Role of host spingolipids against fungal infections

宿主鞘脂对抗真菌感染的作用

• 批准号: 8922384
• 负责人: Maurizio Del Poeta
• 金额: --
• 依托单位: NORTHPORT VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-10-01 至 2019-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8922384
• 关键词: Affect; Animal Model; Anti-Bacterial Agents; Area; Cell Culture Techniques; Cells; Ceramides; Communicable Diseases; Cryptococcus neoformans; Cryptococcus neoformans infection; Defensins; Diglycerides; Engineering; Enzymes; Goals; Golgi Apparatus; Host resistance; Human; Immune; Immune response; Immune system; Immunocompetent; In Vitro; Individual; Infection; Infection Control; Inflammatory Response; Lecithin; Link; Lipids; Mediating; Military Personnel; Modeling; Mycoses; Neutropenia; Neutrophil Infiltration; Pathogenicity; Pathway interactions; Peptides; Phagocytes; Phagocytosis; Phosphorylcholine; Play; Predisposition; Production; Protein Secretion; Publishing; Recruitment Activity; Regulation; Research; Role; Site; Sphingolipids; Sphingomyelins; T-Lymphocyte; Testing; antimicrobial; base; cell type; clinically relevant; controlled release; extracellular; fungus; in vivo; killings; macrophage; mouse model; neutrophil; novel; novel therapeutic intervention; protein kinase D; public health relevance; response; sphingomyelin synthase

 DESCRIPTION (provided by applicant): The goal of this project is to study the role and mechanisms by which host sphingolipids are involved in controlling the infection caused by the pathogenic fungus Cryptococcus neoformans (Cn). A rapidly emerging area of research is the study of the role of sphingolipids in the regulation of infectious diseases (Reviewed in1). Although some sphingolipids have been linked to antibacterial activity of phagocytic cells,2,3 very little is known about the role of host sphingolipids against fungal infections. One of the host sphingolipid-metabolizing enzymes shown to regulate immune responses is sphingomyelin synthase (SMS), encoded by the SMS1 and SMS2 genes.4-6 SMS transfers a choline phosphate moiety from phosphatidylcholine (PC) to ceramide, therefore producing sphingomyelin (SM) and diacylglycerol (DAG).7-9 Very interestingly, the lipids regulated by SMS have been implicated in the activation of pro-inflammatory responses, suggesting that the regulation of SMS activity in immune cells may assume a critical role in controlling infections. In our preliminary and published studies10,11 we found that: 1) inhibition of SMS activity profoundly impairs the ability of phagocytic cells to kil Cn cells by affecting extracellular killing in absence of phagocytosis; 2) SMS regulates production of DAG at the Golgi; 3) DAG produced at the Golgi by SMS regulates protein secretion via activation of protein kinase D (PKD); 4) inhibition of SMS or PKD blocks extracellular killing of Cn and peptide secretion (such as defensins) by neutrophils; and 5) neutropenia significantly exacerbates Cn infection. Based on these observations, we hypothesize that SMS activity plays a key role in controlling the extracellular killing of neutrophils through the regulation of a DAG-PKD-mediated secretion pathway (Figure 1). Thus, we propose the following aims: 1) To establish the role of SMS against Cn; and 2) To determine the mechanism by which SMS regulates Cn killing. The studies proposed in this applications are significant and novel at different levels: i) they will establish novel animal models for the study of fungal infection that are more clinically relevant to the human infection than current models; ii) they will define the role of phagocytes in the host response to fungal infections; and iii) they will identify novel regulators of the phagocytes' response against the infection which can be engineered to boost the host immune system.

 描述（由申请人提供）： 该项目的目标是研究宿主鞘脂在控制致病真菌新型隐球菌（Cn）引起的感染中的作用和机制。 一个迅速兴起的研究领域是研究鞘脂在传染病调节中的作用（综述1）。尽管一些鞘脂与吞噬细胞的抗菌活性有关2,3，但人们对宿主鞘脂对抗真菌感染的作用知之甚少。鞘磷脂合酶 (SMS) 是调节免疫反应的宿主鞘脂代谢酶之一，由 SMS1 和 SMS2 基因编码。4-6 SMS 将磷酸胆碱部分从磷脂酰胆碱 (PC) 转移到神经酰胺，从而产生鞘磷脂 (SM) 和二酰甘油 (DAG)。7-9 有趣的是，SMS 调节的脂质与促炎反应的激活有关，这表明免疫细胞中 SMS 活性的调节可能在控制感染中发挥关键作用。 在我们的初步和已发表的研究10,11中，我们 发现：1）抑制SMS活性会在没有吞噬作用的情况下影响细胞外杀伤，从而严重损害吞噬细胞杀伤Cn细胞的能力； 2）SMS规范生产 DAG 在高尔基体； 3) SMS 在高尔基体产生的 DAG 通过激活蛋白激酶 D (PKD) 来调节蛋白质分泌； 4) 抑制SMS或PKD可阻断中性粒细胞对Cn的胞外杀伤和肽分泌（如防御素）； 5)中性粒细胞减少症显着加剧Cn感染。基于这些观察结果，我们假设 SMS 活性通过调节 DAG-PKD 介导的分泌途径，在控制中性粒细胞细胞外杀伤方面发挥着关键作用（图 1）。因此，我们提出以下目标： 1）确立短信对抗Cn的作用； 2)确定SMS调节Cn查杀的机制。 本申请中提出的研究在不同层面上都具有重要意义和新颖性：i）他们将建立新的动物模型来研究真菌感染， 与现有模型相比，与人类感染的临床相关性更高； ii) 他们将定义吞噬细胞在宿主对真菌感染的反应中的作用； iii）他们将鉴定吞噬细胞对抗感染反应的新调节因子，这些调节因子可以被设计来增强宿主免疫系统。