Molecular Mechanisms of Plasmodium Falciparum Adherence to the Human Placenta

描述(申请人提供)：疟疾流行地区的大多数孕妇在怀孕期间的某个时候感染胎盘性疟疾(PM)。PM是一种严重的疟疾，会导致产妇并发症，并对胎儿的存活和生长产生负面影响。恶性疟原虫感染红细胞(IRBC)在胎盘母体血腔中的聚集，以及(2)iRBC与胎盘细胞的黏附，如覆盖绒毛的合体滋养层细胞(STB)，面向母体血液循环的绒毛间隙。IRBC细胞与宿主受体黏附的一种机制是通过PfEMP1蛋白，PfEMP1蛋白由寄生虫var基因编码，并以相互排斥的方式在iRBC表面表达。关于胎盘受体，硫酸软骨素A(CS-A)一直被认为与红细胞的细胞黏附有关。其他据称的受体的生理相关性仍然存在争议，大多数PM研究人员同意，其他胎盘受体仍有待描述。知识上的一些差距仍然存在。首先，研究人员主要专注于识别足月胎盘表达的受体，而没有考虑这种组织与早期妊娠期间iRBC之间的关系。其次，他们只研究了绒毛间间隙参与支持细胞黏附，完全忽略了胎盘的基板区域。IRBC细胞是否附着于早期妊娠组织以及它们是否附着于基底板中的细胞仍然是我们目前在原代人类胎盘组织中探索的开放问题。我们首先回顾了可能的受体在早期妊娠组织中的表达，包括绒毛间隙和基底板。在绒毛间隙，我们的结果表明CS-A可能不参与胎盘感染的初始阶段，因为我们没有在与母体血液接触的STB覆盖物上检测到这种抗原。在基板上，我们的结果显示，与母体血液接触的细胞滋养层细胞(CTB)表达ICAM-1，这是一种在非妊娠个体中很好地表征了iRBC的受体。我们推测，IRBC细胞黏附可能涉及特定的分子，这些分子由妊娠早期的人胎盘细胞，包括直接与母体血液接触的STB和CTB，在绒毛间隙和基底板中唯一表达。我们将通过以下实验来验证这一假设。首先(目标1)，我们将确定在空间和时间位置上对妊娠早期红细胞细胞黏附起作用的分子。下一步(目标2)，我们将从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(目标3)，我们将确定参与细胞黏附的同源寄生虫编码的配体。在这些实验的结论中，我们将大大推进我们对iRBC和人类胎盘之间的分子相互作用的理解。我们提议的工作将建立在整个人类妊娠期间研究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：拟议的实验结果将极大地促进我们对恶性疟原虫感染的红细胞(IRBC)与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。作为我们提议的实验的一部分，我们将开发新的实验模型，这些模型将对其他对研究人类妊娠期间胎盘疟疾感兴趣的研究人员有用。我们拟议的工作将切实帮助疟疾领域确定潜在的药物和疫苗目标。

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.