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 with 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 and 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 maintain both CCV and bacterial cytoplasmic pH.
Aim 1 will test the hypothesis that C. burnetii manipulates host lysosomal biogenesis by blocking activation of the transcription factor TFEB.
Aim 2 will test the hypothesis that C. burnetii controls bacterial cytoplasmic pH via carbonic anhydrase-dependent generation of HCO3- and active uptake of K+. Understanding the molecular mechanisms behind C. burnetii survival within the moderately acidic environment of the CCV will allow identification of potential therapeutic targets.
The obligate intracellular bacterial pathogen Coxiella burnetii is the causative agent of human Q fever. We propose to elucidate the molecular mechanisms behind Coxiella?s ability to survive within the acidic intracellular niche. Understanding how Coxiella manipulates and responds to changes in the pH of the Coxiella containing vacuole will identify novel therapeutic targets.
