Sphingolipid-mediated fungal pathogenesis

鞘脂介导的真菌发病机制

• 批准号: 8514913
• 负责人: Maurizio Del Poeta
• 金额: $ 30.79万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8514913
• 关键词: ATP phosphohydrolase; Address; Affect; Agreement; Alveolar; Alveolar Macrophages; Biochemical; Blood Circulation; Brain; Cell membrane; Cells; Ceramide glucosyltransferase; Cryptococcus neoformans; Cryptococcus neoformans infection; Development; Disease Progression; Encephalitis; Environment; Enzymes; Extracellular Space; Functional disorder; Funding; G2 Phase; Glucosylceramides; Goals; Growth; Health; Host Defense; Immune response; Immune system; Immunocompetent; In Vitro; Infection; Inositol; Life; Lung; Maintenance; Mediating; Methylation; Modeling; Mus; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phagolysosome; Phospholipase C; Population; Positioning Attribute; Process; Production; Proliferating; Property; Reaction; Residual state; Role; Saccharomyces cerevisiae; Sphingolipids; Sphingosine; Structure; Testing; Therapeutic; Therapeutic Effect; Transferase Gene; Vaccination; Vertebral column; Virulence; Virulent; extracellular; fungus; insight; killings; methyl group; microorganism; mouse model; mutant; novel; pathogen; prevent

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to study mechanism(s) of pathogenicity of Cryptococcus neoformans (Cn) focusing on how Cn sphingolipids regulate fungal virulence and counteract the host immune response. Cn is a fungal pathogen that, upon entering the lung and disseminating through the bloodstream, causes a life- threatening meningo-encephalitis in susceptible patients. One key feature of Cn is its ability to grow both extracellularly and intracellularly. Being the lung the port of entry of Cn, alveolar macrophages (AMs) are the first line of defense of the host. Thus, the outcome of the interaction between the fungus and AMs greatly determines the progression of the disease. If the immune system of the host is compromised and AMs fail to kill the engulfed Cn cells, these fungal cells survive and proliferate within the phagolysosome of AMs. This implies that the physiopathology of cryptococcosis is determined by fungal growth that can occur in an intracellular compartment (e.g. acidic environment of AM's phagolysosome) and in an extracellular compartment (e.g. neutral/alkaline environment of alveolar spaces and bloodstream). In the past funding cycle, we identified novel fungal factors in the sphingolipid pathway that specifically regulate growth of Cn in each compartment. Particularly, the inositol phosphosphingolipid phospholipase C (Isc1) enzyme was found to be required for intracellular growth of Cn within AMs, whereas the glucosylceramide synthase (Gcs1) was found to be required for extracellular growth of Cn within the alveolar spaces. Importantly, we identified very long chain C26 phytoceramide and glucosylceramide (GlcCer) as the biochemical products of the reactions catalized by Isc1 and Gcs1, respectively. Thus, we hypothesize that Isc1 and Gcs1 regulate pathogenicity by favoring growth in different compartment(s) through the action of the specific sphingolipids that they produce. This hypothesis will be addressed by the following Aims: 1) To study the mechanism by which fungal sphingolipids regulate growth of Cn in the intracellular compartment; 2) To study the mechanism by which fungal sphingolipids regulate growth of Cn in the lung-like extracellular compartment; 3) To determine the therapeutic effect of targeting intracellular and/or extracellular populations of Cn on the outcome of the infection. PUBLIC HEALTH RELEVANCE: Cryptococcus neoformans is an environmental microorganism that causes the most common fungal meningo-encephalitis worldwide. The pathogenesis of this fungal pathogen is not well understood. This proposal focuses on a better understanding of the pathogenic process focusing on how fungal sphingolipids regulates virulence, providing new insights into the development of better therapeutic strategies against this life-threatening fungal brain infection

描述（由申请人提供）：该提案的长期目标是研究密码球菌（CN）致病性的机制，重点是CN鞘脂调节真菌毒力并抵消宿主免疫反应。 CN是一种真菌病原体，在进入肺部并通过血液传播后，会导致易感患者的脑膜脑膜炎。 CN的一个关键特征是它具有细胞外和细胞内生长的能力。作为CN的肺进入港口，肺泡巨噬细胞（AMS）是宿主的第一道防线。因此，真菌与AMS之间相互作用的结果极大地决定了疾病的发展。如果宿主的免疫系统受到损害，AMS无法杀死被吞噬的CN细胞，这些真菌细胞在AMS的吞噬体内生存和增殖。这意味着隐球菌病的生理病理学取决于可能发生在细胞内室（例如AM吞噬体的酸性环境）和细胞外室（例如肺泡空间和血液中的肺泡环境）中的真菌生长。在过去的融资周期中，我们在鞘脂途径中确定了新的真菌因子，这些真菌因子特异性调节了每个隔室中CN的生长。特别是，发现发现AMS内CN的细胞内生长所必需的肌醇磷酸脂磷脂酶C（ISC1）酶，而发现葡萄糖基辛基合酶（GCS1）是必需的。重要的是，我们分别将非常长的链C26植物酰胺和葡萄糖基酰胺（GLCCCER）确定为ISC1和GCS1归类的反应的生化产物。因此，我们假设ISC1和GCS1通过通过其产生的特定鞘脂的作用来利用不同隔室的生长来调节致病性。以下目的将解决这一假设：1）研究真菌鞘脂调节细胞内室中CN生长的机制； 2）研究真菌鞘脂调节肺样细胞外室中CN生长的机制； 3）确定靶向CN细胞内和/或细胞外种群对感染结果的治疗作用。公共卫生相关性：加密型新型人体是一种环境微生物，在全球范围内引起最常见的真菌脑膜脑膜炎。这种真菌病原体的发病机理尚不清楚。该提案的重点是对致病过程的更好理解，重点是真菌鞘脂如何调节毒力，为针对这种威胁生命的真菌脑感染的更好治疗策略提供了新的见解