Kohl, Lisa, Siddique, Md Nur A. Alam, Bodendorfer, Barbara, Berger, Raffaela, Preikschat, Annica, Daniel, Christoph, Oelke, Martha, Liebler-Tenorio, Elisabeth, Schulze-Luehrmann, Jan, Mauermeir, Michael, Yang, Kai-Ting ORCID: 0000-0002-1854-5127, Hayek, Inaya, Szperlinski, Manuela, Andrack, Jennifer, Schleicher, Ulrike, Bozec, Aline, Kroenke, Gerhard, Murray, Peter J., Wirtz, Stefan, Yamamoto, Masahiro, Schatz, Valentin, Jantsch, Jonathan, Oefner, Peter, Degrandi, Daniel, Pfeffer, Klaus, Mertens-Scholz, Katja, Rauber, Simon ORCID: 0000-0001-8306-9334, Bogdan, Christian, Dettmer, Katja, Luehrmann, Anja and Lang, Roland (2023). Macrophages inhibit Coxiella burnetii by the ACOD1-itaconate pathway for containment of Q fever. EMBO Mol. Med., 15 (2). HOBOKEN: WILEY. ISSN 1757-4684

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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: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Kohl, LisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Siddique, Md Nur A. AlamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bodendorfer, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Berger, RaffaelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Preikschat, AnnicaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Daniel, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oelke, MarthaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liebler-Tenorio, ElisabethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schulze-Luehrmann, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mauermeir, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yang, Kai-TingUNSPECIFIEDorcid.org/0000-0002-1854-5127UNSPECIFIED
Hayek, InayaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Szperlinski, ManuelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Andrack, JenniferUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schleicher, UlrikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bozec, AlineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kroenke, GerhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Murray, Peter J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wirtz, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yamamoto, MasahiroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schatz, ValentinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jantsch, JonathanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oefner, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Degrandi, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pfeffer, KlausUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mertens-Scholz, KatjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rauber, SimonUNSPECIFIEDorcid.org/0000-0001-8306-9334UNSPECIFIED
Bogdan, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dettmer, KatjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Luehrmann, AnjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lang, RolandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-692082
DOI: 10.15252/emmm.202215931
Journal or Publication Title: EMBO Mol. Med.
Volume: 15
Number: 2
Date: 2023
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1757-4684
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
TUMOR-NECROSIS-FACTOR; HOST-DEFENSE; ITACONATE; INFECTION; ROLES; ALPHA; CELL; INTERFERON; SUCCINATE; EFFECTORMultiple languages
Medicine, Research & ExperimentalMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69208

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