Coxiella manipulation of cholesterol in the intracellular niche

柯克斯体对细胞内生态位中胆固醇的操纵

基本信息

批准号：
9919527
负责人：
STACEY D GILK
金额：
$ 5.95万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
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：
2018-05-01 至 2020-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9919527
关键词：
Acute Affect Antibiotic Therapy Antibiotics Autophagosome Bacteria Bacterial Proteins Binding Biological Assay Cell Survival Cells Cessation of life Cholesterol Chronic Chronic Disease Clinical Coxiella Coxiella burnetii Data Disease Disease Outbreaks Endocarditis Endoplasmic Reticulum Endosomes Enzymes Fatigue Growth Health Human Immune response In Vitro Individual Infection Life Lipids Lysosomes Maintenance Mediating Membrane Microscopy Modification Molecular Molecular Target Netherlands Organelles Oxidoreductase Pathogenesis Patient Noncompliance Patients Process Proteins Publishing Q Fever Regimen Research Role Site Sterols Symptoms Testing Therapeutic Intervention Toxic effect Type IV Secretion System Pathway Vacuole Virulence Factors Zoonoses base cholesterol-binding protein chronic infection fitness flu insight knock-down macrophage mutant new therapeutic target novel novel therapeutics oxysterol binding protein pathogen pathogenic bacteria recruit small hairpin RNA targeted treatment

项目摘要

PROJECT SUMMARY/ABSTRACT Coxiella burnetii is the causative agent of human Q fever, a zoonotic disease that can cause a debiliting, flu- like illness in acute cases, or a life-threatening endocarditis in chronic patients. Q fever patients present with few distinguishing clinical features, and chronic disease requires a minimum of 18 months of antibiotic treatment, highlighting the need for new therapeutics. An obligate intracellular pathogen, Coxiella survives inside a large, lysosome-like parasitophorous vacuole that is essential for bacterial replication and protects the bacteria from the host immune response. The Coxiella parasitophorous vacuole (CPV) forms through heterotypic fusion with host endosomes and autophagosomes, a process which also delivers cholesterol to the CPV membrane. We recently determined that accumulation of host cholesterol in the CPV is toxic to the bacteria, and hypothesize that Coxiella must deplete CPV cholesterol in order to survive within the host cell. The objective of this application is to test our hypothesis that Coxiella uses two distinct mechanisms to manipulate CPV cholesterol. Aim 1 will test the role of membrane contact sites in cholesterol transfer between the CPV and the host endoplasmic reticulum. Aim 2 will determine the role of putative Coxiella sterol reductases in modifying CPV cholesterol. At the conclusion of these studies, we will have elucidated how Coxiella manipulates host cholesterol to maintain the optimal microenvironment for bacterial surivival.

项目摘要/摘要 Coxiella burnetii是人类Q Fever的病因，这是一种人畜共患病，可能引起衰弱，流感例如急性病例中的疾病，或慢性患者威胁生命的心内膜炎。 Q发烧患者出现很少有区分临床特征，慢性疾病至少需要18个月的抗生素治疗，突出了对新治疗学的需求。 coxiella的强制性细胞内病原体存活在大型的溶酶体样寄生虫液泡中，这对于细菌复制至关重要并保护宿主免疫反应的细菌。 Coxiella寄生虫液泡（CPV）通过与宿主内体和自噬体的异型融合，这一过程也将胆固醇传递给 CPV膜。我们最近确定，宿主在CPV中的积累对细菌，并假设考克斯必须耗尽CPV胆固醇才能在宿主细胞中生存。该应用的目的是检验我们的假设，即Coxiella使用了两种不同的机制操纵CPV胆固醇。 AIM 1将测试膜接触位点在胆固醇转移中的作用 CPV和宿主内质网。 AIM 2将确定推定的Coxiella固醇的作用修饰CPV胆固醇的还原酶。在这些研究的结论下，我们将阐明 Coxiella操纵宿主胆固醇，以维持细菌守流的最佳微环境。