Trophoblast Immune Responses to Placental Malaria

描述（由申请人提供）：疟疾是一个巨大的全球公共卫生问题。恶性疟原虫的发病机制被认为是由几种机制介导的，包括寄生虫感染的红细胞对宿主细胞的细胞粘附和寄生虫毒素的释放。这些毒素和细胞粘附在调节宿主细胞功能中的作用在抗原呈递细胞和内皮细胞中有很好的描述，但在合体滋养层（胎盘中与母体血液直接接触的胎儿细胞）中还没有得到充分的研究。这代表了知识上的一个关键差距，因为胎盘中的恶性疟原虫隔离导致显著的胎盘病理学和不良的分娩结局。本建议的目的是表征功能变化，特别是那些相关的免疫，在合胞体滋养层引起的感染的红细胞和寄生虫毒素的特异性结合。这项研究的中心假设是，合体滋养层作为一种先天免疫细胞对母体恶性疟原虫感染作出反应，并有能力影响局部母体对疟疾的免疫反应。拟议研究的基本原理是，如果合胞体滋养层能够对母体疟疾感染做出免疫反应，有助于保护或发病，那么必须考虑其贡献，以防止与这种感染相关的不良出生结果。该提案的目标将通过一个特定目标来实现，该目标将寻求表征细胞粘附恶性疟原虫感染的红细胞和其他寄生虫成分对合体滋养层免疫功能的影响。这将通过检查感染的红细胞、寄生虫疟原虫色素和糖基磷脂酰肌醇对合胞体滋养层中先天免疫信号传导途径的影响以及这些细胞化学吸引单核细胞的能力来实现。此外，将评估来自疟疾刺激的合胞体滋养层的条件培养基影响单核细胞活化和吞噬功能的能力。这些研究的成功完成将显着推进我们的整体理解的疟疾寄生虫/宿主的关系在母胎界面的免疫生物学，并将奠定基础，为未来的研究，旨在阐明这种关系可以被操纵，以防止不良的出生结果，由于母体疟疾感染。最终，所获得的知识将对目前为预防和控制怀孕期间疟疾以及生活在疟疾流行地区的母亲和婴儿的相关发病率和死亡率而开发新的诊断和干预措施的努力至关重要。 公共卫生相关性：我们对孕妇疟疾发病机制的理解存在重大差距，特别是在胎盘层面。顺利完成拟议的工作将有助于开发更好的疟疾诊断工具和预防疗法，从而降低感染这一毁灭性疾病的孕妇及其婴儿的发病率和死亡率。

DESCRIPTION (provided by applicant): Malaria is an enormous, global public health problem. The pathogenesis of Plasmodium falciparum is thought to be mediated by several mechanisms, including the cytoadherence of parasite-infected red blood cells to host cells and the release of toxins from the parasites. A role for these toxins and cytoadherence in modulating host cell function is well described for antigen presenting cells and endothelium, but has not been adequately explored for syncytiotrophoblast, which is the fetal cell in direct contact with maternal blood in the placenta. This represents a critical gap in knowledge because sequestration of P. falciparum in the placenta leads to significant placental pathology and poor birth outcomes. The objective of this proposal is to characterize functional changes, particularly those relevant to immunity, in syncytiotrophoblast that are elicited by the specific binding of infected red blood cells and parasite toxins. The central hypothesis for the proposed research is that the syncytiotrophoblast responds to maternal P. falciparum infection as an innate immune cell, with capacity to impact the local maternal immune response to malaria. The rationale for the proposed research is that if syncytiotrophoblast is capable of responding immunologically to maternal malaria infection, contributing either to protection or pathogenesis, then its contribution must be considered in efforts to prevent poor birth outcomes associated with this infection. The objectives of the proposal will be achieved through one Specific Aim that will seek to characterize the influence of cytoadherent P. falciparum-infected red blood cells and other parasite components on syncytiotrophoblast immunologic function. This will be accomplished through examination of the impact of infected red blood cells, and parasite hemozoin and glycosylphosphatidyl- inositol on innate immune signaling pathways in syncytiotrophoblast as well as the ability of these cells to chemoattract mononuclear cells. Furthermore, the ability of conditioned media from the malarial-stimulated syncytiotrophoblast to influence monocyte activation and phagocytic function will be assessed. Successful completion of these studies will significantly advance our overall understanding of the immunobiology of the malarial parasite/host relationship at the maternofetal interface and will lay the groundwork for future studies designed to elucidate how this relationship can be manipulated to prevent poor birth outcomes due to maternal malarial infection. Ultimately, the knowledge gained will be pivotal in ongoing efforts to develop new diagnostics and interventions for the prevention and control of malaria during pregnancy and associated morbidity and mortality for mothers and infants living in malarious areas. PUBLIC HEALTH RELEVANCE: There are major gaps in our understanding of the pathogenesis of malaria in pregnant women, especially at the placental level. Successful completion of the proposed work will contribute to the development of improved diagnostic tools and preventive therapies for malaria that can reduce morbidity and mortality for both pregnant women and their infants who are exposed to this devastating disease.