Trophoblast Immune Responses to Placental Malaria

滋养层细胞对胎盘疟疾的免疫反应

基本信息

批准号：
8069974
负责人：
JULIE M MOORE
金额：
$ 18.38万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-15 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8069974
关键词：
Accounting Affect Antigen-Presenting Cells Area Binding Biology Birth Blood Catabolism Cell Culture System Cell physiology Cells Cellular biology Cessation of life Chemotaxis Child Chronic Conditioned Culture Media Development Diagnostic Disease Disease Outcome Endothelium Erythrocytes Exposure to Fetal Growth Retardation Fetus Future Glycosylphosphatidylinositols Goals Hematogenous Hemoglobin Host-Parasite Relations Immune Immune response Immunity Immunobiology Immunologics Immunology Immunotherapy In Vitro Infant Infection Infiltration Inflammatory Investigation Knowledge Life Ligands Malaria Maternal-Fetal Exchange Mediating Molecular Biology Mononuclear Morbidity - disease rate Mothers Outcome Parasites Pathogenesis Pathology Pathway interactions Placenta Plasmodium falciparum Play Polysaccharides Population Pregnancy Pregnant Women Preventive Preventive Intervention Public Health Research Research Design Resources Risk Role Signal Pathway Syncytiotrophoblast System Testing Toxin Vaccine Design Vaccines Virulent Work adverse outcome base cell type chemokine cytokine experience extracellular fetal fetus cell hemozoin improved innate immune function innovation monocyte mortality novel novel diagnostics prevent public health relevance receptor response tool trophoblast

项目摘要

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.

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多种机制介导的，包括寄生虫感染的红细胞对宿主细胞的细胞粘附以及寄生虫释放毒素。对于抗原呈递细胞和内皮细胞，这些毒素和细胞粘附在调节宿主细胞功能中的作用已被充分描述，但对于合体滋养层（胎盘中与母体血液直接接触的胎儿细胞）尚未得到充分探索。这代表了知识上的一个关键差距，因为胎盘中恶性疟原虫的隔离会导致严重的胎盘病理学和不良的出生结果。该提案的目的是描述合体滋养层的功能变化，特别是与免疫相关的变化，这些变化是由受感染的红细胞和寄生虫毒素的特异性结合引起的。拟议研究的中心假设是，合体滋养层作为先天免疫细胞对母体恶性疟原虫感染做出反应，有能力影响母体对疟疾的局部免疫反应。拟议研究的基本原理是，如果合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，那么在努力预防与这种感染相关的不良出生结果时必须考虑其贡献。该提案的目标将通过一项具体目标来实现，该具体目标将寻求表征细胞粘附的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。这将通过检查受感染的红细胞、寄生虫疟原虫色素和糖基磷脂酰肌醇对合体滋养层先天免疫信号传导途径的影响以及这些细胞趋化单核细胞的能力来完成。此外，还将评估来自疟疾刺激的合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增进我们对母胎界面处疟疾寄生虫/宿主关系的免疫生物学的整体理解，并将为未来的研究奠定基础，这些研究旨在阐明如何操纵这种关系，以防止因母体感染而导致的不良出生结果。疟疾感染。最终，所获得的知识对于持续努力开发新的诊断和干预措施以预防和控制怀孕期间的疟疾以及生活在疟疾地区的母亲和婴儿的相关发病率和死亡率至关重要。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，特别是在胎盘水平。成功完成拟议工作将有助于开发改进的疟疾诊断工具和预防疗法，从而降低接触这种毁灭性疾病的孕妇及其婴儿的发病率和死亡率。