Limitation of TCA Cycle Intermediates Represents an Oxygen-Independent Nutritional Antibacterial Effector Mechanism of Macrophages

摘要

In hypoxic and inflamed tissues, oxygen (O2)-dependentantimicrobial defenses are impaired due to ashortage of O2. To gain insight into the mechanismsthat control bacterial infection under hypoxic conditions,we infected macrophages with the obligateintracellular pathogen Coxiella burnetii, the causativeagent of Q fever. Our experiments revealed that hypoxiaimpeded C. burnetii replication in a hypoxiainduciblefactor (HIF) 1a-dependent manner. Mechanistically,under hypoxia, HIF1a impaired the activityof STAT3, which in turn reduced the intracellular levelof TCA cycle intermediates, including citrate, andimpeded C. burnetii replication in macrophages.However, bacterial viability was maintained, allowingthe persistence of C. burnetii, which is a prerequisitefor the development of chronic Q fever. This knowledgewill open future research avenues on the pathogenesisof chronic Q fever. In addition, the regulationof TCA cycle metabolites by HIF1a representsa previously unappreciated mechanism of host defenseagainst intracellular pathogens.