High-density lipoprotein and A. fumigatus pathogenesis

描述(申请人提供)：高密度脂蛋白(高密度脂蛋白)是通过血液传播的蛋白质和脂质的集合，历史上几乎只在胆固醇反向运输和预防心血管疾病的背景下进行研究。本研究的目的是探索高密度脂蛋白与抵抗侵袭性曲霉病(IA)之间的新联系。侵袭性曲霉病是一种由霉菌病原体烟曲霉引起的危及生命的感染。在高密度脂蛋白中发现的最丰富的蛋白质是载脂蛋白A-I(apoA-I)，这是一种脂质结合分子，它是这些颗粒所具有的许多心脏保护功能的基础。我们的初步数据显示，apoA-I(-/-)小鼠显著增加了对实验性IA的易感性，首次证明脂蛋白代谢和 真菌的发病机制是有联系的。与感染野生型的小鼠相比，AF感染的apoA-I(-/-)小鼠表现出更大的真菌负担、更多的炎症和更快的死亡率。体外研究表明，apoA-I能与AF分生孢子结合并抑制其萌发，表明其具有抗真菌活性。此外，apoA-I与培养的巨噬细胞的相互作用增强了其杀灭分生孢子的能力，表明apoA-I具有与真菌清除有关的免疫调节作用。基于这些发现，我们假设apoA-I通过(1)通过对真菌的抑制作用和对宿主细胞的刺激作用来限制真菌负荷，以及(2)通过调节炎症反应来促进清除，而不触发损伤性的过度炎症，从而保护组织免受IA期间的损伤。目的1确定载脂蛋白A-I在房颤感染过程中控制真菌负荷的机制，重点是直接抗真菌作用和促进先天免疫细胞抗真菌活性的间接作用。高密度脂蛋白在循环中的主要作用是预防血管炎症；目标2将确定载脂蛋白A-I在房颤诱导的炎症中的作用及其与IA小鼠模型致死结局的关系。最后，无论载脂蛋白A-I是通过控制真菌负荷(目标1)还是通过限制破坏性宿主炎症(目标2)来预防房颤感染，其有益效果表明在IA期间控制载脂蛋白A-I水平可用于改善治疗结果。目的3将验证这样一个假设，即肺和/或全身apoA-I或其肽类似物的增加，提供了对烟曲霉菌的治疗性保护。这项研究的发现有可能将针对高密度脂蛋白的治疗方法带入传染病的肺保护领域。高密度脂蛋白已经在心血管疾病的开发过程中。1

DESCRIPTION (provided by applicant): High-density lipoproteins (HDL) are blood-borne assemblies of protein and lipid that have been historically studied almost exclusively in the context of reverse cholesterol transport and the protection from cardiovascular disease. The purpose of this study is to explore a new link between HDL and the defense against invasive aspergillosis (IA), a life-threatening infection caused by the mold pathogen Aspergillus fumigatus. The most abundant protein found in HDL is apolipoprotein A-I (apoA-I), a lipid-binding molecule that underlies many of the cardioprotective functions attributed to these particles. Our preliminary data has shown that apoA-I(-/-) mice have dramatically increased susceptibility to experimental IA, demonstrating for the first time that lipoprotein metabolism and fungal pathogenesis are linked. AF-infected apoA-I(-/-) mice revealed a greater fungal burden, increased inflammation, and accelerated mortality compared to infected wild type mice. In vitro studies revealed that apoA-I binds to AF conidia and impairs germination, suggesting antifungal activity. In addition, the interaction of apoA-I with cultured macrophages enhanced their ability t kill conidia, suggesting that apoA-I has immunomodulatory effects that are relevant to fungal clearance. Based on these findings, we hypothesize that apoA-I protects against tissue injury during IA by (1) limiting fungal burden via inhibitory effects on the fungus and stimulatory effect on host cells, and (2) by adjusting the inflammatory response to promote clearance without triggering injurious hyperinflammation. Aim 1 will determine the mechanism by which apoA-I controls fungal burden during AF infection, focusing on direct antifungal effects as well as indirect effects on promoting the antifungal activity of innate immune cells. A major role for HDL in the circulation is preventing vascular inflammation; Aim 2 will determine the contribution of apoA-I to AF-induced inflammation and its relationship to fatal outcome in mouse models of IA. Finally, regardless of whether apoA-I protects against AF infection by controlling fungal burden (Aim 1) or by limiting destructive host inflammation (Aim 2), its beneficial effects suggest that manipulating apoA-I levels could be used to improve therapeutic outcome during IA. Aim 3 will test the hypothesis that pulmonary and/or systemic increases in apoA-I, or its peptide analogs, confer therapeutic protection against A. fumigatus. The findings from this study have the potential to bring treatments that are targeted to HDL, which are already in the developmental pipeline in the context of cardiovascular disease, into the realm of pulmonary protection in infectious disease. 1