Hayek, Inaya and Fischer, Fabian and Schulze-Luehrmann, Jan and Dettmer, Katja and Sobotta, Katharina and Schatz, Valentin and Kohl, Lisa and Boden, Katharina and Lang, Roland and Oefner, Peter J. and Wirtz, Stefan and Jantsch, Jonathan and Luehrmann, Anja (2019) Limitation of TCA Cycle Intermediates Represents an Oxygen-Independent Nutritional Antibacterial Effector Mechanism of Macrophages. CELL REPORTS, 26 (13). 3502-+. ISSN 2211-1247,
Full text not available from this repository. (Request a copy)Abstract
In hypoxic and inflamed tissues, oxygen (O-2)-dependent antimicrobial defenses are impaired due to a shortage of O-2. To gain insight into the mechanisms that control bacterial infection under hypoxic conditions, we infected macrophages with the obligate intracellular pathogen Coxiella burnetii, the causative agent of Q fever. Our experiments revealed that hypoxia impeded C. burnetii replication in a hypoxia-inducible factor (HIF) 1 alpha-dependent manner. Mechanistically, under hypoxia, HIF1 alpha impaired the activity of STAT3, which in turn reduced the intracellular level of TCA cycle intermediates, including citrate, and impeded C. burnetii replication in macrophages. However, bacterial viability was maintained, allowing the persistence of C. burnetii, which is a prerequisite for the development of chronic Q fever. This knowledge will open future research avenues on the pathogenesis of chronic Q fever. In addition, the regulation of TCA cycle metabolites by HIF1 alpha represents a previously unappreciated mechanism of host defense against intracellular pathogens.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | TUMOR-NECROSIS-FACTOR; COXIELLA-BURNETII; PHASE-I; Q-FEVER; HYPOXIA; ACTIVATION; SYNTHASE; IMMUNITY; CITRATE; HOST; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Funktionelle Genomik (Prof. Oefner) Medicine > Lehrstuhl für Innere Medizin I |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 20 Apr 2020 07:13 |
| Last Modified: | 20 Apr 2020 07:13 |
| URI: | https://pred.uni-regensburg.de/id/eprint/27335 |
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