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; 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传播组件，在历史上几乎完全研究了在反向胆固醇转运的背景下进行的，并且对心血管疾病的保护。这项研究的目的是探索HDL与防御侵入性曲霉菌病（IA）之间的新联系，这是霉菌病原体曲霉菌引起的威胁生命的感染。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，是归因于这些颗粒的许多心脏保护函数的基础。我们的初步数据表明，apoA-I（ - / - ）小鼠对实验IA的敏感性显着提高，这是第一次证明脂蛋白代谢和 真菌发病机理是连接的。与感染的野生型小鼠相比，感染AF感染的ApoA-I（ - / - ）小鼠具有更大的真菌负担，炎症增加和加速死亡率。体外研究表明，ApoA-I与AF分生孢子结合并损害发芽，表明抗真菌活性。此外，ApoA-I与培养的巨噬细胞的相互作用增强了其能力T杀死分生孢子，这表明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限制真菌负担来保护IA期间的组织损伤，对宿主细胞的抑制作用和刺激作用，以及（2）通过不触发伤害性高症而促进清除的炎症反应来促进清除率。 AIM 1将确定APOA-I在AF感染过程中控制真菌负担的机制，重点关注直接抗真菌效应以及对促进先天免疫细胞抗真菌活性的间接影响。 HDL在循环中的主要作用是预防血管炎症。 AIM 2将确定APOA-I对AF引起的炎症的贡献及其与IA小鼠模型中的致命结果的关系。最后，无论APOA-I是否通过控制真菌负担（AIM 1）或限制破坏性宿主炎症（AIM 2）来防止AF感染（AIM 2），其有益效果都表明可以使用APOA-I水平来改善I​​A期间的治疗结果。 AIM 3将检验以下假设：ApoA-I或其肽类似物的肺和/或全身增加，允许对烟曲霉的治疗保护进行保护。这项研究的发现有可能将针对HDL的治疗方法带入心血管疾病中已经处于发育渠道中的HDL，进入了传染病的肺部保护领域。 1