Coxiella survival mechanisms in the intracellular niche

项目摘要/摘要 伯氏柯克斯体是人类Q热的病原体，Q热是一种人畜共患疾病，可导致虚弱的流感- 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 目前几乎没有明显的临床特征，慢性疾病至少需要18个月的 抗生素治疗，强调了新疗法的必要性。专性胞内病原体柯克斯体 在感染细胞内的空泡内存活，该空泡具有功能吞噬溶酶体的特征，包括 活性蛋白酶和磷酸酶以及中等酸性的pH，这是伯氏梭菌的一个物理化学参数 被巧妙地改编成。伯氏梭菌是一种严格的中等嗜酸菌，能够有效地运输、分解代谢营养物质。 在无宿主细胞和胞内条件下，只能在很窄的pH范围内复制。目标是 这一应用的目的是识别寄主和病原体因子，这些因子对维持CCV和细菌都有作用 细胞质pH。目标1将验证伯氏梭菌通过碳素控制细菌细胞质pH的假设 依赖于脱水酶的二氧化碳代谢，以及处于代谢休眠状态的C. 伯氏杆菌能保护病原体免受酸胁迫。目标2将检验伯氏梭菌调节CCV的假设 PH通过操纵宿主溶酶体的生物发生。了解伯氏梭菌背后的分子机制 在酸性CCV内存活将有助于确定潜在的治疗靶点。

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.