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，孕妇及其未出生孩子的健康受到疟疾感染的危害。当孕妇感染疟疾时，产妇贫血、早产和低出生体重儿，或者在低流行或流行情况下发现的严重病例，通常会发生孕产妇死亡、流产和死产。虽然促炎细胞因子反应在疟疾发病机制中发挥作用，但很少有机制研究探讨了妊娠中的这种可能性。为了解决这个重要问题，我们开发了一种妊娠期间疟疾小鼠模型，其特征是妊娠中期胎儿丢失，类似于人类妊娠期间严重疟疾的结果。本申请的目的是表征介导疟疾引起的妊娠丢失的免疫致病机制。中心假设提出，血期疟疾期间产生的 Th1/促炎细胞因子在妊娠损害中发挥关键作用。该项目的具体目标是确定可溶性免疫致病效应物以及贫血在感染疟疾的小鼠胎儿丢失中的相对作用，描述胎儿细胞在此过程中的作用，并描述感染疟疾的小鼠胎盘病理学的分子基础。老鼠。这些目标将通过评估已知在 Chabaudi 疟原虫 AS 感染期间产生 Th1/促炎和 Th2/抗炎细胞因子倾向的小鼠的妊娠结局，并利用在操纵宿主细胞因子反应的因子中具有无效突变的小鼠来实现。介导免疫发病机制。贫血的基因操作将用于评估疟疾贫血和细胞因子在介导胎儿丢失中的相关作用。还将检查胎儿滋养层细胞对疟疾感染做出反应、操纵胎盘免疫环境和诱导病理的能力。最后，将分析异常凝血和/或纤维蛋白溶解在诱导胎盘损伤和胎儿流产中的作用，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，以降低妊娠期间与疟疾相关的发病率和死亡率。此外，这项工作有望通过深入了解胎儿/母体关系的复杂性以及传染病对这种关系的影响来推动生殖免疫学领域的发展。