Role of host cell metabolism in supporting intracellular Trypanosma cruzi growth

宿主细胞代谢在支持细胞内克氏锥虫生长中的作用

基本信息

批准号：
8422979
负责人：
BARBARA A BURLEIGH
金额：
$ 20.19万
依托单位：
HARVARD SCHOOL OF PUBLIC HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-07 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8422979
关键词：
Acids Address Area Biochemical Genetics Biology Carbon Cells Chagas Disease Chronic Climate Cytoplasm Cytoskeleton Data Diabetes Mellitus Disease Progression Employee Strikes Environment Equilibrium Exhibits Fatty Acids Gatekeeping Gene Expression Generations Genes Genetic Glucose Glycogen Goals Growth Hela Cells Human Infection Kinetics Knowledge Laboratories Link Little&apos s Disease Maintenance Malignant Neoplasms Mammalian Cell Measures Metabolic Metabolic Diseases Metabolic Pathway Metabolism Methodology Muscle Cells Muscle Fibers Myocarditis Parasites Pathway interactions Peroxisome Proliferator-Activated Receptors Phenotype Process Protocols documentation Role Source Staging Testing Tissues Tropism Trypanosoma cruzi Very Long Chain Fatty Acid blood glucose regulation cell type fatty acid metabolism fatty acid oxidation genome-wide in vivo lipid metabolism metabolic abnormality assessment novel obligate intracellular parasite oxidation particle pathogen pyruvate dehydrogenase kinase 4 tool

项目摘要

DESCRIPTION (provided by applicant): Trypanosoma cruzi, the protozoan parasite that causes human Chagas' disease, is an obligate intracellular pathogen that lives and divides in the cytoplasm of its mammalian host cell. Despite its importance in tissue infection, persistence and disease, little is currently known about the biology of the intracellular amastigote stage of T cruzi. In particular, the essential contributions of the host cell toward the support of intracelluar replication and survival of T. cruzi remain largely unknown. With a view to identifying critical hot cell regulators of intracellular T. cruzi infection, my laboratory has established and conducted a high-throughput genome-wide functional screen to identify host cell pathways/processes that function as regulators of intracellular parasite growth. Host cell fatty acid metabolism emerged in this screen as a major pathway regulating growth of intracellular T. cruzi amastigotes in HeLa cells. We also made the observation that intracellular T. cruzi amastigotes sequester host cell glycogen, where glycogen particles are highly enriched in the vicinity of the cytosolic amastigotes. These novel findings are strongly suggestive of the ability of T. cruzi to modulate host metabolic functions in infected host cells. In support of this hypothesis, PDK4, the main regulator of the shift between glucose and fatty acid utilization in cells (favoring fatty acid utilization) was shown to be important for supporting intracellular T. cruzi growth. This is intriguing given that T. cruzi exhibit tropism in vivo for muscle cells that are biased toward fatt acid utilization. While many of the tools exist to study metabolism in mammalian cells, these tools have yet to be applied to the study of host cell metabolism in the context of T. cruzi infection. Thus, the aim of this exploratory R21 proposal is to establish an experimental framework with methodologies and tools developed primarily for studies of metabolic disease (diabetes, cancer etc) that will allow us to determine the extent to which host cell metabolism is altered in T. cruzi-infected host cells and how this impacts intracellular parasite growth. Understanding the intimate relationship between host metabolism and T. cruzi amastigote growth will provide a critical piece of biology that is currently lacking in our knowledge of T. cruzi-host interactions and will help to elucidate novel targets for the control of T. cruzi growth

描述（由申请人提供）：Cruzi锥虫是导致人类chagas病的原生动物寄生虫，是一种强制性细胞内病原体，其哺乳动物宿主细胞的细胞质生存和分裂。尽管它在组织感染，持久性和疾病中的重要性，但目前对T Cruzi的细胞内膜片阶段的生物学知之甚少。特别是，宿主细胞对支持克鲁西t. t. t. t. t. t. t. t. t. t。t。t。t。t。t. t。t。t。t。t。t。t。t. beplya的基本贡献。为了确定细胞内T. cruzi感染的关键热细胞调节剂，我的实验室已经建立并进行了高通量全基因组功能筛选，以识别作为细胞内寄生虫生长调节剂的宿主细胞途径/过程。宿主细胞脂肪酸代谢出现该屏幕是调节HeLa细胞中细胞内T. amastigotes生长的主要途径。我们还观察到了细胞内t. cruzi amastigotes隔离宿主糖原，其中糖原颗粒在胞质杂物的附近高度富集。这些新颖的发现强烈暗示了克鲁齐（T. cruzi）在受感染宿主细胞中调节宿主代谢功能的能力。为了支持这一假设，PDK4是细胞中葡萄糖和脂肪酸利用率之间转移的主要调节剂（有利于脂肪酸利用）对于支持细胞内T. cruzi的生长很重要。鉴于克鲁兹（T.尽管存在许多用于研究哺乳动物细胞中新陈代谢的工具，但这些工具尚未应用于在克鲁齐（T. cruzi）感染的背景下研究宿主细胞代谢。因此，该探索性R21提案的目的是建立一个实验框架，其主要用于代谢疾病的方法（糖尿病，癌症等）开发的方法和工具，这将使我们能够确定Cruzi感染的宿主宿主细胞中宿主细胞代谢的改变程度，这如何影响细胞内帕拉斯特寄生虫的生长。了解宿主代谢与克鲁兹木马杂志的亲密关系将提供关键的生物学，目前我们对Cruzi-Host相互作用的知识缺乏，并将有助于阐明新的目标来控制T. Cruzi的增长。