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：
10270536
负责人：
STACEY D GILK
金额：
$ 35.9万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-10-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10270536
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.

项目概要/摘要伯内特柯克斯体是人类 Q 热的病原体，这是一种人畜共患疾病，可导致衰弱、流感例如急性病例中的疾病，或慢性患者中危及生命的心内膜炎。 Q热患者出现很少有明显的临床特征，慢性疾病需要至少 18 个月的抗生素治疗治疗，强调了对新疗法的需求。柯克斯体是一种专性细胞内病原体，能够存活在一个巨大的溶酶体样寄生液泡内，该液泡对于细菌复制至关重要并保护细菌细菌来自宿主的免疫反应。柯克斯体寄生液泡 (CPV) 形成于与宿主内体和自噬体的异型融合，这一过程还将胆固醇传递到 CPV膜。我们最近确定，CPV 中宿主胆固醇的积累对细菌，并假设柯克斯体必须消耗 CPV 胆固醇才能在宿主细胞内生存。此应用程序的目的是检验我们的假设，即柯克斯体使用两种不同的机制来操纵 CPV 胆固醇。目标 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。目标 2 将确定假定的柯克斯体甾醇的作用改变 CPV 胆固醇的还原酶。在这些研究结束时，我们将阐明如何柯克斯体操纵宿主胆固醇以维持细菌生存的最佳微环境。