Plasmodium Sporozoite-Kupffer Cell Passage

描述：（由申请人提供）：疟疾仍然是全世界人类死亡的主要原因。尽管这一健康问题的严重性，令人惊讶的是，很少有人知道的分子机制，在亚细胞水平上的疟原虫入侵到肝脏。了解子孢子的靶向，进入和存活在肝脏是 非常重要的是，开发新的方法来对抗肝脏阶段的 疟疾在被感染的蚊子传播后的几分钟内， 会迅速靶向肝脏并感染肝细胞为了到达它们在哺乳动物宿主肝细胞中增殖的初始位点，子孢子必须穿过连续的窦状隙细胞层。为了达到这一目的，子孢子选择性地识别、侵入和穿过 肝窦枯否细胞，肝脏的静止吞噬细胞。 该提案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，并安全地通过库普弗细胞，肝脏的专业固定吞噬细胞，以达到其在宿主肝脏中的初始护士细胞，肝细胞。我们的目的是描述疟原虫子孢子和库普弗细胞之间的分子识别机制，确定库普弗细胞的组成， 在啮齿动物模型中测定寄生虫对巨噬细胞活化的影响。我们还将研究P. gallinaceum（其红细胞外形式可以在吞噬细胞内分化和增殖）与禽类枯否细胞之间的相互作用。 最后，我们希望将从这些动物模型中获得的数据与人枯否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.