Molecular Mechanisms of Plasmodium Falciparum Adherence to the Human Placenta

描述（由申请人提供）：疟疾流行地区的大多数孕妇在妊娠期间的某个时间点感染胎盘型疟疾（PM）。PM是一种严重的疟疾，导致产妇并发症，并对胎儿的存活和生长产生负面影响。PM被定义为（1）恶性疟原虫感染的红细胞（iRBC）在胎盘的母体血液空间中的积累，以及（2）iRBC与胎盘细胞的细胞粘附，如覆盖绒毛膜绒毛并面向母体血液循环的绒毛间隙的合胞体滋养层（STB）。iRBC与宿主受体细胞粘附的一种机制是通过PfEMP 1蛋白，PfEMP 1蛋白由寄生虫var基因编码，并以互斥方式在iRBC表面表达。关于胎盘受体，硫酸软骨素A（CS-A）一直与iRBC细胞粘附有关。其他声称的受体的生理相关性仍然存在争议，大多数PM研究人员认为，其他胎盘受体仍有待描述。在知识方面仍然存在一些差距。首先，研究人员主要集中在识别由足月胎盘表达的受体，而没有考虑妊娠早期该组织与iRBC之间的关系。其次，他们只研究了绒毛间隙参与支持细胞粘附，完全忽略了胎盘的基板区域。iRBC是否细胞粘附于早期妊娠组织以及它们是否细胞粘附于基板中的细胞仍然是我们目前正在用原代人胎盘组织探索的开放性问题。我们首先回顾了妊娠早期绒毛间隙和基底板组织中假定受体的表达。在绒毛间隙，我们的研究结果表明，CS-A可能不参与胎盘感染的初始阶段，因为我们没有检测到这种抗原的STB覆盖，是在接触母体血液。在基板中，我们的研究结果表明，与母体血液接触的细胞滋养层（CTB）表达ICAM-1，这是非妊娠个体中iRBC的一种充分表征的受体。我们假设iRBC细胞粘附可能涉及妊娠早期人类胎盘细胞（包括与母体血液直接接触的STB和CTB）在绒毛间隙和基板中独特表达的特定分子。我们将通过以下实验来验证这一假设。首先（目的1），我们将确定分子的空间和时间定位发挥作用，在妊娠早期iRBC细胞粘附。接下来（目标2），我们将在功能上确定这些分子是否作为iRBC的早期妊娠胎盘受体。最后（目的3），我们将确定同源寄生虫编码的配体参与细胞粘附。在这些实验结束时，我们将大大提高我们对iRBC和人胎盘之间分子相互作用的理解。我们提出的工作将建立研究整个人类妊娠PM的实验系统，并帮助疟疾领域确定治疗这种疾病的潜在药物和疫苗靶点。公共卫生相关性：所提出的实验的结果将大大推进我们对恶性疟原虫感染的红细胞（iRBC）和妊娠早期人类胎盘组织之间的配体-受体分子相互作用的理解。作为我们拟议实验的一部分，我们将开发新的实验模型，这将有助于其他有兴趣研究整个人类妊娠期胎盘疟疾的研究人员。我们提出的工作将切实帮助疟疾领域确定潜在的药物和疫苗靶点。

DESCRIPTION (provided by applicant): The majority of pregnant women in malaria-endemic regions contract placental malaria (PM) at some point during gestation. PM is a severe form of malaria, leading to maternal complications and negatively affecting the survival and growth of the fetus. PM is defined as (1) the accumulation of Plasmodium falciparum-infected red blood cells (iRBCs) in the maternal blood spaces of the placenta, and (2) the cytoadherence of iRBCs to placental cells, such as syncytiotrophoblasts (STBs) that cover the chorionic villi and face the intervillous space where maternal blood circulates. One mechanism for iRBC cytoadherence to host receptors is through PfEMP1 proteins, encoded by parasite var genes and expressed on the surface of iRBCs in a mutually exclusive manner. With respect to placental receptors, chondroitin sulfate A (CS-A) has been consistently implicated in iRBC cytoadhesion. The physiological relevance of other purported receptors remains controversial, and most PM researchers agree that additional placental receptors remain to be described. Some gaps in knowledge remain. First, investigators have primarily focused on identifying receptors expressed by term placentas and have not considered the relationship between this tissue and iRBCs during early gestation. Second, they have only studied the involvement of the intervillous space in supporting cytoadhesion, completely ignoring the basal plate region of the placenta. Whether iRBCs cytoadhere to early gestation tissue and whether they cytoadhere to cells in the basal plate remain open questions that we are currently exploring with primary human placental tissue. We first reviewed the expression of putative receptors in early gestation tissue, both in the intervillous space and the basal plate. In the intervillous space, our results suggest that CS-A may not be involved in the initial stages of placental infection because we did not detect this antigen on the STB covering that is in contact with maternal blood. In the basal plate, our results reveal that cytotrophoblasts (CTBs) in contact with maternal blood express ICAM-1, a well-characterized receptor for iRBCs in non-pregnant individuals. We hypothesize that iRBC cytoadhesion may involve specific molecules that are uniquely expressed in both the intervillous space and the basal plate by early gestation human placental cells, including STBs and CTBs that are in direct contact with maternal blood. We will test this hypothesis with the following experiments. First (Aim 1), we will identify molecules that are spatially and temporally positioned to play a role in early gestation iRBC cytoadhesion. Next (Aim 2), we will functionally determine if these molecules act as early gestation placental receptors for iRBCs. Finally (Aim 3), we will identify cognate parasite-encoded ligands involved in cytoadhesion. At the conclusion of these experiments, we will have substantially advanced our understanding of the molecular interactions between iRBCs and the human placenta. Our proposed work will establish experimental systems for studying PM throughout human gestation and aid the malaria field in identifying potential drug and vaccine targets for treating this condition. PUBLIC HEALTH RELEVANCE: The results of the proposed experiments will substantially advance our understanding of the ligand-receptor molecular interactions between Plasmodium falciparum-infected red blood cells (iRBCs) and early gestation human placental tissue. As part of our proposed experiments, we will develop novel experimental models that will be useful to other researchers interested in studying placental malaria throughout human gestation. Our proposed work will realistically aid the malaria field in identifying potential drug and vaccine targets.