Neutral lipid metabolism during Toxoplasma infection

弓形虫感染期间的中性脂质代谢

基本信息

批准号：
9914210
负责人：
Isabelle Coppens
金额：
$ 40.94万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-04 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9914210
关键词：
AIDS/HIV problem Abbreviations Acquired Immunodeficiency Syndrome Acyl Coenzyme A Adverse effects Animals Biochemical Biogenesis Biological Biological Assay Brain Cells Cholesterol Cholesterol Esters Chorioretinitis Complement Cyst Cytoplasm Cytosol Data Development Diglycerides Docking Drug Targeting Encephalitis Enzymes Fatty Acids Genetic Screening Goals Golgi Apparatus Growth HIV High Prevalence Immunity In Vitro Infection Intercept Invaded Lesion Light Lipids Low-Density Lipoproteins Mammalian Cell Mediating Membrane Microscopy Molecular Morphology Myocarditis Neurons Nutrient Oleic Acids Opportunistic Infections Organelles Parasites Pathway interactions Patients Phagocytes Pharmaceutical Preparations Population Prevalence Process Property Proteins Proteomics Recrudescences Regimen Risk Source Sphingolipids Sterol O-Acyltransferase Stream Surface Techniques Therapeutic Intervention Thick Tissues Toxoplasma Toxoplasma gondii Toxoplasmosis Tumor stage Vaccines Vacuole Vesicle acute infection adipocyte differentiation auxotrophy base chronic infection diacylglycerol O-acyltransferase lipid metabolism new therapeutic target novel therapeutics obligate intracellular parasite pandemic disease pathogen recruit toxoplasmic encephalitis trafficking uptake

项目摘要

SUMMARY Toxoplasma gondii is an opportunistic protozoan parasite that poses a significant risk to AIDS/HIV patients. Current treatments for toxoplasmosis are ineffective against the long-lived encysted stage of T. gondii. Thus, a constant stream of new drugs based on the identification of novel drug targets is required to offer long-term protection against cyst reactivation. Toxoplasma is an obligate intracellular parasite that multiplies in the cytoplasm of mammalian cells within a parasitophorous vacuole that does not fuse with any host organelles. Differentiated parasites into cyst forms (bradyzoites) are surrounded by a thick cyst wall within mammalian cells. How these parasites acquire their nutrients from the host cell has been an intriguing question in the field. We previously demonstrated that one mechanism developed by replicating tachyzoites to gain access to lipids is through the recruitment and sequestration of host nutrient-filled organelles into the parasitophorous vacuole. For example, these parasites retrieve cholesterol and sphingolipids from host endocytic organelles and Golgi- derived vesicles internalized into the vacuole, respectively. We provide new evidence that the cyst forms also salvage cholesterol. Present in all mammalian cells, lipid droplets represent an opportune source of neutral lipids for a lipid scavenger such as Toxoplasma. We show that both tachyzoites and bradyzoites rely on host lipid droplets for growth in vitro and infectivity in animals. Exogenous addition of fatty acids to the medium stimulate lipid droplet biogenesis in tachyzoites and bradyzoites, indicating that these parasites are capable of scavenging fatty acids that they use to esterify neutral lipids for storage in their own LD. The overall goal of our proposal is to unravel the mechanisms of host neutral lipid uptake and storage in tachyzoites and bradyzoites by identifying parasite effectors involved in these pathways. Specific Aim 1 will identify the parasite effectors involved in host lipid droplet recognition and sequestration into the parasitophorous vacuole. Specific Aim 2 will investigate the source of cholesterol for bradyzoites and the importance of enzymes synthesizing neutral lipids for chronic infection. Specific Aim 3 will investigate the content and biological properties of the lipid droplets in tachyzoites and bradyzoites. We will intend to open new avenues for therapeutic interventions based on restricting the parasite’s access to major host lipid sources and blocking lipid storage pathways in Toxoplasma.

概括弓形虫是一种机会性原生动物寄生虫，对艾滋病/艾滋病毒患者构成重大风险。目前弓形虫病的治疗方法对长寿命包囊阶段的弓形虫无效。需要基于新药物靶点识别的源源不断的新药才能提供长期的服务防止囊肿重新激活。弓形虫是一种专性细胞内寄生虫，可在细胞内繁殖。寄生液泡内的哺乳动物细胞的细胞质，不与任何宿主细胞器融合。哺乳动物体内分化为包囊形式（缓殖子）的寄生虫被厚厚的包囊壁包围这些寄生虫如何从宿主细胞获取营养一直是该领域的一个有趣的问题。我们之前证明了一种通过复制速殖子来获取脂质而开发的机制是通过将宿主充满营养的细胞器招募和隔离到寄生液泡中。例如，这些寄生虫从宿主内吞细胞器和高尔基体中回收胆固醇和鞘脂。我们提供了新的证据表明囊肿也形成了。脂滴存在于所有哺乳动物细胞中，是中性胆固醇的适当来源。我们发现速殖子和缓殖子都依赖于宿主。用于体外生长和动物感染性的脂滴向培养基中外源添加脂肪酸。刺激速殖子和缓殖子中的脂滴生物发生，表明这些寄生虫能够他们用来酯化中性脂质以储存在自己的LD中的清除脂肪酸的总体目标。我们的建议是揭示速殖子和宿主中性脂质摄取和储存的机制通过识别参与这些途径的寄生虫效应子来识别缓殖子具体目标 1 将识别寄生虫。参与宿主脂滴识别和隔离到寄生特异性真空中的效应器。目标2将研究缓殖子的胆固醇来源以及酶合成的重要性具体目标 3 将研究中性脂质用于慢性感染的含量和生物学特性。我们将打算为治疗干预开辟新的途径。基于限制寄生虫接触主要宿主脂质来源并阻断脂质储存途径弓形虫。