Plasmodium Sporozoite-Kupffer Cell Passage

描述：(申请人提供)：疟疾仍然是全球人类死亡的主要原因。尽管这种健康问题很严重，但令人惊讶的是，人们对疟疾在亚细胞水平上入侵肝脏的分子机制知之甚少。了解子孢子靶向肝脏、进入肝脏和在肝脏中存活是 非常重要的是要开发新的方法来对抗肝期的 疟疾。在被感染的蚊子传播后的几分钟内，疟疾子孢子 迅速定位于肝脏并感染肝细胞。为了到达它们在哺乳动物宿主中繁殖的初始位置，肝细胞、子孢子必须穿过连续的肝窦细胞层。为了做到这一点，子孢子选择性地识别、入侵和通过 肝窦Kupffer细胞，肝脏的稳定吞噬细胞。 这项建议的广泛的长期目标是了解哺乳动物疟原虫物种已经开发出的策略，以选择性地识别、主动入侵并安全地通过枯否细胞，枯否细胞是肝脏的专业静止吞噬细胞，到达它们在宿主肝脏中的初始哺育细胞，即肝细胞。我们的目标是表征疟疾子孢子和库普弗细胞之间的分子识别机制，以确定疟疾子孢子和库普弗细胞的组成 目的是为了在啮齿动物模型中确定寄生虫对巨噬细胞激活的影响。我们还将研究氏杆菌和禽库普弗细胞之间的相互作用。氏杆菌的红外型可以在吞噬细胞内分化和繁殖。 最后，我们希望将从这些动物模型获得的数据与人类Kupffer细胞和恶性疟原虫子孢子之间的相互作用进行比较。

DESCRIPTION: (provided by the applicant): Malaria remains a major cause of death in humans worldwide. Despite the severity of this health problem, it is surprising that very little is known about the molecular mechanisms governing the invasion of Plasmodium into the liver at the subcellular level. Understanding sporozoite targeting to, entry into, and survival in the liver is of great importance to develop new approaches to fight the hepatic phase of malaria. Within minutes after transmission by an infected mosquito, malaria sporozoites are rapidly targeted to the liver and infect hepatocytes. To reach their initial site of multiplication in the mammalian host, the hepatocyte, sporozoites have to cross the continuous layer of sinusoidal cells. To accomplish this, sporozoites selectively recognize, invade, and pass through sinusoidal Kupffer cells, the stationary phagocytes of the liver. The broad long-term objective of this proposal is to understand the strategies mammalian Plasmodium species have developed to selectively recognize, actively invade, and safely passage through Kupffer cells, the professional stationary phagocytes of the liver, to reach their initial nurse cell in the host liver, the hepatocyte. We aim to characterize the molecular recognition mechanism between malaria sporozoites and Kupffer cells, to define the composition of the compartment that harbors the parasites, and to determine the effect of the parasites on macrophage activation in a rodent model. We will also examine the interaction between P. gallinaceum, whose exoerythrocytic forms can differentiate and multiply inside phagocytic cells, and avian Kupffer cells. Finally, we wish to compare the data obtained from these animal models with the interaction between human Kupffer cells and P. falciparum sporozoites.