Immunopathogenesis of Severe Malaria During Pregnancy

描述（由申请人提供）：在世界许多地区，疟疾感染危及孕妇及其未出生婴儿的健康。当孕妇感染疟疾时，通常会发生产妇贫血、早产和低出生体重婴儿，或者在低流行或流行情况下发现的严重病例中，产妇死亡、流产和死胎。虽然促炎细胞因子反应在疟疾发病机制中的作用已被提出，但很少有机制研究探讨了妊娠中的这种可能性。为了解决这一重要问题，我们开发了一种妊娠期间疟疾的小鼠模型，其特征在于妊娠中期胎儿丢失，类似于妊娠期间人类严重疟疾中观察到的结果。本申请的目的是表征介导疟疾诱导的妊娠丢失的免疫病理机制。中心假说认为，Th 1/促炎细胞因子在血液阶段疟疾期间产生的妊娠妥协中起着关键作用。该项目的具体目标是确定可溶性免疫致病效应物和贫血在疟疾感染小鼠胎儿丢失中的相对作用，描述胎儿细胞在这一过程中的作用，并描述疟疾感染小鼠胎盘病理学的分子基础。这些目标将通过评估妊娠结局的小鼠与已知的倾向Th 1/促炎和Th 2/抗炎细胞因子的生产过程中疟原虫chabaudi AS感染，并通过利用小鼠无效突变的因素，操纵宿主细胞因子的反应和介导的免疫发病机制。贫血的遗传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的反应和操纵胎盘免疫环境以及诱导病理的能力。最后，凝血和/或纤溶异常在诱导胎盘损伤和胎儿丢失中的作用，以及这些异常对细胞因子产生模式的依赖性，将进行分析。这些研究最终将有助于制定干预措施和疫苗，以减少与妊娠期疟疾有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进生殖免疫学领域。

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.