Kohl, Lisa and Siddique, Md Nur A. Alam and Bodendorfer, Barbara and Berger, Raffaela and Preikschat, Annica and Daniel, Christoph and Oelke, Martha and Liebler-Tenorio, Elisabeth and Schulze-Luehrmann, Jan and Mauermeir, Michael and Yang, Kai-Ting and Hayek, Inaya and Szperlinski, Manuela and Andrack, Jennifer and Schleicher, Ulrike and Bozec, Aline and Kroenke, Gerhard and Murray, Peter J. and Wirtz, Stefan and Yamamoto, Masahiro and Schatz, Valentin and Jantsch, Jonathan and Oefner, Peter and Degrandi, Daniel and Pfeffer, Klaus and Mertens-Scholz, Katja and Rauber, Simon and Bogdan, Christian and Dettmer, Katja and Luehrmann, Anja and Lang, Roland (2023) Macrophages inhibit Coxiella burnetii by the ACOD1-itaconate pathway for containment of Q fever. EMBO MOLECULAR MEDICINE, 15 (2). ISSN 1757-4676, 1757-4684
Full text not available from this repository. (Request a copy)Abstract
Infection with the intracellular bacterium Coxiella (C.) burnetii can cause chronic Q fever with severe complications and limited treatment options. Here, we identify the enzyme cis-aconitate decarboxylase 1 (ACOD1 or IRG1) and its product itaconate as protective host immune pathway in Q fever. Infection of mice with C. burnetii induced expression of several anti-microbial candidate genes, including Acod1. In macrophages, Acod1 was essential for restricting C. burnetii replication, while other antimicrobial pathways were dispensable. Intratracheal or intraperitoneal infection of Acod1(-/-) mice caused increased C. burnetii burden, weight loss and stronger inflammatory gene expression. Exogenously added itaconate restored pathogen control in Acod1(-/-) mouse macrophages and blocked replication in human macrophages. In axenic cultures, itaconate directly inhibited growth of C. burnetii. Finally, treatment of infected Acod1(-/-) mice with itaconate efficiently reduced the tissue pathogen load. Thus, ACOD1-derived itaconate is a key factor in the macrophage-mediated defense against C. burnetii and may be exploited for novel therapeutic approaches in chronic Q fever.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | TUMOR-NECROSIS-FACTOR; HOST-DEFENSE; ITACONATE; INFECTION; ROLES; ALPHA; CELL; INTERFERON; SUCCINATE; EFFECTOR; Cis-aconitate decarboxylase 1; Coxiella burnetii; Immune responsive gene 1; immunometabolism; itaconate |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Funktionelle Genomik (Prof. Oefner) Medicine > Lehrstuhl für Medizinische Mikrobiologie und Hygiene |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 05 Mar 2024 10:58 |
| Last Modified: | 05 Mar 2024 10:58 |
| URI: | https://pred.uni-regensburg.de/id/eprint/58268 |
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