The Lung and Malaria

描述(由申请人提供)：这项申请的广泛、长期目标是更好地了解肺部在疟原虫感染中的作用。肺部在疾病的两个阶段起着至关重要的作用。1)肝脏(第一代)裂殖子以分体的形式离开肝脏，即包裹在肝细胞膜上的大包寄生虫，并进入肺部，在那里它们被释放到血液中。在感染的静止期和有症状的血液期之间的这一关键过渡完全没有被探索过。由于只有一小部分肝裂殖子参与了生命周期的这一关键阶段，针对这一瓶颈可能有助于预防临床疟疾。2)后续世代的红细胞裂殖子可以隔离到肺微循环中，在那里它们触发炎症过程，损伤内皮细胞，由于血-肺泡屏障的破坏而导致肺水肿。急性肺损伤(ALI)及其最严重的形式--急性呼吸窘迫综合征(ARDS)是严重疟疾患者的重要且往往是致命的并发症。受感染的红细胞、白细胞和血小板在肺微循环中隔离的能力已经被证明，主要是在人类尸检材料中，在一定程度上也在实验性重症疟疾的小鼠模型中被证明，但关于最终导致疟疾ALI/ARDS的炎性级联反应的个体细胞相互作用的动力学尚不清楚。我们计划利用体内显微成像的最新进展，使用转基因寄生虫和小鼠，结合高度特异的荧光报告底物和分子探针，来解决这些重要问题。具体目的是建立小鼠活体肺部显微镜模型，2)确定与疟疾ALI/ARDS发病机制相关的细胞相互作用的动力学，以及3)表征与肺微循环中的裂殖体停止和裂殖子释放相关的事件。提高对寄生虫与肺部相互作用的了解可能有助于指导干预措施，以减少每年数百万人死于疟疾，特别是幼童。 与公共卫生相关：肺部在疟疾感染的两个关键阶段起着至关重要的作用。该项目旨在描述感染疟原虫的小鼠肺微血管中的动态细胞过程。更好地了解肺部在疟疾感染中的作用，可能有助于设计新的方法，以减轻携带这种寄生虫的10亿人的临床症状，并拯救每年死于这种毁灭性热带疾病的200万至300万人的生命，其中大多数是儿童。

DESCRIPTION (provided by applicant): The broad, long-term objective of this application is to obtain a better understanding of the role of the lungs in a Plasmodium infection. The lungs contribute crucially to two stages of the disease. 1) Hepatic (first-generation) merozoites leave the liver as merosomes, large packets of parasites enclosed in hepatocyte membrane, and travel to the lungs where they are released into the blood. This critical transition between the silent liver phase and the symptomatic blood phase of the infection is completely unexplored. Because only a small number of hepatic merozoites are involved in this crucial segment of the life cycle, targeting this bottleneck may allow prevention of clinical malaria. 2) The subsequent generations of erythrocytic merozoites can sequester to the pulmonary microcirculation where they trigger inflammatory processes that damage endothelial cells leading to pulmonary edema due to breakdown of the blood-alveolar barrier. Acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS), are important and frequently fatal complications in patients with severe malaria. The ability of infected red blood cells, leukocytes, and platelets to sequester within the pulmonary microcirculation has been demonstrated, predominantly in human autopsy material and to a certain degree also in a murine model of experimental severe malaria, but nothing is known about the dynamics of individual cellular interactions along the inflammatory cascade that ultimately leads to malarial ALI/ARDS. We plan to exploit the recent advances in intravital microscopic imaging, using transgenic parasites and mice in combination with highly specific fluorogenic reporter substrates and molecular probes, to address these important questions. Specific aims are to establish a murine model for intravital microscopy of the lungs, 2) define the dynamics of the cellular interactions associated with the pathogenesis of malarial ALI/ARDS, and 3) characterize the events associated with merosome arrest and merozoite release in the pulmonary microcirculation. Improved knowledge on parasite interaction with the lungs may help guide interventions to reduce the millions of annual deaths due to malaria, particularly in young children. PUBLIC HEALTH RELEVANCE: The lungs play a crucial role at two crucial stages of a malaria infection. This project aims to characterize dynamic cellular processes in the pulmonary microvasculature of Plasmodium-infected mice. A better understanding of the role of the lungs in a malaria infection may help design new approaches to reduce clinical symptoms in the 1 billion people that carry the parasite and to save the lives of the 2-3 million people, most of them children, who succumb to this devastating tropical disease every year.