Determinants of Plasmodium liver invasion

描述（由申请人提供）：疟疾是最致命的传染病之一，估计每年造成200万人死亡。尽管关于寄生虫周期的知识相当多，但我们对寄生虫如何感染脊椎动物宿主的理解是不完整的。当被感染的蚊子在吸血时递送子孢子时，感染开始。子孢子找到它们进入循环的途径，并且在它们通过的所有器官中，它们特异性地靶向并感染肝脏。先前的工作已经确定，子孢子附着于高度硫酸化的肝脏特异性糖胺聚糖（GAG），这些糖胺聚糖突出肝血管（称为窦状隙）的有孔壁。两种细胞类型排列在窦状隙中：内皮细胞和特化的巨噬细胞，称为枯否细胞。已知为了到达肝细胞，子孢子侵入库普弗细胞，而不是内皮细胞，表明子孢子-库普弗识别发生。尽管它对感染的结果很重要，但这一识别步骤的分子基础在很大程度上仍然未知。在初步工作中，我们已经确定了三个肽从噬菌体展示库，结合特异性库普弗细胞引起的子孢子入侵的抑制。通过将肽与枯否细胞上的靶蛋白交联，我们将鉴定和表征用于子孢子入侵的候选枯否细胞受体。我们推测，肽模仿子孢子蛋白质的构象，与库普弗细胞相互作用。我们将产生针对每种肽的抗体，并使用这些抗体来鉴定和表征在侵袭过程中可能与库普弗细胞相互作用的子孢子蛋白。这些蛋白质有可能成为开发预防肝脏感染的疟疾疫苗的候选者。公共卫生相关性：疟疾是最致命的传染病之一，估计每年造成200万人死亡。在受感染的蚊子将疟原虫子孢子递送到其宿主后，疟原虫子孢子进入循环并特异性地识别和侵入肝巨噬细胞（枯否细胞）。本项目旨在鉴定和鉴定与子孢子侵入肝枯否细胞有关的蛋白质（枯否受体和子孢子配体）。

DESCRIPTION (provided by applicant): Malaria is one of the deadliest infectious diseases and kills an estimated 2 million persons every year. Even though a considerable body of knowledge exists on the parasite cycle, our understanding of how the parasite infects its vertebrate host is incomplete. Infection is initiated when an infected mosquito delivers sporozoites at the time of blood feeding. The sporozoites find their way to the circulation and of all organs through which they transit, they specifically target and infect the liver. Previous work has established that sporozoites attach to highly sulfated, liver-specific glycosaminoglycans (GAGs) that protrude the fenestrated walls of the liver blood vessels, called sinusoids. Two cell types line the sinusoids: endothelial cells and specialized macrophages, termed Kupffer cells. It is known that to reach the hepatocytes, sporozoites invade Kupffer cells, not endothelial cells, indicating that sporozoite-Kupffer recognition takes place. Despite its importance for the outcome of infection, the molecular basis for this recognition step remains largely unknown. In preliminary work we have identified three peptides from a phage display library that bind specifically to Kupffer cells causing an inhibition of sporozoite invasion. By crosslinking the peptides to their target protein on the Kupffer cells, we will identify and characterize candidate Kupffer cell receptors for sporozoite invasion. We hypothesize that the peptides mimic the conformation of sporozoite proteins that interact with the Kupffer cells. We will produce antibodies against each of the peptides and use these antibodies to identify and characterize the sporozoite proteins that presumably interact with the Kupffer cells during invasion. Such proteins have the potential of becoming candidates for development of a malaria vaccine that prevents liver infection. PUBLIC HEALTH RELEVANCE: Malaria is one of the deadliest infectious diseases and kills an estimated 2 million persons every year. After an infected mosquito delivers Plasmodium sporozoites to its host it enters the circulation and specifically recognize and invade liver macrophages (Kupffer cells). This project is to identify and characterize the proteins (Kupffer receptors and sporozoite ligands) involved in sporozoite invasion of liver Kupffer cells.