Coxiella survival mechanisms in the intracellular niche

细胞内生态位中的柯克斯体存活机制

基本信息

批准号：
10797442
负责人：
STACEY D GILK
金额：
$ 5.47万
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：
2022
资助国家：
美国
起止时间：
2022-07-13 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10797442
关键词：
Acute Animals Antibiotic Therapy Antibiotics Bacteria Biogenesis Biological Carbon Dioxide Catabolism Cells Characteristics Chronic Chronic Disease Clinical Coxiella Coxiella burnetii Cytoplasm Data Desiccation Digestion Disease Disease Outbreaks Endocarditis Enzymes Epidemiology Exposure to Fatigue Growth Homeostasis Human Immune response Individual Infection Knowledge Life Lysosomes Maintenance Metabolic Metabolism Modeling Molecular Netherlands Nutrient Pathogenesis Pathway interactions Patient Noncompliance Patients Peptide Hydrolases Phagocytes Phagolysosome Phosphoric Monoester Hydrolases Proteins Q Fever Regimen Regulation Replication Initiation Reproduction spores Role Stress Testing Transcriptional Activation Vacuole Variant Virulence Zoonoses acid stress biological adaptation to stress carbonate dehydratase chronic infection flu gene network human pathogen intracellular parasitism new therapeutic target novel novel therapeutics pH Homeostasis pathogen pathogenic bacteria response therapeutic target transcription factor

项目摘要

PROJECT SUMMARY/ABSTRACT Coxiella burnetii is the causative agent of human Q fever, a zoonotic disease that can cause a debilitating, flu- like illness in acute cases, or a life-threatening endocarditis in chronically infected 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 vacuole within infected cells that has characteristics of a functional phagolysosome, including active proteases and phosphatases and moderately acidic pH, a physicochemical parameter to which C. burnetii is exquisitely adapted. C. burnetii is a strict moderate acidophile capable of efficient nutrient transport, catabolism and replication only within a narrow pH range under both host cell-free and intracellular conditions. The objective of this application is to identify host and pathogen factors that function to maintain both CCV and bacterial cytoplasmic pH. Aim 1 will test the hypothesis that C. burnetii controls bacterial cytoplasmic pH via carbonic anhydrase-dependent metabolism of CO2 and also how the metabolically dormant Small Cell Variant of C. burnetii protects the pathogen against acid stress. Aim 2 will test the hypothesis that C. burnetii regulates CCV pH by manipulating host lysosomal biogenesis. Understanding the molecular mechanisms behind C. burnetii survival within the acidic CCV will allow identification of potential therapeutic targets.

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，可能导致令人衰弱，流感例如急性病例中的疾病，或者在长期感染的患者中威胁生命的心内膜炎。 Q发烧患者存在很少有明显的临床特征，慢性疾病至少需要18个月抗生素治疗，强调了对新治疗剂的需求。专性细胞内病原体Coxiella 在感染细胞内的液泡中生存，该细胞具有功能性吞噬体的特征，包括活性蛋白酶和磷酸酶以及中等酸性的pH，一种物理化学参数精美地适应了。 C. burnetii是一种严格的中度嗜酸脂，能够有效的营养运输，分解代谢在无宿主细胞和细胞内条件下，仅在狭窄的pH范围内复制。目标该应用的是识别可维持CCV和细菌功能的宿主和病原体因子细胞质pH。 AIM 1将测试C. burnetii通过碳控制细菌细胞质pH的假设 CO2的赤铁酶依赖性代谢以及代谢性休眠的小细胞变体。伯内蒂（Burnetii）保护病原体免受酸性胁迫。 AIM 2将检验C. burnetii调节CCV的假设通过操纵宿主溶酶体生物发生的pH。了解C. burnetii背后的分子机制酸性CCV内的生存将允许鉴定潜在的治疗靶标。