High-density lipoprotein and A. fumigatus pathogenesis

高密度脂蛋白与烟曲霉发病机制

• 批准号: 8709034
• 负责人: DAVID S ASKEW
• 金额: $ 35.87万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8709034
• 关键词: Alveolar Macrophages; Anti-Inflammatory Agents; Anti-inflammatory; Antifungal Agents; Apolipoprotein A-I; Aspergillosis; Aspergillus; Aspergillus fumigatus; Binding; Blood; Blood Circulation; Cardiovascular Diseases; Cells; Cholesterol; Clinical; Communicable Diseases; Data; Development; Enzymes; Epithelial; Equilibrium; Evaluation; Exposure to; Fatal Outcome; Genes; Germination; Goals; Grant; Growth; High Density Lipoproteins; Human; Hyphae; Immune; Immune response; Immune system; Immunocompromised Host; Immunosuppression; In Vitro; Industrial fungicide; Infection; Infection Control; Inflammation; Inflammatory Response; Injury; Knowledge; Life; Link; Lipid Binding; Lipids; Lipoproteins; Liquid substance; Lung; Malignant Neoplasms; Mediating; Membrane; Metabolism; Mission; Mitochondria; Molds; Mus; Outcome; Pathogenesis; Pathology; Patients; Pattern recognition receptor; Plasma; Predisposition; Prevention; Property; Proteins; Public Health; Recovery; Research; Risk; Role; Specificity; Staging; Testing; Therapeutic; Time; Tissues; Transplantation; United States National Institutes of Health; Wild Type Mouse; Work; base; cell type; cytokine; fungus; human disease; improved; killings; macrophage; mortality; mouse model; neutrophil; novel therapeutic intervention; particle; pathogen; patient population; peptide analog; prevent; response; reverse cholesterol transport; uptake; vascular inflammation

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

描述（由申请人提供）：高密度脂蛋白（HDL）是蛋白质和脂质的血液传播组件，历史上几乎仅在胆固醇逆向转运和预防心血管疾病的背景下进行了研究。本研究的目的是探索HDL与侵袭性曲霉病（IA）防御之间的新联系，侵袭性曲霉病是由霉菌病原体烟曲霉引起的危及生命的感染。在HDL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，是这些颗粒的许多心脏保护功能的基础。我们的初步数据表明，apoA-I（-/-）小鼠对实验性IA的易感性显著增加，首次证明脂蛋白代谢和 真菌的发病机制是有联系的。AF感染的apoA-I（-/-）小鼠显示出更大的真菌负荷，炎症增加，并加速死亡率相比，感染的野生型小鼠。体外研究表明apoA-I与AF分生孢子结合并损害萌发，表明具有抗真菌活性。此外，apoA-I与培养的巨噬细胞的相互作用增强了它们杀死分生孢子的能力，表明apoA-I具有与真菌清除相关的免疫调节作用。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）通过调节炎症反应以促进清除而不触发有害的过度炎症来保护IA期间的组织损伤。目的1将确定apoA-I在AF感染期间控制真菌负荷的机制，重点是直接抗真菌作用以及促进先天免疫细胞抗真菌活性的间接作用。HDL在循环中的主要作用是防止血管炎症;目的2将确定apoA-I对AF诱导的炎症的贡献及其与IA小鼠模型中的致死性结局的关系。最后，无论apoA-I是通过控制真菌负荷（Aim 1）还是通过限制破坏性宿主炎症（Aim 2）来预防AF感染，其有益作用表明，在IA期间，操纵apoA-I水平可用于改善治疗结果。目的3将检验肺和/或全身apoA-I或其肽类似物的增加赋予针对A的治疗保护的假设。烟熏。这项研究的发现有可能将针对HDL的治疗方法（在心血管疾病的背景下已经处于开发管道中）带入感染性疾病的肺保护领域。1