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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：
10664843
负责人：
STACEY D GILK
金额：
$ 55.16万
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/10664843
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，或慢性感染患者中危及生命的心内膜炎。 Q热病患者没有什么明显的临床特征，慢性疾病需要至少 18 个月的治疗抗生素治疗，凸显了对新疗法的需求。专性细胞内病原体，柯克斯体在受感染细胞内的液泡中存活，该细胞具有功能性吞噬溶酶体的特征，包括活性蛋白酶和磷酸酶以及中等酸性的 pH 值（这是 C. burnetii 的物理化学参数）是经过精心改造的。 C.burnetii 是一种严格的中度嗜酸菌，能够有效地进行营养物质运输、分解代谢在宿主无细胞和细胞内条件下，仅在狭窄的 pH 范围内复制。目标该应用的目的是识别宿主和病原体因子，这些因子可维持 CCV 和细菌的功能。细胞质pH值。目标 1 将检验伯纳特梭菌通过碳酸控制细菌细胞质 pH 值的假设 CO2 的脱水酶依赖性代谢，以及代谢休眠的小细胞变体 C. 伯内特菌保护病原体免受酸胁迫。目标 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来调节 pH 值。了解伯氏念珠菌背后的分子机制在酸性 CCV 内存活将有助于识别潜在的治疗靶点。