The Lung and Malaria

描述（由申请人提供）：本申请的广泛、长期目标是更好地了解肺在疟原虫感染中的作用。肺部对疾病的两个阶段起着至关重要的作用。 1)肝（第一代）裂殖子以裂殖体的形式离开肝脏，裂殖体是包裹在肝细胞膜中的大包寄生虫，并行进到肺部，在那里它们被释放到血液中。这种在无症状的肝脏阶段和有症状的血液阶段之间的关键转变是完全未知的。因为只有少量的肝裂殖子参与生命周期的这一关键阶段，针对这一瓶颈可能会预防临床疟疾。 2)红细胞裂殖子的后续世代可以隔离到肺微循环，在那里它们触发损伤内皮细胞的炎性过程，导致由于肺泡屏障的破坏而导致的肺水肿。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和经常致命的并发症。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得到证实，主要是在人类尸检材料中，在一定程度上也在实验性严重疟疾的小鼠模型中，但对个体细胞相互作用的动力学沿着最终导致疟疾ALI/ARDS的炎症级联反应一无所知。 我们计划利用活体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性的荧光报告底物和分子探针，以解决这些重要的问题。具体目标是建立一个小鼠模型，用于肺的活体显微镜检查，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，3）表征与肺微循环中的裂殖体阻滞和裂殖子释放相关的事件。更好地了解寄生虫与肺部的相互作用可能有助于指导干预措施，以减少每年因疟疾死亡的数百万人，特别是幼儿。 公共卫生相关性：肺在疟疾感染的两个关键阶段起着至关重要的作用。该项目旨在描述疟原虫感染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，以减少10亿携带寄生虫的人的临床症状，并挽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.