Immunopathogenesis of Severe Malaria During Pregnancy

描述（由申请人提供）：在世界许多地区，孕妇及其未出生儿童的健康受到疟疾感染的威胁。当孕妇感染疟疾、产妇贫血、早产和婴儿出生体重过低时，或在低流行或流行情况下发现的严重情况下，通常会发生产妇死亡、流产和死产。虽然促炎细胞因子反应在疟疾发病机制中的作用已被提出，但很少有机制研究探讨妊娠期这种可能性。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，类似于人类妊娠期严重疟疾的结果。本应用程序的目的是表征免疫致病机制，介导疟疾引起的妊娠损失。中心假说提出血期疟疾期间产生的th1 /促炎细胞因子在妊娠妥协中起关键作用。该项目的具体目的是鉴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，表征胎儿细胞在这一过程中的作用，并表征疟疾感染小鼠胎盘病理的分子基础。这些目标将通过评估chabaudi AS感染期间已知Th1/促炎和Th2/抗炎细胞因子产生倾向的小鼠的妊娠结局，以及利用操纵宿主细胞因子反应和介导免疫发病机制的因子零突变的小鼠来实现。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的亲属作用。胎儿滋养细胞对疟疾感染的反应能力、操纵胎盘免疫环境和诱导病理的能力也将被检查。最后，将分析异常凝血和/或纤溶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。这些研究最终将有助于开发干预措施和疫苗，以减少怀孕期间与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/母亲关系的复杂性以及传染病对这种关系的影响，推动生殖免疫学领域的发展。

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.