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理被认为是由多种机制介导的，包括寄生虫感染的红细胞向宿主细胞的细胞加热以及从寄生虫中释放毒素。这些毒素和细胞加容在调节宿主细胞功能中的作用很好地描述了抗原呈递细胞和内皮，但尚未充分探索合成细胞的合成细胞，该细胞是直接与Placenta中母体血液接触的胎儿细胞。这代表了知识的危险差距，因为胎盘中恶性疟原虫的隔离会导致胎盘病理学明显和出生不良的结局。该建议的目的是表征功能变化，尤其是与免疫相关的功能变化，在合成肌细胞细胞中，这些变化是由感染的红细胞和寄生虫毒素的特异性结合引起的。拟议的研究的中心假设是，合成毒素细胞对孕产妇的恶性疟原虫感染反应是一种先天免疫细胞，具有影响局部母体免疫反应对疟疾的局部免疫反应的能力。拟议的研究的理由是，如果合成细胞育肥细胞能够对产妇疟疾感染进行免疫反应，从而有助于保护或发病机理，那么必须考虑其贡献以防止与这种感染相关的较差的出生结果。该提案的目标将通过一个特定的目的来实现，该目标将试图表征细胞辅助性恶性疟原虫感染的红细胞和其他寄生虫成分对合成肌细胞的免疫功能的影响。这将通过检查感染的红细胞的影响，寄生虫血元和糖基磷脂酰肌醇对合成蛋白胞育细胞中先天性免疫信号通路的影响以及这些细胞对化学涂层单核细胞的能力。此外，将评估来自疟疾刺激的合成型成素细胞影响单核细胞激活和吞噬功能的能力。这些研究的成功完成将大大提高我们对Maternofetal界面上疟疾寄生虫/宿主关系的免疫生物学的总体理解，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产妇疟疾而导致的不良出生结果。最终，获得的知识将是为了开发新的诊断和干预措施，以预防和控制怀孕期间疟疾的新诊断和干预措施以及对疟疾地区的母亲和婴儿相关的发病率和死亡率的努力至关重要。 公共卫生相关性：我们对孕妇疟疾发病机理的理解存在很大的差距，尤其是在胎盘一级。拟议工作的成功完成将有助于开发改善疟疾的诊断工具和预防疗法，从而减少暴露于这种毁灭性疾病的孕妇及其婴儿的发病率和死亡率。