Trophoblast Immune Responses to Placental Malaria

描述(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与宿主细胞的黏附和寄生虫释放毒素。这些毒素和细胞黏附在调节宿主细胞功能中的作用在抗原提呈细胞和内皮细胞中已有很好的描述，但对于合体滋养层细胞还没有充分的研究，合体滋养层细胞是胎儿细胞与胎盘中的母体血液直接接触。这代表着知识上的严重差距，因为将恶性疟原虫隔离在胎盘中会导致严重的胎盘病理和不良的出生结局。这项建议的目的是描述合体滋养层细胞的功能变化，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。这项研究的中心假设是，合体滋养层细胞作为先天性免疫细胞对母体恶性疟原虫感染做出反应，具有影响当地母体对疟疾的免疫反应的能力。拟议研究的理由是，如果合体滋养层细胞能够对母体疟疾感染做出免疫反应，有助于保护或致病，那么在努力防止与这种感染相关的不良出生结局时，必须考虑它的贡献。该提案的目标将通过一个具体目标来实现，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体滋养层细胞免疫功能的影响。这将通过检查感染的红细胞、寄生虫血球蛋白和糖基磷脂酰肌醇对合体滋养层细胞固有免疫信号通路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体滋养层细胞的条件培养液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极大地促进我们对母胎界面疟疾寄生虫/宿主关系的整体免疫生物学的了解，并将为未来旨在阐明如何处理这种关系以防止因母亲疟疾感染而导致的不良出生结局的研究奠定基础。归根结底，所获得的知识将对为预防和控制孕期疟疾以及生活在疟疾流行地区的母婴的相关发病率和死亡率制定新的诊断和干预措施的持续努力发挥关键作用。 与公共卫生的相关性：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。拟议工作的成功完成将有助于改进疟疾的诊断工具和预防性治疗，从而降低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.