Coxiella survival mechanisms in the intracellular niche

项目总结/摘要 贝氏柯克斯体是人类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， 如急性疾病，或慢性感染患者危及生命的心内膜炎。Q热患者 目前几乎没有明显的临床特征，慢性疾病需要至少18个月的治疗。 抗生素治疗，突出了对新疗法的需求。一种专性胞内病原体，柯克斯体 在感染细胞内的空泡内存活，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pH，这是C.贝氏 是非常适合的。C.贝氏菌是一种严格的中度嗜酸菌，能够有效地运输营养物质， 并且在无宿主细胞和细胞内条件下仅在窄pH范围内复制。客观 本申请的目的是鉴定起维持CCV和细菌CCV的作用的宿主和病原体因子。 目的1将检验C.伯氏菌通过碳调节细菌细胞质pH 脱水酶依赖的CO2代谢以及代谢休眠的C. 贝氏菌保护病原体免受酸胁迫。目标2将检验假设C.贝氏菌调节CCV 通过操纵宿主溶酶体生物发生来调节pH。了解C.贝氏 在酸性CCV中的存活将允许鉴定潜在的治疗靶点。

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.