Coagulation Disorders Cells Cessation of life Child Coagulation Process Communicable Diseases Contracts Dependence Environment Epidemic Erythrocytes Failure Fetal Resorption Fetus Fibrinolysis Genes Goals Health Hemorrhage Histopathology Human Immune Immune response Immunologics Immunotherapy Inbred Mouse Induced Abortion Infection Inflammatory Inflammatory Response Pathway Interferon Type II Intervention Investigation Knowledge Laboratory Animals Low Birth Weight Infant Malaria Malaria Vaccines Malaria prevention Mediating Minor Modeling Molecular Morbidity - disease rate Mothers Mus Mutant Strains Mice Nature Necrosis Neonatal Mortality Outcome Parasitemia Parasites Pathogenesis Pathologic Processes Pathology Pattern Placenta Plasma Plasmodium chabaudi Play Pregnancy Pregnancy Outcome Pregnancy loss Pregnant Women Premature Labor Prevention Process Production Relative (related person)Reproductive Immunology Research Research Personnel Resources Risk Role Staging Testing Ursidae Family Vaccines Vascular blood supply Work abortion animal facility base burden of illness case finding chemokine cytokine experience fetal fetus cell genetic manipulation improved innovation insight mortality mouse model novel null mutation pregnancy immunology pregnant preimplantation prenatal programs response stillbirth success therapy development tool transmission process trophoblast unborn child

项目摘要

DESCRIPTION (provided by applicant): The health of pregnant women and their unborn children is jeopardized by malarial infection in many regions of the world. When pregnant women contract malaria, maternal anemia, preterm labor, and low birth weight babies, or, in severe cases found in low endemic or epidemic situations, maternal death, abortion, and stillbirth, commonly occur. While a role for pro-inflammatory cytokine responses in malarial pathogenesis has been suggested, few mechanistic studies have explored this possibility in pregnancy. To address this important problem, we have developed a murine model for malaria during pregnancy that is characterized by mid-gestational fetal loss, similar to the outcomes seen in human severe malaria during pregnancy. The objective of this application is to characterize the immunopathogenic mechanisms that mediate malaria- induced pregnancy loss. The central hypothesis proposes thatTh1/pro-inflammatory cytokines produced during blood-stage malaria play a pivotal role in the compromise of pregnancy. The specific aims of the project are to identify the soluble immunopathogenic effectors and the relative role of anemia in fetal loss in malaria-infected mice, characterize the roles of fetal cells in this process, and characterize the molecular basis of placental pathology in malaria-infected mice. These aims will be achieved by assessing pregnancy outcome in mice with known tendencies toward Th1/pro-inflammatory and Th2/anti-inflammatory cytokine production during Plasmodium chabaudi AS infection, and by utilizing mice with null mutations in factors that manipulate the host cytokine response and mediate immunopathogenesis. Genetic manipulation of anemia will be used to assess the relatives roles of malarial anemia and cytokines in mediating fetal loss. The ability of fetal trophoblast cells to respond to the malarial infection and manipulate the placental immune environment and induce pathology will also be examined. Finally, the role of abnormal coagulation and/or fibrinolysis in inducing placental damage and fetal loss, and the dependence of these abnormalities on cytokine production patterns, will be analyzed. These studies will ultimately contribute to the development of interventions and vaccines to reduce the morbidity and mortality associated with malaria during pregnancy. Also, this work is expected to advance the field of reproductive immunology by providing insight into the complexities of the fetal/maternal relationship and the impact of infectious diseases on this relationship.

描述（由申请人提供）：在世界许多地区，孕妇及其未出生子女的健康受到疟疾感染的危害。当孕妇患疟疾，产妇贫血，早产和低出生体重婴儿时，或者在低流行或流行病的严重病例中，孕产妇死亡，流产和死产通常会发生。尽管已经提出了促炎细胞因子反应在疟疾发病机理中的作用，但很少有机械研究在妊娠中探讨了这种可能性。为了解决这个重要的问题，我们在怀孕期间开发了一种用于疟疾的鼠模型，其特征是妊娠中期胎儿丧失，类似于怀孕期间人类严重疟疾的结果。该应用的目的是表征介导疟疾诱发妊娠丧失的免疫致病机制。中央假设提出，血阶段疟疾期间产生的TH1/促炎性细胞因子在妊娠折衷方面起关键作用。该项目的具体目的是鉴定可溶性免疫病作用效应子和贫血在疟疾感染小鼠中的相对作用，表征胎儿细胞在此过程中的作用，并表征胎盘病理学在疟疾感染小鼠中的分子基础。这些目的将通过评估具有已知趋势的Th1/促炎性趋势的妊娠结局，而Chabaudi疟原虫期间的Th2/抗炎性细胞因子产生作为感染，并利用用无效的小鼠在操纵宿主细胞因子反应和介导免疫原理的因素中使用无效的小鼠。贫血的遗传操纵将用于评估疟疾贫血和细胞因子在介导胎儿丧失中的亲属作用。还将检查胎儿滋养细胞对疟疾感染反应并操纵胎盘免疫环境和诱导病理学的能力。最后，将分析异常凝血和/或纤维蛋白溶解在诱发胎盘损伤和胎儿丧失中的作用，以及这些异常对细胞因子产生模式的依赖性。这些研究最终将有助于开发干预措施和疫苗，以降低怀孕期间与疟疾相关的发病率和死亡率。同样，这项工作有望通过洞悉胎儿/产妇关系的复杂性以及传染病对这种关系的影响来推进生殖免疫学领域。