cPLA2, eicosanoids, and responses to fungal pathogens

cPLA2、类二十烷酸和对真菌病原体的反应

• 批准号: 8053029
• 负责人: CHRISTINA Carroll LESLIE
• 金额: $ 29.36万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8053029
• 关键词: Acute; Agonist; Alveolar Macrophages; Apoptotic; Arachidonic Acids; Aspergillus fumigatus; C Type Lectin Receptors; Calcium; Candida albicans; Catalytic Domain; Cells; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Development; Eicosanoid Production; Eicosanoids; Emigrations; Environment; Enzymes; Equilibrium; Ethers; Functional disorder; Goals; Greater sac of peritoneum; Host Defense; Human; Immune response; In Vitro; Infection; Inflammation; Lead; Leukocytes; Leukotrienes; Lipids; Lung; Lymphocyte; Mediating; Mus; Mycoses; Ozone; Pathway interactions; Pattern recognition receptor; Peritoneal; Peritoneal Macrophages; Peritonitis; Phagosomes; Phosphatidylinositol Phosphates; Phospholipases A; Phosphorylation; Play; Process; Production; Prostaglandin Production; Public Health; Receptor Signaling; Research; Resolution; Role; Shapes; Signal Pathway; Site; Tissues; Vascular Permeabilities; autocrine; cytokine; dectin 1; disorder control; fungus; in vivo; insight; interest; lipid mediator; lysophosphatidylserine; macrophage; microbial; mouse dectin-2; neutrophil; novel; novel strategies; pathogen; receptor; response; surfactant

The objectives of Project 1 are to study the mechanisms of activation of Group IVA cytosolic phospholipase A{2} (cPLA{2}a) in resident peritoneal and alveolar macrophages by the opportunistic fungal pathogens Candida albicans and Aspergillus fumigatus, and to determine the role of eicosanoids in regulating immune responses to fungal infection in vivo. Fungi activate cPLA{2}a in macrophages that promotes arachidonic acid release and production of prostaglandins and leukotrienes. Eicosanoids regulate acute inflammation and immune responses such as vascular permeability, emigration and function of leukocytes, production of cytokines, and lymphocyte differentiation. There has been considerable interest in elucidating mechanisms regulating host responses to fungal infection, however, the mechanisms regulating cPLA{2}a activation by C. albicans and A. fumigatus and the role of lipid mediators in regulating fungal infection are poorly understood. We hypothesize that C. albicans and A. fumigatus engage C-type lectin receptors (dectin-1 and dectin-2) and MyD88-dependent pathways to activate cPLA{2}a and eicosanoid production. A comparison of resident macrophages from the peritoneal cavity and from the lung, and fungal infection at these distinct sites, will provide insight into how these unique tissue environments influence responses to fungal infection. The Specific Aims are: (1) to identify the pattern recognition receptors engaged by C. albicans and (2) the mechanisms for cPLA{2}a activation and eicosanoid production in peritoneal macrophages; (3) to elucidate how eicosanoids modulate responses of peritoneal macrophages to C. albicans in vitro and regulate inflammation in C. albicans peritonitis in vivo; and (4) to determine mechanisms of cPLA{2}a activation and eicosanoid production by C. albicans and A. fumigatus in mouse and human alveolar macrophages, and the role of cPLA{2}a in regulating host responses to A. fumigatus lung infection. We hypothesize that eicosanoids play a protective role in fungal host defense by modulating cell recruitment and the balance of cytokine production. Once infection is contained, cPLA{2}a activation and eicosanoid production also protect the lung from excess inflammation by enhancing clearance of apoptotic neutrophils through the novel lipid mediator lysophosphatidylserine (Project 2). However, environmental insults such as ozone (Project 3) can lead to production of novel lipid mediators that interfere with these protective pathways. We will define how lipid mediators regulate host defense, the amplitude of inflammation and its resolution.

项目1的目的是研究条件致病菌白色念珠菌和烟曲霉对常驻腹膜和肺泡巨噬细胞中IVA组胞浆磷脂酶A{2}(CPLA{2}a)的激活机制，并确定二十烷类化合物在体内调节真菌感染免疫反应中的作用。真菌激活巨噬细胞中的CPLA{2}a，促进花生四烯酸的释放和前列腺素和白三烯的产生。二十烷酸类化合物调节急性炎症和免疫反应，如血管通透性、迁移和白细胞功能，产生 细胞因子和淋巴细胞分化。人们对阐明宿主对真菌感染反应的调控机制很感兴趣，但对白色念珠菌和烟曲霉菌激活CPLA{2}a的调控机制以及脂质介质在调控真菌感染中的作用知之甚少。我们假设白色念珠菌和烟曲霉菌通过C型凝集素受体(Dectin-1和Dectin-2)和MyD88依赖的途径激活CPLA{2}a和二十烷类化合物的产生。对来自腹膜腔和肺部的常驻巨噬细胞以及这些不同部位的真菌感染进行比较，将有助于深入了解这些独特的组织环境如何影响对真菌感染的反应。这个 具体目标是：(1)鉴定白色念珠菌参与的模式识别受体；(2)Cpla{2}a激活和腹膜巨噬细胞产生二十烷类化合物的机制；(3)阐明二十烷类化合物如何在体外调节腹膜巨噬细胞对白念珠菌的反应，并在体内调节白念珠菌腹膜炎的炎症反应；以及(4)确定Cpla{2}a激活和Cpla在小鼠和人肺泡巨噬细胞中激活和产生二十烷类化合物的机制，以及Cpla{2}a在调节宿主对烟曲霉菌肺部感染的反应中的作用。我们推测二十烷类化合物通过调节细胞募集和细胞因子产生的平衡，在真菌宿主防御中起到保护作用。一旦感染得到控制，CPLA{2}a的激活和二十烷类化合物的产生还可以通过新型脂质介质溶血磷脂酰丝氨酸(项目2)增强对凋亡的中性粒细胞的清除，从而保护肺免受过度炎症的影响。然而，臭氧(项目3)等环境污染会导致干扰这些保护途径的新型脂质介质的产生。我们将定义脂质介质如何调节宿主防御、炎症的幅度及其消退。