Macrophages inhibit Coxiella burnetii by the ACOD1-itaconate pathway for containment of Q fever

Kohl L, Siddique MNAA, Bodendorfer B, Berger R, Preikschat A, Daniel C, Ölke M, Liebler-Tenorio E, Schulze-Lührmann J, Mauermeir M, Yang KT, Hayek I, Szperlinski M, Andrack J, Schleicher U, Bozec A, Krönke G, Murray PJ, Wirtz S, Yamamoto M, Schatz V, Jantsch J, Oefner P, Degrandi D, Pfeffer K, Mertens-Scholz K, Rauber S, Bogdan C, Dettmer K, Lührmann A, Lang R (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Embo Molecular Medicine Wiley-VCH Verlag / Wiley Open Access

DOI: 10.15252/emmm.202215931

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.

Authors with CRIS profile

Lisa Kohl Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene Md Nur A Alam Siddique Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene Christoph Daniel Department of Nephropathology Jan Schulze-Lührmann Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene Michael Mauermeir Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene Kai-Ting Yang Department of Medicine 3 – Rheumatology and Immunology Inaya Hayek Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene Ulrike Schleicher Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene Aline Bozec Gerhard Krönke Medizinische Fakultät Stefan Wirtz Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Simon Rauber Department of Medicine 3 – Rheumatology and Immunology Christian Bogdan Lehrstuhl für Mikrobiologie und Infektionsimmunologie Anja Lührmann Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene Roland Lang Professur für Angeborene Immunität und Pathogenerkennung

Involved external institutions

Friedrich-Loeffler-Institut (FLI), Bundesforschungsinstitut für Tiergesundheit DE Germany (DE) Universität Regensburg DE Germany (DE) Heinrich-Heine-Universität Düsseldorf DE Germany (DE) Universitätsklinikum Regensburg DE Germany (DE) Max-Planck-Institut für Biochemie / Max Planck Institute of Biochemistry DE Germany (DE) Osaka University / 大阪大学 JP Japan (JP)

How to cite

APA:

Kohl, L., Siddique, M.N.A.A., Bodendorfer, B., Berger, R., Preikschat, A., Daniel, C.,... Lang, R. (2022). Macrophages inhibit Coxiella burnetii by the ACOD1-itaconate pathway for containment of Q fever. Embo Molecular Medicine. https://doi.org/10.15252/emmm.202215931

MLA:

Kohl, Lisa, et al. "Macrophages inhibit Coxiella burnetii by the ACOD1-itaconate pathway for containment of Q fever." Embo Molecular Medicine (2022).

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