Trophoblast Immune Responses to Placental Malaria

滋养层细胞对胎盘疟疾的免疫反应

• 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
• 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

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释放毒素。这些毒素和细胞粘附在调节宿主细胞功能中的作用已被很好地描述为抗原提呈细胞和内皮，但尚未充分探讨合胞滋养细胞的作用，合胞滋养细胞是胎盘中与母体血液直接接触的胎儿细胞。这代表了一个关键的知识缺口，因为在胎盘中隔离恶性疟原虫会导致显著的胎盘病理和不良的分娩结果。本提案的目的是表征功能变化，特别是与免疫有关的功能变化，在合胞滋养细胞中，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。该研究的中心假设是，合胞滋养细胞作为一种先天免疫细胞对母体恶性疟原虫感染作出反应，并有能力影响母体对疟疾的局部免疫反应。提出这项研究的基本原理是，如果合胞滋养细胞能够对母体疟疾感染作出免疫反应，在保护或致病方面发挥作用，那么在预防与这种感染相关的不良分娩结果的努力中必须考虑到它的作用。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性恶性疟原虫感染的红细胞和其他寄生虫成分对合胞滋养细胞免疫功能的影响。这将通过检查受感染的红细胞、寄生虫血色素和糖基磷脂酰肌醇对合胞滋养细胞先天免疫信号通路的影响以及这些细胞对单核细胞的化学吸引能力来完成。此外，从疟疾刺激的合胞滋养细胞中提取的条件培养基影响单核细胞活化和吞噬功能的能力将被评估。这些研究的成功完成将大大促进我们对母胎界面上疟疾寄生虫/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，旨在阐明如何操纵这种关系，以防止由于孕产妇疟疾感染而导致的不良分娩结果。最终，所获得的知识将对正在进行的努力至关重要，这些努力将为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制定新的诊断和干预措施。